Healthy Volunteer
Conditions
Keywords
Pharmacokinetics, S-648414, Food effect, Antiretroviral, Drug-drug interaction
Brief summary
The primary objective of Part 1 of the study is to evaluate the safety and tolerability of S-648414 after administration of a single oral dose of S-648414 in healthy adult study participants. The primary objective of Part 2 is to evaluate the safety and tolerability of S-648414 after administration of multiple oral doses of S-648414 in healthy adult study participants. The primary objectives of Part 3 are evaluate the safety and tolerability of S-648414 after administration of multiple oral doses of S-648414 in healthy adult study participants, and to evaluate the effect of S-648414 on the pharmacokinetics (PK) of dolutegravir and the effect of dolutegravir on the PK of S-648414 in healthy adult study participants.
Detailed description
Amendment 2 of the study Protocol added a third part (Part 3) to the study. The revised Official Title for the Protocol is: A Phase 1, Randomized, Double-Blind, Single-Ascending-Dose, and Food Effect Study to Assess the Safety, Tolerability, Ventricular Repolarization, and Pharmacokinetics of S-648414 in Healthy Adult Study Participants (Part 1); A Phase 1, Randomized, Double-Blind, Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of S-648414 and A Drug-Drug Interaction Study with the CYP3A Substrate, Midazolam, in Healthy Adult Study Participants (Part 2); and A Phase 1 Open-Label Study to Assess the Effect of S-648414 on the Pharmacokinetics of Dolutegravir and the Effect of Dolutegravir on the Pharmacokinetics of S-648414 in Healthy Adult Study Participants (Part 3)
Interventions
DRUGS-648414
Tablet for oral administration
DRUGPlacebo
Tablet for oral administration
DRUGMidazolam
Solution for oral administration
DRUGDolutegravir
Tablet for oral administration
Sponsors
Shionogi
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Parts 1 and 2 were blinded studies. Part 3 was an open-label study and, therefore, did not include blinding.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male or female adults ≥ 18 years in USA or ≥ 20 years in Japan to ≤ 55 years of age, at the time of signing the informed consent form (ICF). a) Specific to Japan sites: enrollment in Part 3 (Group I and J) will consist of only White or Black or African American race. 2. Capable of giving signed informed consent 3. Body mass index (BMI) ≥ 18.5 to \< 32.0 kg/m² at the Screening visit． 4. Considered medically healthy as determined by the investigator or subinvestigator (suitably qualified), based on medical history and clinical evaluations including physical examination, clinical laboratory tests, vital sign measurements, and 12-lead electrocardiogram (ECG) at Screening and at upon admission to the Clinical Research Unit (CRU) and prior to administration of study intervention on Day 1. 5. Female study participants must not be a woman of childbearing potential and must either be postmenopausal (defined as no menses for 12 months without an alternative medical cause; follicle-stimulating hormone (FSH) to be tested for confirmation at Screening) or premenopausal with 1 of the following documented: hysterectomy, tubal ligation, bilateral salpingectomy, or bilateral oophorectomy. 6. Male study participants must agree to use contraception during the treatment period and for at least 3 months after the last dose of study intervention.
Exclusion criteria
1. Considered by the investigator or subinvestigator (suitably qualified) to be ineligible for the study due to a history of or current condition of significant metabolic or endocrine, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal (GI), urological, immunological, neurological, or psychiatric disorders with clinical manifestations. 2. History or presence of cancer in last 5 years except for non-melanoma skin cancers. 3. Risk factors for: 1. Torsades de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT Syndrome or Brugada Syndrome) 2. Unexplained syncope, sick sinus syndrome, second- or third-degree atrioventricular (AV) block, myocardial infarction, pulmonary congestion, cardiac arrhythmia, angina, prolonged QT interval, or conduction abnormalities 4. History of GI surgery or disease including, but not limited to, gastric band/gastric resection and/or intestinal resection and/or duodenal disease (ie, celiac disease) that may result in clinically significant malabsorption (except for an appendectomy). 5. History of hypersensitivity or severe side effects induced by a drug. 6. Any condition requiring medication and/or other treatment, such as dietary restriction and physical therapy. 7. History of significant multiple and/or severe allergic symptoms including food allergy (NOTE: Study participants with seasonal allergies may participate unless they have ongoing symptoms). 8. Used drugs or substances known to be inducers or inhibitors of cytochrome P450 enzymes and/or P-glycoprotein within 28 days prior to admission to the CRU. 9. Used prescription or over-the-counter (OTC) drugs, antacids, proton pump inhibitors, H2 antagonists, Chinese herbal medicines, oral cannabidiol, vitamins, minerals, herbal, and dietary supplements within 14 days prior to admission to the CRU. 10. Refuses to abstain from ingesting caffeine- or xanthine-containing products/medications (eg, coffee, tea, cola drinks, other caffeinated beverages, or chocolate) from 24 hours prior to admission to the CRU or refuses to refrain from consuming such products throughout the study (including Follow-up period). 11. Consumed alcohol or used alcohol-containing products within 72 hours prior to admission to the CRU or refuses to refrain from consuming such products throughout the study (including Follow-up period). 12. History of recreational drug use in the previous 6 months, or has a history of problematic alcohol use (defined as study participants who regularly consume excessive amounts of alcohol, defined as \> 3 glasses of alcoholic beverages per day (1 glass is approximately equivalent to: beer \[284 mL/10 ounces (oz.)\], wine \[125 mL/4 oz.\] or distilled spirits \[25 mL/1 oz.\]). 13. A positive drug or alcohol screen at the Screening visit or upon admission to the CRU. 14. Used tobacco- or nicotine-containing products (including cigarette, pipe, cigar, chewing, nicotine patch, nicotine gum, or Vaping product) within 6 months prior to admission to the CRU or refuses to refrain from using tobacco- or nicotine-containing products throughout the study (including Follow-up period). 15. Consumed grapefruit, grapefruit juice, Seville orange juice, orange juice, apple juice, vegetables from the mustard green family (eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard greens), or charbroiled meats within 7 days prior to admission to the CRU or refuses to refrain from consuming such products throughout the study (including Follow-up period). 16. A corrected QT (QTc) interval of \> 450 msec for males and \> 470 msec for females (Fridericia's method) at the Screening visit or upon admission to the CRU. 17. Systolic blood pressure is outside the range of 90 to 140 mm Hg, diastolic blood pressure is outside the range of 50 to 90 mm Hg, or pulse rate is outside the range of 40 to 100 beats per minute (bpm) or considered ineligible by the investigator or subinvestigator at the Screening visit or upon admission to the CRU. 18. Total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) values are greater than the upper limit of normal (ULN), or estimated glomerular filtration rate (eGFR) \< 90 mL/min/1.73 m² at Screening or upon admission to the CRU. 19. A positive serological test for untreated syphilis, positive hepatitis B surface antigen, positive hepatitis C virus antibody, or positive human immunodeficiency virus (HIV) antigen/antibody result at the Screening visit. 20. Participated in any other investigational trials or has been exposed to other investigational drugs within 28 days or 5 half-lives of the previously administered investigational drug (date derived from last study procedure \[blood collection or dosing\] of previous trial), whichever is longer, prior to admission to the CRU. 21. Previously received S-648414. 22. Poor venous access. 23. Donated blood or had significant blood loss within 56 days of study admission to the CRU or donated plasma within 7 days prior to until admission to the CRU. 24. Considered inappropriate for participation in the study for any reason by the investigator or subinvestigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From dosing on Day 1 or Day 14 up to 10 days post dose | A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death. |
| Part 2: Number of Participants With Treatment-emergent Adverse Events | From the first dose up to 10 days after end of dosing (25 days); A TEAE was summarized to a given treatment if the event onset/worsening occurred any time after the dose of that treatment and before the dose of the next treatment. | A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death. |
| Part 3: Number of Participants With Treatment-emergent Adverse Events | From the first dose up to Day 36; A TEAE was summarized to a given treatment if the event onset/worsening occurred any time after the dose of that treatment and before the dose of the next treatment. | A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death. |
| Part 3: Maximum Plasma Concentration (Cmax) of S-648414 | Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). |
| Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414 | Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). |
| Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ) | Day 22 and Day 29 (24 hours post-dosing on Days 21 and 28) | The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). |
| Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414 | Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). Area under the concentration-time curve over the dosing interval τ (24 hours) was calculated by the linear up/log down trapezoidal method. |
| Part 3: Apparent Total Clearance (CL/F) of S-648414 | Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). Apparent total clearance was calculated as CL/F = Dose/AUC0-τ |
| Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir | Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose. | The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. |
| Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir | Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose. | The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. |
| Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ) | Day 8 and Day 29 (24 hours post-dosing on Day 7 and Day 28). | The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. |
| Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir | Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose. | The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. Area under the concentration-time curve over the dosing interval τ (24 hours) was calculated by the linear up/log down trapezoidal method. |
| Part 3: Apparent Total Clearance (CL/F) of Dolutegravir | Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose. | The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. Apparent total clearance calculated as CL/F =Dose/AUC0-τ |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) of S-648414 Following Single and Multiple-dose Administration | Day 1 and day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | Area under the concentration-time curve over the dosing interval (24 hours) on Day 1 and Day 14, calculated by the linear up/log down trapezoidal method. |
| Part 2: Terminal Elimination Half-life (t1/2,z) of S-648414 Following Multiple-dose Administration | Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose. | Terminal elimination half-life, where t1/2,z = (ln2)/λz on Day 14. |
| Part 2: Terminal Elimination Rate Constant (λz) of S-648414 Following Multiple-dose Administration | Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose. | Terminal elimination rate constant, where λz is the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase on Day 14. |
| Part 2: Apparent Total Clearance (CL/F) of S-648414 Following Multiple-dose Administration | Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | Apparent total clearance estimated according to: CL/F = Dose/AUC0-τ on Day 14 |
| Part 2: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 Following Multiple-dose Administration | Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose. | Apparent volume of distribution in the terminal elimination phase on Day 14, estimated according to: Vz /F = Dose/AUC0-τ/λz |
| Part 2: Fraction of S-648414 Dose Excreted in Urine Over the Dosing Interval (Feu0- τ) Following Multiple-dose Administration | Day 14 0-24 hours postdose | Fraction of dose excreted in urine over the dosing interval τ (24 hours) on Day 14 calculated as Aeu0-τ/Dose × 100, where Aeu0-τ is the amount of drug excreted in urine over the dosing interval τ (24 hours). |
| Part 2: Renal Clearance (CLR) of S-648414 Following Multiple-dose Administration | Day 14 0-24 hours postdose | Renal clearance on Day 14, calculated as CLR = Aeu0-τ/AUC0-τ, where Aeu0-τ is the amount of drug excreted in urine over the dosing interval τ (24 hours) |
| Part 2: Maximum Plasma Concentration (Cmax) of Midazolam | Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). |
| Part 2: Time to Maximum Plasma Concentration of Midazolam | Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). |
| Part 2: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) for Midazolam | Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing, calculated by linear up/log down trapezoidal method. |
| Part 2: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Midazolam | Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). Area under the concentration-time curve extrapolated from time zero to infinity defined as AUC0-last + (Clast/λz), where Clast is the last measurable plasma concentration and λz is the plasma terminal elimination rate constant. |
| Part 2: Terminal Elimination Half-life for Midazolam | Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). |
| Part 2: Terminal Elimination Rate Constant for Midazolam | Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). |
| Part 2: Mean Residence Time for Midazolam | Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose. | The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). Mean residence time was calculated as MRT = AUMC0-inf/AUC0-inf where AUMC0-inf is the area under the first moment curve extrapolated to infinity. |
| Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. | Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The QT interval is a measure between Q and T wave in heart's electrical cycle. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔQTcF) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QTcF as covariate. |
| Parts 1: Change From Baseline in Heart Rate (HR) | Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. | Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median HR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG values from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in HR (ΔHR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline HR as covariate. |
| Part 1: Change From Baseline in PR Interval | Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. | Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The PR interval is the time from the onset of the P-wave to the start of the next QRS complex. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median PR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in PR interval (ΔPR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline PR as covariate. |
| Part 1: Change From Baseline in QRS Interval | Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. | Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The QRS complex is a combination of the Q wave, R wave and S wave on an ECG tracing, and represents ventricular depolarization. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QRS in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in QRS interval (ΔQRS) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QRS as covariate. |
| Part 1: Maximum Plasma Concentration (Cmax) of S-648414 | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose. | — |
| Part 1: Placebo-corrected Change From Baseline in Heart Rate | Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. | Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median HR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured values from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔHR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline HR as covariate. Placebo-corrected ΔHR (ΔΔHR) was calculated as the adjusted mean ΔHR in the S-648414 group minus adjusted mean ΔHR in the placebo group at each time point. |
| Part 1: Placebo-corrected Change From Baseline in PR Interval | Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. | Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median PR interval in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔPR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline PR as covariate. Placebo-corrected ΔPR (ΔΔPR) was calculated as the adjusted mean ΔPR in the S-648414 group minus adjusted mean ΔPR in the placebo group at each time point. |
| Part 1: Placebo-corrected Change From Baseline in QRS Duration | Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. | Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QRS duration in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in QRS duration (ΔQRS) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QRS as covariate. Placebo-corrected ΔQRS (ΔΔQRS) was calculated as the adjusted mean ΔQRS in the S-648414 group minus adjusted mean ΔQRS in the placebo group at each time point. |
| Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. | A participant was determined as an outlier if the following criteria (assessed separately) were met for the ECG intervals at any time point: QTcF: * Treatment-emergent value of \> 450 and ≤ 480 ms when not present at Baseline (new onset) * Treatment-emergent value of \> 480 and ≤ 500 ms when not present at Baseline (new onset) * Treatment-emergent value of \> 500 ms when not present at Baseline (new onset) * Increase of QTcF (ΔQTcF) from Baseline of \> 30 and ≤ 60 ms * Increase of QTcF from Baseline \> 60 ms HR: * Decrease of HR from Baseline \> 25% resulting in HR \< 50 bpm * Increase of HR from Baseline \> 25% resulting in HR \> 100 bpm PR: * Increase of PR from Baseline \> 25% resulting in PR \> 200 ms QRS: * Increase of QRS from Baseline \> 25% resulting in QRS \> 120 ms |
| Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. | T-wave abnormalities were categorized as follows: * Normal T wave: Any positive T wave not meeting any criterion below * Flat T wave: T amplitude \< 1 mm (either positive or negative) including flat isoelectric line * Notched T wave (+): Presence of notch(es) of at least 0.05 mV amplitude on ascending or descending arm of the positive T wave * Biphasic: T wave that contains a second component with an opposite phase that is at least 0.1 mV deep (both positive/negative and negative/positive and polyphasic T waves included) * Normal T wave (-): T amplitude that is negative, without biphasic T wave or notches * Notched T wave (-): Presence of notch(es) of at least 0.05 mV amplitude on descending or ascending arm of the negative T wave * U waves: Presence of abnormal U waves |
| Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose. | Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔQTcF) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF in the S-648414 group minus adjusted mean ΔQTcF in the placebo group at each time point. |
| Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414 | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose. | — |
| Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414 | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose. | Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing, calculated by the linear trapezoidal method when concentrations are increasing and by the logarithmic trapezoidal method when concentrations are decreasing (linear up/log down trapezoidal method). |
| Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414 | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose. | Area under the concentration-time curve extrapolated from time zero to infinity defined as AUC0-last + (Clast/λz), where Clast is the last measurable plasma concentration and λz is the plasma terminal elimination rate constant. |
| Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414 | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose. | Terminal elimination half-life calculated as t1/2,z = (ln2)/λz, where λz is the terminal elimination rate constant. |
| Part 1: Terminal Elimination Rate Constant (λz) of S-648414 | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose. | — |
| Part 1: Mean Residence Time (MRT) of S-648414 | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose. | Mean residence time, calculated as MRT = AUMC0-inf / AUC0-inf, where AUMC0-inf is the area under the first moment curve extrapolated to infinity. |
| Part 1: Apparent Total Clearance (CL/F) of S-648414 | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose. | Apparent total clearance estimated according to: CL/F = Dose / AUC0-inf. |
| Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose. | Apparent volume of distribution in the terminal elimination phase was estimated according to: Vz /F = Dose / AUC0-inf / λz. |
| Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96) | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose | The fraction of S-648414 dose excreted in urine from 0 to 96 hours postdose was calculated as: Cumulative amount of S-648414 excreted in urine from time zero to 96 hours postdose (Aeu0-96) / Dose × 100 |
| Part 1: Renal Clearance (CLR) of S-648414 | Day 1 and Day 14 (for participants in the 100 mg dose group only) predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose | Renal clearance was estimated according to: CLR = cumulative amount of S-648414 excreted in urine from time zero to 96 hours postdose (Aeu0-96) / area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last). |
| Part 2: Maximum Plasma Concentration (Cmax) of S-648414 Following Single and Multiple-dose Administration | Day 1 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose; Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose. | — |
| Part 2: Time to Maximum Plasma Concentration (Tmax) of S-648414 Following Single and Multiple-dose Administration | Day 1 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose; Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose. | — |
Countries
Japan, United States
Participant flow
Recruitment details
The study consisted of Part 1 (single ascending dose \[SAD\], food effect, and effects on electrocardiogram \[ECG\] parameters), Part 2 (multiple ascending dose \[MAD\] and drug-drug interaction with midazolam, a CYP3A substrate), and Part 3 (the effect of S-648414 on the pharmacokinetics (PK) of dolutegravir and the effect of dolutegravir on the PK of S-648414). Parts 1 and 2 were conducted at a single site in the United States, and Part 3 was conducted at a single site in Japan.
Pre-assignment details
In Part 1 healthy participants were sequentially assigned to 1 of 6 ascending dose groups; within each dose group participants were randomized in a 3:1 ratio (4:1 in the 100 mg dose group) to receive S-648414 or placebo. In Part 2 healthy participants were assigned to 1 of 2 dose groups with 8 study participants randomized to receive S-648414 and 2 study participants receiving placebo per group. In Part 3 healthy participants were enrolled in 1 of 2 dose groups.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Placebo Participants received a single oral dose of matching placebo to S-648414 in a fasted state on Day 1. Two participants assigned to the 100 mg dose cohort also received a single oral dose of matching placebo in a fed state (after a high-fat meal) on Day 14. | 12 |
| Part 1: 10 mg S-648414 Participants received a single oral dose of 10 mg S-648414 in a fasted state on Day 1. | 6 |
| Part 1: 30 mg S-648414 Participants received a single oral dose of 30 mg S-648414 in a fasted state on Day 1. | 6 |
| Part 1: 100 mg S-648414 Participants received a single oral dose of 100 mg S-648414 in a fasted state on Day 1 followed by a single dose of S-648414 in a fed state (after a high-fat meal) on Day 14. | 8 |
| Part 1: 250 mg S-648414 Participants received a single oral dose of 250 mg S-648414 in a fasted state on Day 1. | 6 |
| Part 1: 500 mg S-648414 Participants received a single oral dose of 500 mg S-648414 in a fasted state on Day 1. | 6 |
| Part 1: 1000 mg S-648414 Participants received a single oral dose of 1000 mg S-648414 in a fasted state on Day 1. | 6 |
| Part 2: Placebo + Midazolam Participants received matching placebo to S-648414 once a day on Days 1 to 14 and a single oral dose of 5 mg midazolam alone on Day -2 and co-administered with the placebo dose on Day 14. | 4 |
| Part 2: 50 mg S-648414 + Midazolam Participants received 50 mg S-648414 once a day on Days 1 to 14 and a single oral dose of 5 mg midazolam alone on Day -2 and co-administered with the S-648414 dose on Day 14. | 8 |
| Part 2: 30 mg S-648414 + Midazolam Participants received 30 mg S-648414 once a day on Days 1 to 14 and a single oral dose of 5 mg midazolam alone on Day -2 and co-administered with the S-648414 dose on Day 14. | 8 |
| Part 3: 100 mg S-648414 + Dolutegravir Participants received 50 mg dolutegravir orally once a day on Days 1 to 7, 100 mg S-648414 orally once a day on Days 15 to 21, and 50 mg dolutegravir co-administered with 100 mg S-648414 orally once a day on Days 22 to 28. | 14 |
| Part 3: 200 mg S-648414 + Dolutegravir Participants received 50 mg dolutegravir orally once a day on Days 1 to 7, 200 mg S-648414 orally once a day on Days 15 to 21, and 50 mg dolutegravir co-administered with 200 mg S-648414 orally once a day on Days 22 to 28. | 14 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1: 10 mg S-648414 | Part 1: Placebo | Part 1: 30 mg S-648414 | Part 1: 100 mg S-648414 | Part 1: 250 mg S-648414 | Part 1: 500 mg S-648414 | Part 1: 1000 mg S-648414 | Total | Part 2: Placebo + Midazolam | Part 2: 50 mg S-648414 + Midazolam | Part 2: 30 mg S-648414 + Midazolam | Part 3: 100 mg S-648414 + Dolutegravir | Part 3: 200 mg S-648414 + Dolutegravir |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Part 1 | 38.0 years STANDARD_DEVIATION 10.55 | 33.3 years STANDARD_DEVIATION 8.53 | 40.3 years STANDARD_DEVIATION 8.98 | 35.5 years STANDARD_DEVIATION 7.8 | 28.5 years STANDARD_DEVIATION 5.68 | 32.5 years STANDARD_DEVIATION 14.87 | 36.5 years STANDARD_DEVIATION 11.22 | 34.8 years STANDARD_DEVIATION 9.74 | — | — | — | — | — |
| Age, Continuous Part 2 | — | — | — | — | — | — | — | 35.9 years STANDARD_DEVIATION 8.51 | 36.0 years STANDARD_DEVIATION 10.03 | 37.3 years STANDARD_DEVIATION 9.97 | 34.4 years STANDARD_DEVIATION 7.03 | — | — |
| Age, Continuous Part 3 | — | — | — | — | — | — | — | 35.1 years STANDARD_DEVIATION 6.4 | — | — | — | 35.4 years STANDARD_DEVIATION 6.7 | 34.9 years STANDARD_DEVIATION 6.32 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 3 Participants | 4 Participants | 1 Participants | 2 Participants | 3 Participants | 27 Participants | 0 Participants | 3 Participants | 3 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 7 Participants | 3 Participants | 4 Participants | 5 Participants | 4 Participants | 3 Participants | 71 Participants | 4 Participants | 5 Participants | 5 Participants | 12 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 5 Participants | 2 Participants | 3 Participants | 4 Participants | 2 Participants | 2 Participants | 39 Participants | 2 Participants | 3 Participants | 5 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 6 Participants | 4 Participants | 5 Participants | 2 Participants | 4 Participants | 4 Participants | 58 Participants | 2 Participants | 5 Participants | 3 Participants | 12 Participants | 8 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 10 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 12 Participants | 5 Participants | 7 Participants | 6 Participants | 4 Participants | 5 Participants | 88 Participants | 3 Participants | 6 Participants | 7 Participants | 14 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk | EG020 affected / at risk | EG021 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 2 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 20 | 0 / 4 | 0 / 8 | 0 / 8 | 0 / 2 | 0 / 7 | 0 / 8 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 2 / 12 | 0 / 2 | 0 / 6 | 1 / 6 | 2 / 8 | 2 / 8 | 1 / 6 | 1 / 6 | 2 / 6 | 0 / 20 | 2 / 4 | 2 / 8 | 3 / 8 | 0 / 2 | 1 / 7 | 1 / 8 | 3 / 14 | 3 / 14 | 4 / 14 | 2 / 14 | 5 / 14 | 2 / 14 |
| serious Total, serious adverse events | 0 / 12 | 0 / 2 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 20 | 0 / 4 | 0 / 8 | 0 / 8 | 0 / 2 | 0 / 7 | 0 / 8 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.
Time frame: From dosing on Day 1 or Day 14 up to 10 days post dose
Population: The safety analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events (SAEs) | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related SAE | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related TEAE | 1 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 2 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any gastrointestinal AEs | 1 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any ocular AEs | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events (SAEs) | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any gastrointestinal AEs | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related TEAE | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any ocular AEs | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related SAE | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any gastrointestinal AEs | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related TEAE | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related SAE | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events (SAEs) | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any ocular AEs | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any ocular AEs | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events (SAEs) | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any gastrointestinal AEs | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related TEAE | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related SAE | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 1 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related SAE | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 2 to 4 | 1 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 2 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events (SAEs) | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any ocular AEs | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any gastrointestinal AEs | 1 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related TEAE | 1 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related SAE | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 2 to 4 | 1 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 2 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related TEAE | 1 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any gastrointestinal AEs | 1 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any ocular AEs | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events (SAEs) | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 1 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related TEAE | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any gastrointestinal AEs | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any ocular AEs | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related SAE | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events (SAEs) | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 1 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any gastrointestinal AEs | 0 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any ocular AEs | 0 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related SAE | 0 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related TEAE | 0 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
| Part 1: 500 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events (SAEs) | 0 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related TEAE | 2 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any gastrointestinal AEs | 2 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any ocular AEs | 0 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-emergent adverse event (TEAE) | 2 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any treatment-related SAE | 0 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious adverse events (SAEs) | 0 Participants |
| Part 1: 1000 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
Primary
Part 2: Number of Participants With Treatment-emergent Adverse Events
A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.
Time frame: From the first dose up to 10 days after end of dosing (25 days); A TEAE was summarized to a given treatment if the event onset/worsening occurred any time after the dose of that treatment and before the dose of the next treatment.
Population: The safety analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 0 Participants |
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 0 Participants |
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 0 Participants |
| Part 1: Placebo - Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAEs | 0 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 1 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 2 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 2 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 2 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 2 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 2 Participants |
| Part 1: Placebo - Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAEs | 0 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 2 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 2 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 2 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAEs | 0 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 0 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 1 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 1 Participants |
| Part 1: 10 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 2 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 1 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAEs | 0 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 2 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 3 Participants |
| Part 1: 30 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAEs | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 1 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 1 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAEs | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 1 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAEs | 0 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 0 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 0 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 0 Participants |
| Part 1: 250 mg S-648414 | Part 2: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
Primary
Part 3: Apparent Total Clearance (CL/F) of Dolutegravir
The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. Apparent total clearance calculated as CL/F =Dose/AUC0-τ
Time frame: Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Apparent Total Clearance (CL/F) of Dolutegravir | 0.669 L/hr | Geometric Coefficient of Variation 19.7 |
| Part 1: Placebo - Fed | Part 3: Apparent Total Clearance (CL/F) of Dolutegravir | 0.560 L/hr | Geometric Coefficient of Variation 13.4 |
| Part 1: 10 mg S-648414 | Part 3: Apparent Total Clearance (CL/F) of Dolutegravir | 0.716 L/hr | Geometric Coefficient of Variation 20.1 |
| Part 1: 30 mg S-648414 | Part 3: Apparent Total Clearance (CL/F) of Dolutegravir | 0.683 L/hr | Geometric Coefficient of Variation 17.6 |
Primary
Part 3: Apparent Total Clearance (CL/F) of S-648414
The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). Apparent total clearance was calculated as CL/F = Dose/AUC0-τ
Time frame: Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Apparent Total Clearance (CL/F) of S-648414 | 2.45 L/hr | Geometric Coefficient of Variation 17.6 |
| Part 1: Placebo - Fed | Part 3: Apparent Total Clearance (CL/F) of S-648414 | 2.43 L/hr | Geometric Coefficient of Variation 15.4 |
| Part 1: 10 mg S-648414 | Part 3: Apparent Total Clearance (CL/F) of S-648414 | 2.47 L/hr | Geometric Coefficient of Variation 11.4 |
| Part 1: 30 mg S-648414 | Part 3: Apparent Total Clearance (CL/F) of S-648414 | 2.51 L/hr | Geometric Coefficient of Variation 12.5 |
Primary
Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir
The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir. Area under the concentration-time curve over the dosing interval τ (24 hours) was calculated by the linear up/log down trapezoidal method.
Time frame: Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir | 74790 ng*hr/mL | Geometric Coefficient of Variation 19.7 |
| Part 1: Placebo - Fed | Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir | 89290 ng*hr/mL | Geometric Coefficient of Variation 13.4 |
| Part 1: 10 mg S-648414 | Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir | 69850 ng*hr/mL | Geometric Coefficient of Variation 20.1 |
| Part 1: 30 mg S-648414 | Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir | 73210 ng*hr/mL | Geometric Coefficient of Variation 17.6 |
Comparison: The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed AUC0-τ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-τ of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.1176, 1.2754]
Comparison: The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed AUC0-τ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-τ of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.9881, 1.1119]
Primary
Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414
The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28). Area under the concentration-time curve over the dosing interval τ (24 hours) was calculated by the linear up/log down trapezoidal method.
Time frame: Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414 | 40800 ng*hr/mL | Geometric Coefficient of Variation 17.6 |
| Part 1: Placebo - Fed | Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414 | 41080 ng*hr/mL | Geometric Coefficient of Variation 15.4 |
| Part 1: 10 mg S-648414 | Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414 | 81010 ng*hr/mL | Geometric Coefficient of Variation 11.4 |
| Part 1: 30 mg S-648414 | Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414 | 79820 ng*hr/mL | Geometric Coefficient of Variation 12.5 |
Comparison: The effect of dolutegravir on the PK of S-648414 was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed AUC0-τ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-τ of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.9679, 1.0479]
Comparison: The effect of dolutegravir on the PK of S-648414 was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed AUC0-τ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-τ of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.9605, 1.0105]
Primary
Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir
The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.
Time frame: Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir | 4910 ng/mL | Geometric Coefficient of Variation 15.9 |
| Part 1: Placebo - Fed | Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir | 5800 ng/mL | Geometric Coefficient of Variation 12.2 |
| Part 1: 10 mg S-648414 | Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir | 4720 ng/mL | Geometric Coefficient of Variation 19.6 |
| Part 1: 30 mg S-648414 | Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir | 4950 ng/mL | Geometric Coefficient of Variation 15.9 |
Comparison: The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cmax as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cmax of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.1171, 1.2477]
Comparison: The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cmax as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cmax of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.9656, 1.1373]
Primary
Part 3: Maximum Plasma Concentration (Cmax) of S-648414
The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).
Time frame: Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population includes all study participants with at least 1 PK parameter estimated appropriately.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Maximum Plasma Concentration (Cmax) of S-648414 | 2740 ng/mL | Geometric Coefficient of Variation 20.3 |
| Part 1: Placebo - Fed | Part 3: Maximum Plasma Concentration (Cmax) of S-648414 | 2720 ng/mL | Geometric Coefficient of Variation 21.3 |
| Part 1: 10 mg S-648414 | Part 3: Maximum Plasma Concentration (Cmax) of S-648414 | 5150 ng/mL | Geometric Coefficient of Variation 14.1 |
| Part 1: 30 mg S-648414 | Part 3: Maximum Plasma Concentration (Cmax) of S-648414 | 5020 ng/mL | Geometric Coefficient of Variation 15.3 |
Comparison: The effect of dolutegravir on the PK of S-648414 was assessed by analysis of variance (ANOVA) fit with a linear mixed effect model with the natural log (ln)-transformed Cmax as the dependent variable, treatment as fixed effect, and participant as random effect. The difference and 90% confidence interval (CI) between the ln-transformed Cmax of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.9232, 1.0645]
Comparison: The effect of dolutegravir on the PK of S-648414 was assessed by an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cmax as the dependent variable, treatment as fixed effect, and participant as random effect. The difference and 90% CI between the ln-transformed Cmax of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.8916, 1.0671]
Primary
Part 3: Number of Participants With Treatment-emergent Adverse Events
A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug. A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above. The investigator assessed the intensity of each AE according to the following: Grade 1 (Mild): No or minimal interference with usual activities. Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated. Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated. Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.
Time frame: From the first dose up to Day 36; A TEAE was summarized to a given treatment if the event onset/worsening occurred any time after the dose of that treatment and before the dose of the next treatment.
Population: The safety analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 0 Participants |
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 0 Participants |
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 3 Participants |
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 2 Participants |
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAE | 0 Participants |
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: Placebo - Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 2 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 3 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 0 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 0 Participants |
| Part 1: Placebo - Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAE | 0 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 4 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 0 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 2 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 0 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAE | 0 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 10 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 0 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAE | 0 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 2 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 0 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 30 mg S-648414 | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 2 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 3 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 2 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAE | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 2 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 5 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE | 2 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any ocular AEs | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study drug discontinuation | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 2 to 4 | 1 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related SAE | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any gastrointestinal AEs | 1 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-related TEAE | 1 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any serious adverse events | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE with severity Grade 3 to 4 | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 3: Number of Participants With Treatment-emergent Adverse Events | Any TEAE leading to study discontinuation | 0 Participants |
Primary
Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ)
The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.
Time frame: Day 8 and Day 29 (24 hours post-dosing on Day 7 and Day 28).
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ) | 1980 ng/mL | Geometric Coefficient of Variation 23.1 |
| Part 1: Placebo - Fed | Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ) | 2660 ng/mL | Geometric Coefficient of Variation 17.6 |
| Part 1: 10 mg S-648414 | Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ) | 1850 ng/mL | Geometric Coefficient of Variation 25.7 |
| Part 1: 30 mg S-648414 | Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ) | 2000 ng/mL | Geometric Coefficient of Variation 23.9 |
Comparison: The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cτ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cτ of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.2352, 1.4636]
Comparison: The effect of S-648414 on the plasma PK of dolutegravir was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cτ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cτ of dolutegravir plus S-648414 and dolutegravir alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.0137, 1.1441]
Primary
Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ)
The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).
Time frame: Day 22 and Day 29 (24 hours post-dosing on Days 21 and 28)
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ) | 1210 ng/mL | Geometric Coefficient of Variation 27.7 |
| Part 1: Placebo - Fed | Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ) | 1250 ng/mL | Geometric Coefficient of Variation 16.3 |
| Part 1: 10 mg S-648414 | Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ) | 2590 ng/mL | Geometric Coefficient of Variation 16.5 |
| Part 1: 30 mg S-648414 | Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ) | 2360 ng/mL | Geometric Coefficient of Variation 14.5 |
Comparison: The effect of dolutegravir on the PK of S-648414 was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cτ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cτ of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.9421, 1.1377]
Comparison: The effect of dolutegravir on the PK of S-648414 was assessed using an ANOVA fitted with a linear mixed effect model with the natural log-transformed Cτ as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cτ of S-648414 + dolutegravir and S-648414 alone were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.8791, 0.9411]
Primary
Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir
The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.
Time frame: Day 7 and Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir | 3.50 hours |
| Part 1: Placebo - Fed | Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir | 2.75 hours |
| Part 1: 10 mg S-648414 | Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir | 3.50 hours |
| Part 1: 30 mg S-648414 | Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir | 4.00 hours |
Primary
Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414
The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).
Time frame: Day 21 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose. Day 28 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Placebo - Fasted | Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 2.00 hours |
| Part 1: Placebo - Fed | Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 2.25 hours |
| Part 1: 10 mg S-648414 | Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 2.50 hours |
| Part 1: 30 mg S-648414 | Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 2.25 hours |
Secondary
Part 1: Apparent Total Clearance (CL/F) of S-648414
Apparent total clearance estimated according to: CL/F = Dose / AUC0-inf.
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Apparent Total Clearance (CL/F) of S-648414 | 2.76 L/hr | Geometric Coefficient of Variation 17.5 |
| Part 1: Placebo - Fed | Part 1: Apparent Total Clearance (CL/F) of S-648414 | 2.72 L/hr | Geometric Coefficient of Variation 19.6 |
| Part 1: 10 mg S-648414 | Part 1: Apparent Total Clearance (CL/F) of S-648414 | 2.61 L/hr | Geometric Coefficient of Variation 10.9 |
| Part 1: 30 mg S-648414 | Part 1: Apparent Total Clearance (CL/F) of S-648414 | 2.71 L/hr | Geometric Coefficient of Variation 14.4 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Apparent Total Clearance (CL/F) of S-648414 | 2.62 L/hr | Geometric Coefficient of Variation 21 |
| Part 1: 100 mg S-648414 Fed | Part 1: Apparent Total Clearance (CL/F) of S-648414 | 2.21 L/hr | Geometric Coefficient of Variation 26.5 |
| Part 1: 250 mg S-648414 | Part 1: Apparent Total Clearance (CL/F) of S-648414 | 2.62 L/hr | Geometric Coefficient of Variation 23.6 |
Secondary
Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414
Apparent volume of distribution in the terminal elimination phase was estimated according to: Vz /F = Dose / AUC0-inf / λz.
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 | 91.7 liters | Geometric Coefficient of Variation 21.2 |
| Part 1: Placebo - Fed | Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 | 81.0 liters | Geometric Coefficient of Variation 21.2 |
| Part 1: 10 mg S-648414 | Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 | 83.5 liters | Geometric Coefficient of Variation 11 |
| Part 1: 30 mg S-648414 | Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 | 88.9 liters | Geometric Coefficient of Variation 19.5 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 | 91.0 liters | Geometric Coefficient of Variation 17.3 |
| Part 1: 100 mg S-648414 Fed | Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 | 70.8 liters | Geometric Coefficient of Variation 31.7 |
| Part 1: 250 mg S-648414 | Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 | 89.3 liters | Geometric Coefficient of Variation 23.9 |
Secondary
Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414
Area under the concentration-time curve extrapolated from time zero to infinity defined as AUC0-last + (Clast/λz), where Clast is the last measurable plasma concentration and λz is the plasma terminal elimination rate constant.
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414 | 3620 ng*hr/mL | Geometric Coefficient of Variation 17.5 |
| Part 1: Placebo - Fed | Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414 | 11040 ng*hr/mL | Geometric Coefficient of Variation 19.6 |
| Part 1: 10 mg S-648414 | Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414 | 38300 ng*hr/mL | Geometric Coefficient of Variation 10.9 |
| Part 1: 30 mg S-648414 | Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414 | 36940 ng*hr/mL | Geometric Coefficient of Variation 14.4 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414 | 95510 ng*hr/mL | Geometric Coefficient of Variation 21 |
| Part 1: 100 mg S-648414 Fed | Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414 | 226600 ng*hr/mL | Geometric Coefficient of Variation 26.5 |
| Part 1: 250 mg S-648414 | Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414 | 382000 ng*hr/mL | Geometric Coefficient of Variation 23.6 |
Comparison: The dose proportionality of plasma PK parameters of S-648414 was examined for all fasted groups in Part 1 using the power model. The power model assumes a linear relationship between the ln-transformed parameter and ln-transformed dose where ln(AUC0-inf) = Intercept + Slope × ln(Dose) + Random error95% CI: [0.9866, 1.0695]
Comparison: The effect of food on the plasma PK of S-648414 was examined after a single dose of 100 mg S-648414 in the fed and fasted state using an ANOVA fitted with a linear mixed effect model, with ln-transformed AUC0-inf as the dependent variable, treatment as a fixed effect, and participant as random effect. The difference and 90% CI between the fed and fasted state ln-transformed AUC0-inf were estimated, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.8643, 1.0766]
Secondary
Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414
Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing, calculated by the linear trapezoidal method when concentrations are increasing and by the logarithmic trapezoidal method when concentrations are decreasing (linear up/log down trapezoidal method).
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414 | 3431 ng*hr/mL | Geometric Coefficient of Variation 18.1 |
| Part 1: Placebo - Fed | Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414 | 10610 ng*hr/mL | Geometric Coefficient of Variation 19.3 |
| Part 1: 10 mg S-648414 | Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414 | 36370 ng*hr/mL | Geometric Coefficient of Variation 9.2 |
| Part 1: 30 mg S-648414 | Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414 | 34910 ng*hr/mL | Geometric Coefficient of Variation 14.2 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414 | 89330 ng*hr/mL | Geometric Coefficient of Variation 20.2 |
| Part 1: 100 mg S-648414 Fed | Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414 | 215300 ng*hr/mL | Geometric Coefficient of Variation 27.1 |
| Part 1: 250 mg S-648414 | Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414 | 359300 ng*hr/mL | Geometric Coefficient of Variation 23.3 |
Comparison: The dose proportionality of plasma PK parameters of S-648414 was examined for all fasted groups in Part 1 using the power model. The power model assumes a linear relationship between the ln-transformed parameter and ln-transformed dose where ln(AUC0-last) = Intercept + Slope × ln(Dose) + Random error95% CI: [0.984, 1.0665]
Comparison: The effect of food on the plasma PK of S-648414 was examined after a single dose of 100 mg S-648414 in the fed and fasted state using an ANOVA fitted with a linear mixed effect model, with ln-transformed AUC0-last as the dependent variable, treatment as a fixed effect, and participant as random effect. The difference and 90% CI between the fed and fasted state ln-transformed AUC0-last were estimated, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.8585, 1.073]
Secondary
Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF)
Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The QT interval is a measure between Q and T wave in heart's electrical cycle. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔQTcF) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QTcF as covariate.
Time frame: Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose.
Population: The QT/QTc population included all study participants randomly assigned to study intervention and who took at least 1 dose of study intervention.who had measurements at Baseline as well as on-treatment, with at least 1 post-dose time point with a valid ΔQTcF value. Participants with available data at each time point are included. Cardiodynamic ECG assessments were performed for Part 1 only.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 6 hours postdose | -5.3 ms | Standard Error 2.52 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2.5 hours postdose | -2.5 ms | Standard Error 1.39 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 12 hours postdose | -0.9 ms | Standard Error 2.44 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1.5 hours postdose | -1.1 ms | Standard Error 1.4 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 0.5 hours postdose | -3.2 ms | Standard Error 1.16 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 4 hours postdose | -2.3 ms | Standard Error 1.54 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 3 hours postdose | -1.9 ms | Standard Error 1.24 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1 hour postdose | -2.2 ms | Standard Error 1.19 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 24 hours postdose | -1.4 ms | Standard Error 1.19 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 8 hours postdose | -4.1 ms | Standard Error 1.71 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2 hours postdose | -0.1 ms | Standard Error 1.38 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 3 hours postdose | 2.3 ms | Standard Error 1.73 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 6 hours postdose | -12.0 ms | Standard Error 3.55 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2.5 hours postdose | -1.7 ms | Standard Error 1.94 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 0.5 hours postdose | -3.2 ms | Standard Error 1.61 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 4 hours postdose | -0.2 ms | Standard Error 2.16 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2 hours postdose | -2.1 ms | Standard Error 1.93 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 12 hours postdose | -1.8 ms | Standard Error 3.44 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1.5 hours postdose | -1.2 ms | Standard Error 1.96 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1 hour postdose | -0.4 ms | Standard Error 1.66 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 24 hours postdose | -4.9 ms | Standard Error 1.66 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 8 hours postdose | -6.7 ms | Standard Error 2.41 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 4 hours postdose | -0.6 ms | Standard Error 2.16 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 3 hours postdose | -1.3 ms | Standard Error 1.73 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1 hour postdose | -2.4 ms | Standard Error 1.66 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 12 hours postdose | 0.9 ms | Standard Error 3.44 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1.5 hours postdose | -2.6 ms | Standard Error 1.96 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 0.5 hours postdose | -5.6 ms | Standard Error 1.61 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 8 hours postdose | -0.3 ms | Standard Error 2.41 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2 hours postdose | -1.0 ms | Standard Error 1.93 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 6 hours postdose | -2.3 ms | Standard Error 3.56 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2.5 hours postdose | -1.5 ms | Standard Error 1.94 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 24 hours postdose | -1.2 ms | Standard Error 1.66 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 3 hours postdose | -0.6 ms | Standard Error 1.5 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 0.5 hours postdose | -4.8 ms | Standard Error 1.4 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1 hour postdose | -3.2 ms | Standard Error 1.44 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1.5 hours postdose | -1.1 ms | Standard Error 1.69 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2 hours postdose | -1.9 ms | Standard Error 1.67 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2.5 hours postdose | -1.1 ms | Standard Error 1.68 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 4 hours postdose | 0.1 ms | Standard Error 1.87 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 6 hours postdose | -1.2 ms | Standard Error 3.08 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 8 hours postdose | -3.2 ms | Standard Error 2.08 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 12 hours postdose | 1.0 ms | Standard Error 2.98 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 24 hours postdose | -2.1 ms | Standard Error 1.44 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2.5 hours postdose | 0.4 ms | Standard Error 1.97 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 0.5 hours postdose | -4.1 ms | Standard Error 1.64 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 4 hours postdose | 0.2 ms | Standard Error 2.18 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2 hours postdose | -1.2 ms | Standard Error 1.95 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 6 hours postdose | -4.6 ms | Standard Error 3.57 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1.5 hours postdose | 1.8 ms | Standard Error 1.98 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 24 hours postdose | -0.8 ms | Standard Error 1.69 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 8 hours postdose | -5.9 ms | Standard Error 2.43 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1 hour postdose | -0.9 ms | Standard Error 1.69 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 12 hours postdose | -1.3 ms | Standard Error 3.45 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 3 hours postdose | 2.6 ms | Standard Error 1.76 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 6 hours postdose | -4.6 ms | Standard Error 3.59 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1.5 hours postdose | 3.1 ms | Standard Error 2.02 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 0.5 hours postdose | -5.6 ms | Standard Error 1.69 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2.5 hours postdose | 2.5 ms | Standard Error 2.01 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 3 hours postdose | -0.4 ms | Standard Error 1.8 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 8 hours postdose | -3.4 ms | Standard Error 2.46 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1 hour postdose | -1.0 ms | Standard Error 1.74 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 24 hours postdose | -1.8 ms | Standard Error 1.74 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 12 hours postdose | -3.0 ms | Standard Error 3.48 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 4 hours postdose | 3.6 ms | Standard Error 2.22 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2 hours postdose | 2.4 ms | Standard Error 1.99 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 12 hours postdose | 8.8 ms | Standard Error 3.44 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1.5 hours postdose | 4.9 ms | Standard Error 1.96 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2.5 hours postdose | 8.0 ms | Standard Error 1.95 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 24 hours postdose | 7.5 ms | Standard Error 2.01 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 0.5 hours postdose | 2.0 ms | Standard Error 1.62 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 4 hours postdose | 12.0 ms | Standard Error 2.17 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 2 hours postdose | 6.3 ms | Standard Error 1.93 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 8 hours postdose | 5.0 ms | Standard Error 2.41 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 1 hour postdose | 4.9 ms | Standard Error 1.67 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 6 hours postdose | 2.9 ms | Standard Error 3.56 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) | 3 hours postdose | 10.1 ms | Standard Error 1.74 |
Secondary
Part 1: Change From Baseline in PR Interval
Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The PR interval is the time from the onset of the P-wave to the start of the next QRS complex. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median PR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in PR interval (ΔPR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline PR as covariate.
Time frame: Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose.
Population: The QT/QTc population with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 12 hours postdose | -0.9 ms | Standard Error 2.12 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 6 hours postdose | -2.8 ms | Standard Error 1.56 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 0.5 hours postdose | 0.4 ms | Standard Error 1.29 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 1.5 hours postdose | 0.4 ms | Standard Error 1.74 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 3 hours postdose | -0.1 ms | Standard Error 1.86 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 24 hours postdose | -1.5 ms | Standard Error 1.61 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 2.5 hours postdose | 0.7 ms | Standard Error 1.6 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 4 hours postdose | 0.5 ms | Standard Error 1.67 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 1 hour postdose | 0.9 ms | Standard Error 1.29 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 2 hours postdose | 0.8 ms | Standard Error 1.44 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in PR Interval | 8 hours postdose | -3.2 ms | Standard Error 1.9 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 1 hour postdose | 1.0 ms | Standard Error 1.86 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 0.5 hours postdose | 1.0 ms | Standard Error 1.87 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 24 hours postdose | 0.1 ms | Standard Error 2.32 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 12 hours postdose | 0.4 ms | Standard Error 3.03 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 1.5 hours postdose | 3.4 ms | Standard Error 2.49 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 8 hours postdose | -1.8 ms | Standard Error 2.71 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 6 hours postdose | -1.6 ms | Standard Error 2.24 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 3 hours postdose | 3.6 ms | Standard Error 2.67 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 2 hours postdose | 2.8 ms | Standard Error 2.07 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 2.5 hours postdose | 1.1 ms | Standard Error 2.29 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in PR Interval | 4 hours postdose | 3.0 ms | Standard Error 2.39 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 1.5 hours postdose | 1.0 ms | Standard Error 2.46 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 1 hour postdose | 4.0 ms | Standard Error 1.82 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 2.5 hours postdose | 4.5 ms | Standard Error 2.26 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 2 hours postdose | 3.4 ms | Standard Error 2.03 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 3 hours postdose | 3.7 ms | Standard Error 2.64 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 0.5 hours postdose | 2.2 ms | Standard Error 1.83 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 4 hours postdose | 3.1 ms | Standard Error 2.36 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 6 hours postdose | 0.7 ms | Standard Error 2.21 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 8 hours postdose | 3.6 ms | Standard Error 2.68 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 12 hours postdose | 3.5 ms | Standard Error 3 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in PR Interval | 24 hours postdose | 0.8 ms | Standard Error 2.28 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 1 hour postdose | 1.3 ms | Standard Error 1.6 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 8 hours postdose | -4.5 ms | Standard Error 2.34 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 1.5 hours postdose | 0.9 ms | Standard Error 2.15 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 2.5 hours postdose | -0.1 ms | Standard Error 1.97 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 4 hours postdose | -1.0 ms | Standard Error 2.06 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 3 hours postdose | 1.7 ms | Standard Error 2.3 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 2 hours postdose | -2.3 ms | Standard Error 1.78 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 12 hours postdose | -1.3 ms | Standard Error 2.61 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 0.5 hours postdose | -0.1 ms | Standard Error 1.61 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 24 hours postdose | 0.5 ms | Standard Error 1.99 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in PR Interval | 6 hours postdose | -2.3 ms | Standard Error 1.93 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 2.5 hours postdose | 0.5 ms | Standard Error 2.27 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 1 hour postdose | 1.9 ms | Standard Error 1.84 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 3 hours postdose | -1.5 ms | Standard Error 2.65 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 0.5 hours postdose | 1.3 ms | Standard Error 1.85 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 24 hours postdose | -4.2 ms | Standard Error 2.29 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 1.5 hours postdose | 2.2 ms | Standard Error 2.47 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 4 hours postdose | -0.1 ms | Standard Error 2.37 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 6 hours postdose | -0.9 ms | Standard Error 2.22 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 2 hours postdose | -1.4 ms | Standard Error 2.05 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 8 hours postdose | -5.8 ms | Standard Error 2.69 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in PR Interval | 12 hours postdose | -1.0 ms | Standard Error 3.01 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 24 hours postdose | -2.2 ms | Standard Error 2.29 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 0.5 hours postdose | -3.9 ms | Standard Error 1.84 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 2 hours postdose | -2.1 ms | Standard Error 2.04 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 1.5 hours postdose | 0.8 ms | Standard Error 2.47 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 6 hours postdose | -7.0 ms | Standard Error 2.21 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 8 hours postdose | -5.8 ms | Standard Error 2.69 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 1 hour postdose | -6.4 ms | Standard Error 1.83 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 12 hours postdose | -7.8 ms | Standard Error 3.01 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 3 hours postdose | -5.3 ms | Standard Error 2.64 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 2.5 hours postdose | -5.2 ms | Standard Error 2.26 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in PR Interval | 4 hours postdose | -6.9 ms | Standard Error 2.36 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 4 hours postdose | -1.7 ms | Standard Error 2.36 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 0.5 hours postdose | 0.0 ms | Standard Error 1.83 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 2 hours postdose | 0.2 ms | Standard Error 2.04 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 1.5 hours postdose | 0.9 ms | Standard Error 2.46 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 12 hours postdose | -0.5 ms | Standard Error 3.01 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 6 hours postdose | -3.0 ms | Standard Error 2.21 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 24 hours postdose | -3.1 ms | Standard Error 2.52 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 3 hours postdose | -0.7 ms | Standard Error 2.64 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 8 hours postdose | -1.8 ms | Standard Error 2.68 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 1 hour postdose | 1.0 ms | Standard Error 1.82 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in PR Interval | 2.5 hours postdose | -0.9 ms | Standard Error 2.26 |
Secondary
Part 1: Change From Baseline in QRS Interval
Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The QRS complex is a combination of the Q wave, R wave and S wave on an ECG tracing, and represents ventricular depolarization. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QRS in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in QRS interval (ΔQRS) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QRS as covariate.
Time frame: Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose.
Population: The QT/QTc population with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 24 hours postdose | -0.7 ms | Standard Error 0.39 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 6 hours postdose | -0.5 ms | Standard Error 0.55 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 2.5 hours postdose | -0.1 ms | Standard Error 0.24 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 2 hours postdose | -0.3 ms | Standard Error 0.24 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 12 hours postdose | -1.4 ms | Standard Error 0.38 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 4 hours postdose | 0.2 ms | Standard Error 0.29 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 1.5 hours postdose | 0.5 ms | Standard Error 0.45 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 0.5 hours postdose | -0.3 ms | Standard Error 0.21 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 3 hours postdose | -0.2 ms | Standard Error 0.22 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 1 hour postdose | -0.4 ms | Standard Error 0.22 |
| Part 1: Placebo - Fasted | Part 1: Change From Baseline in QRS Interval | 8 hours postdose | -0.8 ms | Standard Error 0.33 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 8 hours postdose | -0.6 ms | Standard Error 0.47 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 2 hours postdose | 0.2 ms | Standard Error 0.34 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 1 hour postdose | -0.1 ms | Standard Error 0.32 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 6 hours postdose | -0.8 ms | Standard Error 0.78 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 2.5 hours postdose | 0.0 ms | Standard Error 0.34 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 0.5 hours postdose | 0.0 ms | Standard Error 0.31 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 3 hours postdose | 0.0 ms | Standard Error 0.31 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 4 hours postdose | -0.1 ms | Standard Error 0.41 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 24 hours postdose | 0.1 ms | Standard Error 0.55 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 12 hours postdose | 0.0 ms | Standard Error 0.54 |
| Part 1: Placebo - Fed | Part 1: Change From Baseline in QRS Interval | 1.5 hours postdose | -0.2 ms | Standard Error 0.63 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 2.5 hours postdose | 0.2 ms | Standard Error 0.34 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 4 hours postdose | 0.2 ms | Standard Error 0.41 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 3 hours postdose | 0.2 ms | Standard Error 0.31 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 0.5 hours postdose | -0.4 ms | Standard Error 0.3 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 24 hours postdose | 0.1 ms | Standard Error 0.55 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 12 hours postdose | 0.0 ms | Standard Error 0.54 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 1 hour postdose | 0.1 ms | Standard Error 0.32 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 8 hours postdose | -0.2 ms | Standard Error 0.47 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 1.5 hours postdose | 0.0 ms | Standard Error 0.63 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 6 hours postdose | -0.5 ms | Standard Error 0.77 |
| Part 1: 10 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 2 hours postdose | 0.1 ms | Standard Error 0.34 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 12 hours postdose | -0.3 ms | Standard Error 0.47 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 3 hours postdose | 0.1 ms | Standard Error 0.27 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 0.5 hours postdose | 0.2 ms | Standard Error 0.26 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 1 hour postdose | 0.2 ms | Standard Error 0.27 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 1.5 hours postdose | 0.4 ms | Standard Error 0.55 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 2 hours postdose | 0.7 ms | Standard Error 0.29 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 2.5 hours postdose | -0.2 ms | Standard Error 0.3 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 4 hours postdose | 0.5 ms | Standard Error 0.35 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 6 hours postdose | -0.7 ms | Standard Error 0.67 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 8 hours postdose | -0.3 ms | Standard Error 0.41 |
| Part 1: 30 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 24 hours postdose | 0.4 ms | Standard Error 0.48 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 4 hours postdose | 0.3 ms | Standard Error 0.41 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 1 hour postdose | 0.3 ms | Standard Error 0.32 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 2.5 hours postdose | 0.2 ms | Standard Error 0.34 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 1.5 hours postdose | 0.5 ms | Standard Error 0.63 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 8 hours postdose | -0.3 ms | Standard Error 0.47 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 2 hours postdose | 0.1 ms | Standard Error 0.34 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 12 hours postdose | -0.3 ms | Standard Error 0.54 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 3 hours postdose | 0.4 ms | Standard Error 0.31 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 0.5 hours postdose | -0.1 ms | Standard Error 0.31 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 24 hours postdose | -0.1 ms | Standard Error 0.55 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Change From Baseline in QRS Interval | 6 hours postdose | -1.3 ms | Standard Error 0.78 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 2.5 hours postdose | 0.0 ms | Standard Error 0.34 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 4 hours postdose | 0.9 ms | Standard Error 0.41 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 2 hours postdose | 0.4 ms | Standard Error 0.34 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 6 hours postdose | 0.6 ms | Standard Error 0.77 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 1.5 hours postdose | 0.3 ms | Standard Error 0.63 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 24 hours postdose | 0.0 ms | Standard Error 0.55 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 8 hours postdose | 0.2 ms | Standard Error 0.47 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 1 hour postdose | 0.2 ms | Standard Error 0.32 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 0.5 hours postdose | 0.1 ms | Standard Error 0.3 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 12 hours postdose | 0.5 ms | Standard Error 0.54 |
| Part 1: 100 mg S-648414 Fed | Part 1: Change From Baseline in QRS Interval | 3 hours postdose | 0.4 ms | Standard Error 0.31 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 0.5 hours postdose | -.1 ms | Standard Error 0.31 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 2.5 hours postdose | 0.3 ms | Standard Error 0.34 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 3 hours postdose | 0.2 ms | Standard Error 0.31 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 12 hours postdose | 0.5 ms | Standard Error 0.54 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 1.5 hours postdose | 0.6 ms | Standard Error 0.63 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 2 hours postdose | 0.8 ms | Standard Error 0.34 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 1 hour postdose | 0.4 ms | Standard Error 0.32 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 4 hours postdose | 1.0 ms | Standard Error 0.41 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 8 hours postdose | -0.5 ms | Standard Error 0.47 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 24 hours postdose | -0.7 ms | Standard Error 0.64 |
| Part 1: 250 mg S-648414 | Part 1: Change From Baseline in QRS Interval | 6 hours postdose | 0.8 ms | Standard Error 0.78 |
Secondary
Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96)
The fraction of S-648414 dose excreted in urine from 0 to 96 hours postdose was calculated as: Cumulative amount of S-648414 excreted in urine from time zero to 96 hours postdose (Aeu0-96) / Dose × 100
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96) | 30.3 percent excreted | Geometric Coefficient of Variation 22.6 |
| Part 1: Placebo - Fed | Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96) | 25.5 percent excreted | Geometric Coefficient of Variation 20.1 |
| Part 1: 10 mg S-648414 | Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96) | 25.3 percent excreted | Geometric Coefficient of Variation 19.2 |
| Part 1: 30 mg S-648414 | Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96) | 25.1 percent excreted | Geometric Coefficient of Variation 11.1 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96) | 28.7 percent excreted | Geometric Coefficient of Variation 19.8 |
| Part 1: 100 mg S-648414 Fed | Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96) | 31.5 percent excreted | Geometric Coefficient of Variation 10.2 |
| Part 1: 250 mg S-648414 | Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96) | 25.9 percent excreted | Geometric Coefficient of Variation 27.3 |
Secondary
Part 1: Maximum Plasma Concentration (Cmax) of S-648414
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Maximum Plasma Concentration (Cmax) of S-648414 | 151 ng/mL | Geometric Coefficient of Variation 22.8 |
| Part 1: Placebo - Fed | Part 1: Maximum Plasma Concentration (Cmax) of S-648414 | 498 ng/mL | Geometric Coefficient of Variation 17.7 |
| Part 1: 10 mg S-648414 | Part 1: Maximum Plasma Concentration (Cmax) of S-648414 | 1620 ng/mL | Geometric Coefficient of Variation 13.1 |
| Part 1: 30 mg S-648414 | Part 1: Maximum Plasma Concentration (Cmax) of S-648414 | 1430 ng/mL | Geometric Coefficient of Variation 18 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Maximum Plasma Concentration (Cmax) of S-648414 | 3820 ng/mL | Geometric Coefficient of Variation 25.7 |
| Part 1: 100 mg S-648414 Fed | Part 1: Maximum Plasma Concentration (Cmax) of S-648414 | 9260 ng/mL | Geometric Coefficient of Variation 31.9 |
| Part 1: 250 mg S-648414 | Part 1: Maximum Plasma Concentration (Cmax) of S-648414 | 12700 ng/mL | Geometric Coefficient of Variation 26.3 |
Comparison: The dose proportionality of plasma PK parameters of S-648414 was examined for all fasted groups in Part 1 using the power model. The power model assumes a linear relationship between the ln-transformed parameter and ln-transformed dose where ln(Cmax) = Intercept + Slope × ln(Dose) + Random error95% CI: [0.9341, 1.0373]
Comparison: The effect of food on the plasma PK of S-648414 was examined after a single dose of 100 mg S-648414 in the fed state and fasted state using an ANOVA fitted with a linear mixed effect model with ln-transformed Cmax as the dependent variable, treatment as a fixed effect, and participant as random effect.~The difference and 90% CI between the fed and fasted state ln-transformed Cmax were estimated, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.7705, 1.0019]
Secondary
Part 1: Mean Residence Time (MRT) of S-648414
Mean residence time, calculated as MRT = AUMC0-inf / AUC0-inf, where AUMC0-inf is the area under the first moment curve extrapolated to infinity.
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Mean Residence Time (MRT) of S-648414 | 32.5 hours | Geometric Coefficient of Variation 4.3 |
| Part 1: Placebo - Fed | Part 1: Mean Residence Time (MRT) of S-648414 | 29.2 hours | Geometric Coefficient of Variation 9.5 |
| Part 1: 10 mg S-648414 | Part 1: Mean Residence Time (MRT) of S-648414 | 31.5 hours | Geometric Coefficient of Variation 16.1 |
| Part 1: 30 mg S-648414 | Part 1: Mean Residence Time (MRT) of S-648414 | 33.8 hours | Geometric Coefficient of Variation 14.6 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Mean Residence Time (MRT) of S-648414 | 34.2 hours | Geometric Coefficient of Variation 12.6 |
| Part 1: 100 mg S-648414 Fed | Part 1: Mean Residence Time (MRT) of S-648414 | 32.6 hours | Geometric Coefficient of Variation 12.9 |
| Part 1: 250 mg S-648414 | Part 1: Mean Residence Time (MRT) of S-648414 | 34.5 hours | Geometric Coefficient of Variation 13.3 |
Secondary
Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS
A participant was determined as an outlier if the following criteria (assessed separately) were met for the ECG intervals at any time point: QTcF: * Treatment-emergent value of \> 450 and ≤ 480 ms when not present at Baseline (new onset) * Treatment-emergent value of \> 480 and ≤ 500 ms when not present at Baseline (new onset) * Treatment-emergent value of \> 500 ms when not present at Baseline (new onset) * Increase of QTcF (ΔQTcF) from Baseline of \> 30 and ≤ 60 ms * Increase of QTcF from Baseline \> 60 ms HR: * Decrease of HR from Baseline \> 25% resulting in HR \< 50 bpm * Increase of HR from Baseline \> 25% resulting in HR \> 100 bpm PR: * Increase of PR from Baseline \> 25% resulting in PR \> 200 ms QRS: * Increase of QRS from Baseline \> 25% resulting in QRS \> 120 ms
Time frame: Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose.
Population: QT/QTc population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR < 50 (bpm) with a decrease in ΔHR > 25% | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 60 ms | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 500 ms | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR > 100 (bpm) with an increase in ΔHR > 25% | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QRS > 120 (ms) with an increase in ΔQRS > 25% | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 480 and ≤ 500 ms | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | PR > 200 (ms) with an increase in ΔPR > 25% | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 450 and ≤ 480 ms | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 30 and ≤ 60 ms | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | PR > 200 (ms) with an increase in ΔPR > 25% | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 30 and ≤ 60 ms | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 480 and ≤ 500 ms | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 450 and ≤ 480 ms | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR < 50 (bpm) with a decrease in ΔHR > 25% | 1 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QRS > 120 (ms) with an increase in ΔQRS > 25% | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 60 ms | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 500 ms | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR > 100 (bpm) with an increase in ΔHR > 25% | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR > 100 (bpm) with an increase in ΔHR > 25% | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | PR > 200 (ms) with an increase in ΔPR > 25% | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 480 and ≤ 500 ms | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 500 ms | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 450 and ≤ 480 ms | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 30 and ≤ 60 ms | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 60 ms | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR < 50 (bpm) with a decrease in ΔHR > 25% | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QRS > 120 (ms) with an increase in ΔQRS > 25% | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 30 and ≤ 60 ms | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | PR > 200 (ms) with an increase in ΔPR > 25% | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR < 50 (bpm) with a decrease in ΔHR > 25% | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 500 ms | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR > 100 (bpm) with an increase in ΔHR > 25% | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 450 and ≤ 480 ms | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 480 and ≤ 500 ms | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 60 ms | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QRS > 120 (ms) with an increase in ΔQRS > 25% | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 30 and ≤ 60 ms | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 480 and ≤ 500 ms | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 500 ms | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 60 ms | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR < 50 (bpm) with a decrease in ΔHR > 25% | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR > 100 (bpm) with an increase in ΔHR > 25% | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | PR > 200 (ms) with an increase in ΔPR > 25% | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QRS > 120 (ms) with an increase in ΔQRS > 25% | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 450 and ≤ 480 ms | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR > 100 (bpm) with an increase in ΔHR > 25% | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR < 50 (bpm) with a decrease in ΔHR > 25% | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 450 and ≤ 480 ms | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QRS > 120 (ms) with an increase in ΔQRS > 25% | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | PR > 200 (ms) with an increase in ΔPR > 25% | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 500 ms | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 30 and ≤ 60 ms | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 480 and ≤ 500 ms | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 60 ms | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 450 and ≤ 480 ms | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR < 50 (bpm) with a decrease in ΔHR > 25% | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | PR > 200 (ms) with an increase in ΔPR > 25% | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 60 ms | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | HR > 100 (bpm) with an increase in ΔHR > 25% | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 480 and ≤ 500 ms | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QRS > 120 (ms) with an increase in ΔQRS > 25% | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | ΔQTcF > 30 and ≤ 60 ms | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS | QTcF > 500 ms | 0 Participants |
Secondary
Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence
T-wave abnormalities were categorized as follows: * Normal T wave: Any positive T wave not meeting any criterion below * Flat T wave: T amplitude \< 1 mm (either positive or negative) including flat isoelectric line * Notched T wave (+): Presence of notch(es) of at least 0.05 mV amplitude on ascending or descending arm of the positive T wave * Biphasic: T wave that contains a second component with an opposite phase that is at least 0.1 mV deep (both positive/negative and negative/positive and polyphasic T waves included) * Normal T wave (-): T amplitude that is negative, without biphasic T wave or notches * Notched T wave (-): Presence of notch(es) of at least 0.05 mV amplitude on descending or ascending arm of the negative T wave * U waves: Presence of abnormal U waves
Time frame: Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose.
Population: QT/QTc population)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | U-Wave presence | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Normal (-) | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (+) | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Flat | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Biphasic | 0 Participants |
| Part 1: Placebo - Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (-) | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Flat | 1 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | U-Wave presence | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Biphasic | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (+) | 1 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Normal (-) | 0 Participants |
| Part 1: Placebo - Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (-) | 1 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (+) | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (-) | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Biphasic | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Normal (-) | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Flat | 0 Participants |
| Part 1: 10 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | U-Wave presence | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Biphasic | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (+) | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Flat | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Normal (-) | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | U-Wave presence | 0 Participants |
| Part 1: 30 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (-) | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Normal (-) | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Flat | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (+) | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Biphasic | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (-) | 0 Participants |
| Part 1: 100 mg S-648414 Fasted | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | U-Wave presence | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (-) | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Normal (-) | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Biphasic | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Flat | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | U-Wave presence | 0 Participants |
| Part 1: 100 mg S-648414 Fed | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (+) | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Flat | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Normal (-) | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | U-Wave presence | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Biphasic | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (+) | 0 Participants |
| Part 1: 250 mg S-648414 | Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Notched (-) | 0 Participants |
Secondary
Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval
Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. QT interval was corrected for heart rate using Fridericia's correction (QTcF). Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔQTcF) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QTcF as covariate. Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF in the S-648414 group minus adjusted mean ΔQTcF in the placebo group at each time point.
Time frame: Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose.
Population: The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 4 hours postdose | 2.1 ms | Standard Error 2.65 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 6 hours postdose | -6.7 ms | Standard Error 4.36 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 24 hours postdose | -3.6 ms | Standard Error 2.04 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2.5 hours postdose | 0.8 ms | Standard Error 2.38 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 0.5 hours postdose | 0.0 ms | Standard Error 1.98 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2 hours postdose | -2.0 ms | Standard Error 2.37 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 12 hours postdose | -1.0 ms | Standard Error 4.21 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1 hour postdose | 1.7 ms | Standard Error 2.04 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 8 hours postdose | -2.7 ms | Standard Error 2.95 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 3 hours postdose | 4.1 ms | Standard Error 2.13 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1.5 hours postdose | -0.1 ms | Standard Error 2.4 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 3 hours postdose | 0.5 ms | Standard Error 2.14 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 6 hours postdose | 3.0 ms | Standard Error 4.36 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 4 hours postdose | 1.7 ms | Standard Error 2.66 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1 hour postdose | -0.2 ms | Standard Error 2.06 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 0.5 hours postdose | -2.4 ms | Standard Error 1.99 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2 hours postdose | -0.9 ms | Standard Error 2.38 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 24 hours postdose | 0.2 ms | Standard Error 2.05 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2.5 hours postdose | 1.0 ms | Standard Error 2.39 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 12 hours postdose | 1.8 ms | Standard Error 4.22 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 8 hours postdose | 3.7 ms | Standard Error 2.96 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1.5 hours postdose | -1.5 ms | Standard Error 2.41 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2.5 hours postdose | 1.4 ms | Standard Error 2.18 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1.5 hours postdose | 0.0 ms | Standard Error 2.2 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2 hours postdose | -1.8 ms | Standard Error 2.16 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 3 hours postdose | 1.2 ms | Standard Error 1.94 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 4 hours postdose | 2.4 ms | Standard Error 2.42 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 6 hours postdose | 4.0 ms | Standard Error 3.98 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 8 hours postdose | 0.9 ms | Standard Error 2.7 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 12 hours postdose | 1.8 ms | Standard Error 3.85 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 24 hours postdose | -0.7 ms | Standard Error 1.86 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 0.5 hours postdose | -1.6 ms | Standard Error 1.81 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1 hour postdose | -1.0 ms | Standard Error 1.87 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 4 hours postdose | 2.5 ms | Standard Error 2.65 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1.5 hours postdose | 3.0 ms | Standard Error 2.4 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 12 hours postdose | -0.5 ms | Standard Error 4.21 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 6 hours postdose | 0.7 ms | Standard Error 4.36 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2 hours postdose | -1.1 ms | Standard Error 2.36 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 24 hours postdose | 0.5 ms | Standard Error 2.03 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 0.5 hours postdose | -0.9 ms | Standard Error 1.98 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 8 hours postdose | -1.8 ms | Standard Error 2.95 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 3 hours postdose | 4.5 ms | Standard Error 2.12 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1 hour postdose | 1.2 ms | Standard Error 2.04 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2.5 hours postdose | 2.8 ms | Standard Error 2.38 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 0.5 hours postdose | -2.4 ms | Standard Error 2.1 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 6 hours postdose | 0.6 ms | Standard Error 4.41 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2.5 hours postdose | 5.0 ms | Standard Error 2.48 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 8 hours postdose | 0.7 ms | Standard Error 3.03 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1 hour postdose | 1.1 ms | Standard Error 2.16 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 12 hours postdose | -2.1 ms | Standard Error 4.27 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2 hours postdose | 2.5 ms | Standard Error 2.46 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 24 hours postdose | -0.4 ms | Standard Error 2.15 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1.5 hours postdose | 4.2 ms | Standard Error 2.5 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 4 hours postdose | 5.9 ms | Standard Error 2.74 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 3 hours postdose | 1.4 ms | Standard Error 2.24 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 12 hours postdose | 9.6 ms | Standard Error 4.23 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1.5 hours postdose | 6.0 ms | Standard Error 2.42 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 4 hours postdose | 14.3 ms | Standard Error 2.67 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 8 hours postdose | 9.1 ms | Standard Error 2.97 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 3 hours postdose | 12.0 ms | Standard Error 2.15 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 0.5 hours postdose | 5.2 ms | Standard Error 2 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2.5 hours postdose | 10.4 ms | Standard Error 2.4 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 1 hour postdose | 7.0 ms | Standard Error 2.07 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 2 hours postdose | 6.4 ms | Standard Error 2.39 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 6 hours postdose | 8.1 ms | Standard Error 4.37 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval | 24 hours postdose | 8.8 ms | Standard Error 2.36 |
Secondary
Part 1: Placebo-corrected Change From Baseline in Heart Rate
Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median HR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured values from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔHR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline HR as covariate. Placebo-corrected ΔHR (ΔΔHR) was calculated as the adjusted mean ΔHR in the S-648414 group minus adjusted mean ΔHR in the placebo group at each time point.
Time frame: Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose.
Population: The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 12 hours postdose | -1.6 beats per minute | Standard Error 3.12 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 4 hours postdose | -1.4 beats per minute | Standard Error 2.45 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2.5 hours postdose | -2.0 beats per minute | Standard Error 2.22 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 24 hours postdose | -2.2 beats per minute | Standard Error 2.85 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 8 hours postdose | 0.1 beats per minute | Standard Error 2.7 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 3 hours postdose | -2.1 beats per minute | Standard Error 2.39 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1 hour postdose | -4.2 beats per minute | Standard Error 2 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1.5 hours postdose | -2.6 beats per minute | Standard Error 2.04 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2 hours postdose | -2.7 beats per minute | Standard Error 2.26 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 6 hours postdose | -0.6 beats per minute | Standard Error 2.05 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 0.5 hours postdose | -1.1 beats per minute | Standard Error 1.93 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 24 hours postdose | -0.9 beats per minute | Standard Error 2.87 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2 hours postdose | -2.0 beats per minute | Standard Error 2.28 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1.5 hours postdose | 0.1 beats per minute | Standard Error 2.07 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2.5 hours postdose | -3.8 beats per minute | Standard Error 2.25 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 4 hours postdose | 0.4 beats per minute | Standard Error 2.47 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 6 hours postdose | -2.8 beats per minute | Standard Error 2.07 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 8 hours postdose | -0.9 beats per minute | Standard Error 2.72 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 0.5 hours postdose | -2.3 beats per minute | Standard Error 1.95 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1 hour postdose | -3.4 beats per minute | Standard Error 2.03 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 3 hours postdose | -0.7 beats per minute | Standard Error 2.41 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 12 hours postdose | -0.7 beats per minute | Standard Error 3.14 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 3 hours postdose | -1.2 beats per minute | Standard Error 2.18 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 6 hours postdose | -1.0 beats per minute | Standard Error 1.87 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 4 hours postdose | -3.1 beats per minute | Standard Error 2.23 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1 hour postdose | -3.5 beats per minute | Standard Error 1.83 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 0.5 hours postdose | -2.0 beats per minute | Standard Error 1.76 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 24 hours postdose | -1.9 beats per minute | Standard Error 2.6 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1.5 hours postdose | -2.6 beats per minute | Standard Error 1.86 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 12 hours postdose | -1.5 beats per minute | Standard Error 2.85 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2 hours postdose | -2.1 beats per minute | Standard Error 2.06 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 8 hours postdose | -1.7 beats per minute | Standard Error 2.46 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2.5 hours postdose | -3.0 beats per minute | Standard Error 2.03 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 24 hours postdose | 0.4 beats per minute | Standard Error 2.85 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 0.5 hours postdose | -1.0 beats per minute | Standard Error 1.92 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1 hour postdose | -1.1 beats per minute | Standard Error 2 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1.5 hours postdose | 0.0 beats per minute | Standard Error 2.04 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2 hours postdose | -1.3 beats per minute | Standard Error 2.26 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2.5 hours postdose | -1.5 beats per minute | Standard Error 2.22 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 3 hours postdose | -0.8 beats per minute | Standard Error 2.39 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 4 hours postdose | 0.6 beats per minute | Standard Error 2.45 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 6 hours postdose | -1.5 beats per minute | Standard Error 2.05 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 8 hours postdose | 0.3 beats per minute | Standard Error 2.7 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 12 hours postdose | -0.3 beats per minute | Standard Error 3.12 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2.5 hours postdose | 2.0 beats per minute | Standard Error 2.22 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1.5 hours postdose | 0.6 beats per minute | Standard Error 2.04 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 0.5 hours postdose | -1.6 beats per minute | Standard Error 1.93 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 12 hours postdose | 6.4 beats per minute | Standard Error 3.12 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 8 hours postdose | 3.1 beats per minute | Standard Error 2.7 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 6 hours postdose | 2.0 beats per minute | Standard Error 2.05 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1 hour postdose | -2.5 beats per minute | Standard Error 2 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 24 hours postdose | -0.1 beats per minute | Standard Error 2.85 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 4 hours postdose | 1.9 beats per minute | Standard Error 2.45 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2 hours postdose | 0.9 beats per minute | Standard Error 2.26 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 3 hours postdose | 2.9 beats per minute | Standard Error 2.39 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1.5 hours postdose | 0.0 beats per minute | Standard Error 2.04 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 24 hours postdose | 2.9 beats per minute | Standard Error 3.06 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 6 hours postdose | 2.3 beats per minute | Standard Error 2.05 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2.5 hours postdose | -1.5 beats per minute | Standard Error 2.22 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 2 hours postdose | 0.1 beats per minute | Standard Error 2.26 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 0.5 hours postdose | -2.5 beats per minute | Standard Error 1.92 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 8 hours postdose | 2.0 beats per minute | Standard Error 2.7 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 4 hours postdose | 3.1 beats per minute | Standard Error 2.45 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 12 hours postdose | 0.7 beats per minute | Standard Error 3.12 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 1 hour postdose | -2.2 beats per minute | Standard Error 2 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in Heart Rate | 3 hours postdose | 0.4 beats per minute | Standard Error 2.39 |
Secondary
Part 1: Placebo-corrected Change From Baseline in PR Interval
Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median PR interval in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline (ΔPR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline PR as covariate. Placebo-corrected ΔPR (ΔΔPR) was calculated as the adjusted mean ΔPR in the S-648414 group minus adjusted mean ΔPR in the placebo group at each time point.
Time frame: Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose.
Population: The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1 hour postdose | 0.2 ms | Standard Error 2.27 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1.5 hours postdose | 3.0 ms | Standard Error 3.04 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 3 hours postdose | 3.8 ms | Standard Error 3.25 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 0.5 hours postdose | 0.6 ms | Standard Error 2.28 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 8 hours postdose | 1.4 ms | Standard Error 3.31 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 24 hours postdose | 1.6 ms | Standard Error 2.82 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 6 hours postdose | 1.2 ms | Standard Error 2.74 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2 hours postdose | 2.0 ms | Standard Error 2.52 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 12 hours postdose | 1.3 ms | Standard Error 3.7 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 4 hours postdose | 2.5 ms | Standard Error 2.91 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2.5 hours postdose | 0.4 ms | Standard Error 2.79 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 3 hours postdose | 3.8 ms | Standard Error 3.23 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2.5 hours postdose | 3.8 ms | Standard Error 2.77 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 4 hours postdose | 2.7 ms | Standard Error 2.89 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 24 hours postdose | 2.2 ms | Standard Error 2.79 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1 hour postdose | 3.2 ms | Standard Error 2.23 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 12 hours postdose | 4.5 ms | Standard Error 3.68 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 8 hours postdose | 6.8 ms | Standard Error 3.28 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1.5 hours postdose | 0.6 ms | Standard Error 3.02 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 0.5 hours postdose | 1.8 ms | Standard Error 2.24 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 6 hours postdose | 3.5 ms | Standard Error 2.71 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2 hours postdose | 2.6 ms | Standard Error 2.49 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1 hour postdose | 0.5 ms | Standard Error 2.05 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 0.5 hours postdose | -0.5 ms | Standard Error 2.06 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1.5 hours postdose | 0.5 ms | Standard Error 2.76 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2.5 hours postdose | -0.8 ms | Standard Error 2.54 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 3 hours postdose | 1.8 ms | Standard Error 2.96 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 4 hours postdose | -1.5 ms | Standard Error 2.65 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 6 hours postdose | 0.5 ms | Standard Error 2.48 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 8 hours postdose | -1.3 ms | Standard Error 3.01 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 12 hours postdose | -0.4 ms | Standard Error 3.37 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 24 hours postdose | 2.0 ms | Standard Error 2.56 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2 hours postdose | -3.1 ms | Standard Error 2.29 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1.5 hours postdose | 1.8 ms | Standard Error 3.02 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 4 hours postdose | -0.5 ms | Standard Error 2.9 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 0.5 hours postdose | 0.9 ms | Standard Error 2.25 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 8 hours postdose | -2.6 ms | Standard Error 3.29 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 24 hours postdose | -2.7 ms | Standard Error 2.8 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 3 hours postdose | -1.4 ms | Standard Error 3.24 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2.5 hours postdose | -0.2 ms | Standard Error 2.78 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1 hour postdose | 1.0 ms | Standard Error 2.24 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2 hours postdose | -2.2 ms | Standard Error 2.5 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 12 hours postdose | -0.1 ms | Standard Error 3.69 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in PR Interval | 6 hours postdose | 1.9 ms | Standard Error 2.72 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 12 hours postdose | -6.9 ms | Standard Error 3.68 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 0.5 hours postdose | -4.3 ms | Standard Error 2.25 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2.5 hours postdose | -5.9 ms | Standard Error 2.77 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 6 hours postdose | -4.1 ms | Standard Error 2.71 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 24 hours postdose | -0.7 ms | Standard Error 2.8 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 3 hours postdose | -5.2 ms | Standard Error 3.23 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2 hours postdose | -2.9 ms | Standard Error 2.49 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 8 hours postdose | -2.6 ms | Standard Error 3.29 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1.5 hours postdose | 0.4 ms | Standard Error 3.02 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1 hour postdose | -7.2 ms | Standard Error 2.23 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in PR Interval | 4 hours postdose | -7.4 ms | Standard Error 2.89 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 3 hours postdose | -0.5 ms | Standard Error 3.23 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 4 hours postdose | -2.2 ms | Standard Error 2.89 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1.5 hours postdose | 0.5 ms | Standard Error 3.02 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 24 hours postdose | -1.6 ms | Standard Error 2.99 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 6 hours postdose | -0.1 ms | Standard Error 2.71 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 1 hour postdose | 0.2 ms | Standard Error 2.23 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 8 hours postdose | 1.4 ms | Standard Error 3.29 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 12 hours postdose | 0.4 ms | Standard Error 3.68 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 0.5 hours postdose | -0.4 ms | Standard Error 2.24 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2.5 hours postdose | -1.6 ms | Standard Error 2.77 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in PR Interval | 2 hours postdose | -0.6 ms | Standard Error 2.49 |
Secondary
Part 1: Placebo-corrected Change From Baseline in QRS Duration
Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QRS duration in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in QRS duration (ΔQRS) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QRS as covariate. Placebo-corrected ΔQRS (ΔΔQRS) was calculated as the adjusted mean ΔQRS in the S-648414 group minus adjusted mean ΔQRS in the placebo group at each time point.
Time frame: Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose.
Population: The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 12 hours postdose | 1.4 ms | Standard Error 0.66 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1.5 hours postdose | -0.7 ms | Standard Error 0.77 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1 hour postdose | 0.3 ms | Standard Error 0.39 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 3 hours postdose | 0.2 ms | Standard Error 0.38 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 0.5 hours postdose | 0.2 ms | Standard Error 0.37 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 6 hours postdose | -0.3 ms | Standard Error 0.95 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2.5 hours postdose | 0.1 ms | Standard Error 0.42 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2 hours postdose | 0.5 ms | Standard Error 0.42 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 8 hours postdose | 0.2 ms | Standard Error 0.58 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 24 hours postdose | 0.8 ms | Standard Error 0.68 |
| Part 1: Placebo - Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 4 hours postdose | -0.3 ms | Standard Error 0.5 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 12 hours postdose | 1.4 ms | Standard Error 0.66 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2.5 hours postdose | 0.3 ms | Standard Error 0.42 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 24 hours postdose | 0.8 ms | Standard Error 0.67 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1 hour postdose | 0.5 ms | Standard Error 0.39 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 8 hours postdose | 0.7 ms | Standard Error 0.58 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 3 hours postdose | 0.4 ms | Standard Error 0.38 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1.5 hours postdose | -0.6 ms | Standard Error 0.77 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 0.5 hours postdose | -0.1 ms | Standard Error 0.37 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 6 hours postdose | 0.0 ms | Standard Error 0.95 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 4 hours postdose | 0.0 ms | Standard Error 0.5 |
| Part 1: Placebo - Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2 hours postdose | 0.4 ms | Standard Error 0.42 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1 hour postdose | 0.6 ms | Standard Error 0.35 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 0.5 hours postdose | 0.5 ms | Standard Error 0.34 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1.5 hours postdose | -0.1 ms | Standard Error 0.71 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2 hours postdose | 1.1 ms | Standard Error 0.38 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2.5 hours postdose | -0.1 ms | Standard Error 0.38 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 3 hours postdose | 0.3 ms | Standard Error 0.35 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 4 hours postdose | 0.3 ms | Standard Error 0.46 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 8 hours postdose | 0.5 ms | Standard Error 0.53 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 12 hours postdose | 1.1 ms | Standard Error 0.6 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 24 hours postdose | 1.1 ms | Standard Error 0.62 |
| Part 1: 10 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 6 hours postdose | -0.2 ms | Standard Error 0.87 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 3 hours postdose | 0.5 ms | Standard Error 0.38 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2 hours postdose | 0.5 ms | Standard Error 0.42 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 4 hours postdose | 0.1 ms | Standard Error 0.5 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1.5 hours postdose | -0.1 ms | Standard Error 0.77 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 6 hours postdose | -0.8 ms | Standard Error 0.95 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1 hour postdose | 0.7 ms | Standard Error 0.39 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 0.5 hours postdose | 0.2 ms | Standard Error 0.37 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 8 hours postdose | 0.5 ms | Standard Error 0.58 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 12 hours postdose | 1.1 ms | Standard Error 0.66 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 24 hours postdose | 0.6 ms | Standard Error 0.68 |
| Part 1: 30 mg S-648414 | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2.5 hours postdose | 0.3 ms | Standard Error 0.42 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 8 hours postdose | 1.1 ms | Standard Error 0.58 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 6 hours postdose | 1.1 ms | Standard Error 0.95 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1 hour postdose | 0.6 ms | Standard Error 0.39 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 24 hours postdose | 0.7 ms | Standard Error 0.67 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2.5 hours postdose | 0.1 ms | Standard Error 0.42 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 12 hours postdose | 1.9 ms | Standard Error 0.66 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 3 hours postdose | 0.5 ms | Standard Error 0.38 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 0.5 hours postdose | 0.4 ms | Standard Error 0.37 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 4 hours postdose | 0.8 ms | Standard Error 0.5 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1.5 hours postdose | -0.3 ms | Standard Error 0.77 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2 hours postdose | 0.7 ms | Standard Error 0.42 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 24 hours postdose | 0.0 ms | Standard Error 0.75 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 4 hours postdose | 0.8 ms | Standard Error 0.5 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1 hour postdose | 0.8 ms | Standard Error 0.39 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 6 hours postdose | 1.3 ms | Standard Error 0.95 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 3 hours postdose | 0.3 ms | Standard Error 0.38 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 12 hours postdose | 1.9 ms | Standard Error 0.66 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 1.5 hours postdose | 0.0 ms | Standard Error 0.77 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 8 hours postdose | 0.3 ms | Standard Error 0.58 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 0.5 hours postdose | 0.2 ms | Standard Error 0.37 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2.5 hours postdose | 0.4 ms | Standard Error 0.42 |
| Part 1: 100 mg S-648414 Fed | Part 1: Placebo-corrected Change From Baseline in QRS Duration | 2 hours postdose | 1.1 ms | Standard Error 0.42 |
Secondary
Part 1: Renal Clearance (CLR) of S-648414
Renal clearance was estimated according to: CLR = cumulative amount of S-648414 excreted in urine from time zero to 96 hours postdose (Aeu0-96) / area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last).
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose (-12 to 0 hours), 0 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose
Population: PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Renal Clearance (CLR) of S-648414 | 0.884 L/hr | Geometric Coefficient of Variation 11.6 |
| Part 1: Placebo - Fed | Part 1: Renal Clearance (CLR) of S-648414 | 0.721 L/hr | Geometric Coefficient of Variation 25.9 |
| Part 1: 10 mg S-648414 | Part 1: Renal Clearance (CLR) of S-648414 | 0.695 L/hr | Geometric Coefficient of Variation 17.5 |
| Part 1: 30 mg S-648414 | Part 1: Renal Clearance (CLR) of S-648414 | 0.720 L/hr | Geometric Coefficient of Variation 18.4 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Renal Clearance (CLR) of S-648414 | 0.804 L/hr | Geometric Coefficient of Variation 10.3 |
| Part 1: 100 mg S-648414 Fed | Part 1: Renal Clearance (CLR) of S-648414 | 0.732 L/hr | Geometric Coefficient of Variation 30.6 |
| Part 1: 250 mg S-648414 | Part 1: Renal Clearance (CLR) of S-648414 | 0.720 L/hr | Geometric Coefficient of Variation 24.3 |
Secondary
Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414
Terminal elimination half-life calculated as t1/2,z = (ln2)/λz, where λz is the terminal elimination rate constant.
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414 | 23.0 hours | Geometric Coefficient of Variation 5 |
| Part 1: Placebo - Fed | Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414 | 20.7 hours | Geometric Coefficient of Variation 9.9 |
| Part 1: 10 mg S-648414 | Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414 | 22.2 hours | Geometric Coefficient of Variation 16 |
| Part 1: 30 mg S-648414 | Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414 | 22.8 hours | Geometric Coefficient of Variation 14.2 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414 | 24.1 hours | Geometric Coefficient of Variation 12.1 |
| Part 1: 100 mg S-648414 Fed | Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414 | 22.2 hours | Geometric Coefficient of Variation 12.1 |
| Part 1: 250 mg S-648414 | Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414 | 23.7 hours | Geometric Coefficient of Variation 14.2 |
Comparison: The effect of food on the plasma PK of S-648414 was examined after a single dose of 100 mg S-648414 in the fed and fasted state using an ANOVA fitted with a linear mixed effect model, with ln-transformed t1/2,z as the dependent variable, treatment as a fixed effect, and participant as random effect. The difference and 90% CI between the fed and fasted state ln-transformed t1/2,z were estimated, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [0.9949, 1.0606]
Secondary
Part 1: Terminal Elimination Rate Constant (λz) of S-648414
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Terminal Elimination Rate Constant (λz) of S-648414 | 0.0301 1/hour | Geometric Coefficient of Variation 5 |
| Part 1: Placebo - Fed | Part 1: Terminal Elimination Rate Constant (λz) of S-648414 | 0.0336 1/hour | Geometric Coefficient of Variation 9.9 |
| Part 1: 10 mg S-648414 | Part 1: Terminal Elimination Rate Constant (λz) of S-648414 | 0.0313 1/hour | Geometric Coefficient of Variation 16 |
| Part 1: 30 mg S-648414 | Part 1: Terminal Elimination Rate Constant (λz) of S-648414 | 0.0305 1/hour | Geometric Coefficient of Variation 14.2 |
| Part 1: 100 mg S-648414 Fasted | Part 1: Terminal Elimination Rate Constant (λz) of S-648414 | 0.0288 1/hour | Geometric Coefficient of Variation 12.1 |
| Part 1: 100 mg S-648414 Fed | Part 1: Terminal Elimination Rate Constant (λz) of S-648414 | 0.0312 1/hour | Geometric Coefficient of Variation 12.1 |
| Part 1: 250 mg S-648414 | Part 1: Terminal Elimination Rate Constant (λz) of S-648414 | 0.0293 1/hour | Geometric Coefficient of Variation 14.2 |
Secondary
Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414
Time frame: Day 1 and Day 14 (for participants in the 100 mg dose group only) predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96 hours postdose.
Population: The PK parameter population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Placebo - Fasted | Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 1.00 hours |
| Part 1: Placebo - Fed | Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 1.00 hours |
| Part 1: 10 mg S-648414 | Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 1.25 hours |
| Part 1: 30 mg S-648414 | Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 3.00 hours |
| Part 1: 100 mg S-648414 Fasted | Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 1.50 hours |
| Part 1: 100 mg S-648414 Fed | Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 1.50 hours |
| Part 1: 250 mg S-648414 | Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414 | 1.75 hours |
Secondary
Part 2: Apparent Total Clearance (CL/F) of S-648414 Following Multiple-dose Administration
Apparent total clearance estimated according to: CL/F = Dose/AUC0-τ on Day 14
Time frame: Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Apparent Total Clearance (CL/F) of S-648414 Following Multiple-dose Administration | 2.85 L/hr | Geometric Coefficient of Variation 14.9 |
| Part 1: Placebo - Fed | Part 2: Apparent Total Clearance (CL/F) of S-648414 Following Multiple-dose Administration | 2.72 L/hr | Geometric Coefficient of Variation 20.4 |
Secondary
Part 2: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 Following Multiple-dose Administration
Apparent volume of distribution in the terminal elimination phase on Day 14, estimated according to: Vz /F = Dose/AUC0-τ/λz
Time frame: Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 Following Multiple-dose Administration | 88.7 liters | Geometric Coefficient of Variation 13.6 |
| Part 1: Placebo - Fed | Part 2: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 Following Multiple-dose Administration | 93.0 liters | Geometric Coefficient of Variation 28.5 |
Secondary
Part 2: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Midazolam
The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). Area under the concentration-time curve extrapolated from time zero to infinity defined as AUC0-last + (Clast/λz), where Clast is the last measurable plasma concentration and λz is the plasma terminal elimination rate constant.
Time frame: Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Midazolam | 72.81 ng*hr/mL | Geometric Coefficient of Variation 28.7 |
| Part 1: Placebo - Fed | Part 2: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Midazolam | 61.68 ng*hr/mL | Geometric Coefficient of Variation 41.2 |
| Part 1: 10 mg S-648414 | Part 2: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Midazolam | 76.03 ng*hr/mL | Geometric Coefficient of Variation 42.2 |
| Part 1: 30 mg S-648414 | Part 2: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Midazolam | 67.02 ng*hr/mL | Geometric Coefficient of Variation 37.1 |
Comparison: The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed AUC0-inf as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-inf of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.90% CI: [0.6645, 1.0561]
Comparison: The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed AUC0-inf as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-inf of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.90% CI: [0.7213, 1.0085]
Secondary
Part 2: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) for Midazolam
The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing, calculated by linear up/log down trapezoidal method.
Time frame: Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) for Midazolam | 70.17 ng*hr/mL | Geometric Coefficient of Variation 30.7 |
| Part 1: Placebo - Fed | Part 2: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) for Midazolam | 59.83 ng*hr/mL | Geometric Coefficient of Variation 40.5 |
| Part 1: 10 mg S-648414 | Part 2: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) for Midazolam | 73.28 ng*hr/mL | Geometric Coefficient of Variation 40.7 |
| Part 1: 30 mg S-648414 | Part 2: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) for Midazolam | 64.53 ng*hr/mL | Geometric Coefficient of Variation 35.6 |
Comparison: The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed AUC0-last as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-last of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.90% CI: [0.6628, 1.0696]
Comparison: The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed AUC0-last as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed AUC0-last of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.90% CI: [0.7185, 1.0155]
Secondary
Part 2: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) of S-648414 Following Single and Multiple-dose Administration
Area under the concentration-time curve over the dosing interval (24 hours) on Day 1 and Day 14, calculated by the linear up/log down trapezoidal method.
Time frame: Day 1 and day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population with available data at each time point
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) of S-648414 Following Single and Multiple-dose Administration | Day 1 | 5519 ng*hr/mL | Geometric Coefficient of Variation 15.9 |
| Part 1: Placebo - Fasted | Part 2: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) of S-648414 Following Single and Multiple-dose Administration | Day 14 | 10540 ng*hr/mL | Geometric Coefficient of Variation 14.9 |
| Part 1: Placebo - Fed | Part 2: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) of S-648414 Following Single and Multiple-dose Administration | Day 1 | 8983 ng*hr/mL | Geometric Coefficient of Variation 17.9 |
| Part 1: Placebo - Fed | Part 2: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) of S-648414 Following Single and Multiple-dose Administration | Day 14 | 18400 ng*hr/mL | Geometric Coefficient of Variation 20.4 |
Comparison: The dose proportionality of plasma S-648414 AUC0-τ after a single dose of S-648414 (Day 1) was assessed using an ANOVA model fitted to the ln-transformed AUC0-τ, with dose group fitted as a fixed factor.~The point estimates and 90% CIs were generated for the ratios of the 50 mg dose to 30 mg dose ln-transformed AUC0-τ, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.4038, 1.8874]
Comparison: The dose proportionality of plasma S-648414 AUC0-τ after multiple doses of S-648414 (Day 14) was assessed using an ANOVA model fitted to the ln-transformed AUC0-τ, with dose group fitted as a fixed factor.~The point estimates and 90% CIs were generated for the ratios of the 50 mg dose to 30 mg dose ln-transformed AUC0-τ, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.4785, 2.0605]
Comparison: The accumulation ratio of AUC0-τ in the 30 mg dose group was calculated as the ratio of Day 14 to Day 1 using an ANOVA fitted with a linear mixed model with ln-transformed AUC0-τ, Day as a fixed effect and participant as a random effect.~The difference and 90% CI between the ln-transformed AUC0-τ on Day 1 and Day 14 were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.7788, 2.0513]
Comparison: The accumulation ratio of AUC0-τ in the 50 mg dose group was calculated as the ratio of Day 14 to Day 1 using an ANOVA fitted with a linear mixed model with ln-transformed AUC0-τ, Day as a fixed effect and participant as a random effect.~The difference and 90% CI between the ln-transformed AUC0-τ on Day 1 and Day 14 were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.9203, 2.1837]
Secondary
Part 2: Fraction of S-648414 Dose Excreted in Urine Over the Dosing Interval (Feu0- τ) Following Multiple-dose Administration
Fraction of dose excreted in urine over the dosing interval τ (24 hours) on Day 14 calculated as Aeu0-τ/Dose × 100, where Aeu0-τ is the amount of drug excreted in urine over the dosing interval τ (24 hours).
Time frame: Day 14 0-24 hours postdose
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Fraction of S-648414 Dose Excreted in Urine Over the Dosing Interval (Feu0- τ) Following Multiple-dose Administration | 33.3 percent excreted | Geometric Coefficient of Variation 15.7 |
| Part 1: Placebo - Fed | Part 2: Fraction of S-648414 Dose Excreted in Urine Over the Dosing Interval (Feu0- τ) Following Multiple-dose Administration | 35.0 percent excreted | Geometric Coefficient of Variation 25.6 |
Secondary
Part 2: Maximum Plasma Concentration (Cmax) of Midazolam
The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).
Time frame: Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Maximum Plasma Concentration (Cmax) of Midazolam | 18.0 ng/mL | Geometric Coefficient of Variation 33.6 |
| Part 1: Placebo - Fed | Part 2: Maximum Plasma Concentration (Cmax) of Midazolam | 16.8 ng/mL | Geometric Coefficient of Variation 25.6 |
| Part 1: 10 mg S-648414 | Part 2: Maximum Plasma Concentration (Cmax) of Midazolam | 19.5 ng/mL | Geometric Coefficient of Variation 30.6 |
| Part 1: 30 mg S-648414 | Part 2: Maximum Plasma Concentration (Cmax) of Midazolam | 19.3 ng/mL | Geometric Coefficient of Variation 33.2 |
Comparison: The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed Cmax as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cmax of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.90% CI: [0.8057, 1.06]
Comparison: The effect of S-648414 on the PK of midazolam (a CYP3A substrate) was assessed using an ANOVA fitted with a linear mixed effect model with ln-transformed Cmax as the dependent variable, treatment as a fixed effect, and participant as a random effect. The difference and 90% CI between the ln-transformed Cmax of midazolam plus S-648414 and midazolam alone was estimated then back-transformed to obtain the corresponding geometric least squares mean ratios and 90% CIs.90% CI: [0.9299, 1.1415]
Secondary
Part 2: Maximum Plasma Concentration (Cmax) of S-648414 Following Single and Multiple-dose Administration
Time frame: Day 1 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose; Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose.
Population: The PK parameter population with available data at each time point
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Maximum Plasma Concentration (Cmax) of S-648414 Following Single and Multiple-dose Administration | Day 1 | 411 ng/mL | Geometric Coefficient of Variation 22.3 |
| Part 1: Placebo - Fasted | Part 2: Maximum Plasma Concentration (Cmax) of S-648414 Following Single and Multiple-dose Administration | Day 14 | 719 ng/mL | Geometric Coefficient of Variation 13.2 |
| Part 1: Placebo - Fed | Part 2: Maximum Plasma Concentration (Cmax) of S-648414 Following Single and Multiple-dose Administration | Day 1 | 623 ng/mL | Geometric Coefficient of Variation 19.2 |
| Part 1: Placebo - Fed | Part 2: Maximum Plasma Concentration (Cmax) of S-648414 Following Single and Multiple-dose Administration | Day 14 | 1320 ng/mL | Geometric Coefficient of Variation 20.2 |
Comparison: The dose proportionality of plasma S-648414 Cmax after a single dose of S-648414 (Day 1) was assessed using an ANOVA model fitted to the ln-transformed Cmax, with dose group fitted as a fixed factor.~The point estimates and 90% CIs were generated for the ratios of the 50 mg dose to 30 mg dose ln-transformed Cmax, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.2654, 1.818]
Comparison: The dose proportionality of plasma S-648414 Cmax after multiple doses of S-648414 (Day 14) was assessed using an ANOVA model fitted to the ln-transformed Cmax, with dose group fitted as a fixed factor.~The point estimates and 90% CIs were generated for the ratios of the 50 mg dose to 30 mg dose ln-transformed Cmax, then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.5696, 2.1506]
Comparison: The accumulation ratio of Cmax in the 30 mg dose group was calculated as the ratio of Day 14 to Day 1 using an ANOVA fitted with a linear mixed model with ln-transformed Cmax, Day as a fixed effect and participant as a random effect.~The difference and 90% CI between the ln-transformed Cmax on Day 1 and Day 14 were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.525, 2.0057]
Comparison: The accumulation ratio of Cmax in the 50 mg dose group was calculated as the ratio of Day 14 to Day 1 using an ANOVA fitted with a linear mixed model with ln-transformed Cmax, Day as a fixed effect and participant as a random effect.~The difference and 90% CI between the ln-transformed Cmax on Day 1 and Day 14 were estimated then back-transformed to obtain the corresponding geometric least squares mean ratio and 90% CI.90% CI: [1.9741, 2.3313]
Secondary
Part 2: Mean Residence Time for Midazolam
The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14). Mean residence time was calculated as MRT = AUMC0-inf/AUC0-inf where AUMC0-inf is the area under the first moment curve extrapolated to infinity.
Time frame: Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Mean Residence Time for Midazolam | 5.30 hours | Geometric Coefficient of Variation 8.6 |
| Part 1: Placebo - Fed | Part 2: Mean Residence Time for Midazolam | 4.44 hours | Geometric Coefficient of Variation 28.3 |
| Part 1: 10 mg S-648414 | Part 2: Mean Residence Time for Midazolam | 4.93 hours | Geometric Coefficient of Variation 33.8 |
| Part 1: 30 mg S-648414 | Part 2: Mean Residence Time for Midazolam | 4.40 hours | Geometric Coefficient of Variation 38 |
Secondary
Part 2: Renal Clearance (CLR) of S-648414 Following Multiple-dose Administration
Renal clearance on Day 14, calculated as CLR = Aeu0-τ/AUC0-τ, where Aeu0-τ is the amount of drug excreted in urine over the dosing interval τ (24 hours)
Time frame: Day 14 0-24 hours postdose
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Renal Clearance (CLR) of S-648414 Following Multiple-dose Administration | 0.948 L/hr | Geometric Coefficient of Variation 18.4 |
| Part 1: Placebo - Fed | Part 2: Renal Clearance (CLR) of S-648414 Following Multiple-dose Administration | 0.952 L/hr | Geometric Coefficient of Variation 18.1 |
Secondary
Part 2: Terminal Elimination Half-life for Midazolam
The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).
Time frame: Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Terminal Elimination Half-life for Midazolam | 5.07 hours | Geometric Coefficient of Variation 18.7 |
| Part 1: Placebo - Fed | Part 2: Terminal Elimination Half-life for Midazolam | 4.64 hours | Geometric Coefficient of Variation 32.4 |
| Part 1: 10 mg S-648414 | Part 2: Terminal Elimination Half-life for Midazolam | 4.41 hours | Geometric Coefficient of Variation 41.1 |
| Part 1: 30 mg S-648414 | Part 2: Terminal Elimination Half-life for Midazolam | 4.54 hours | Geometric Coefficient of Variation 39.5 |
Secondary
Part 2: Terminal Elimination Half-life (t1/2,z) of S-648414 Following Multiple-dose Administration
Terminal elimination half-life, where t1/2,z = (ln2)/λz on Day 14.
Time frame: Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Terminal Elimination Half-life (t1/2,z) of S-648414 Following Multiple-dose Administration | 21.6 hours | Geometric Coefficient of Variation 12.5 |
| Part 1: Placebo - Fed | Part 2: Terminal Elimination Half-life (t1/2,z) of S-648414 Following Multiple-dose Administration | 23.7 hours | Geometric Coefficient of Variation 11 |
Secondary
Part 2: Terminal Elimination Rate Constant for Midazolam
The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).
Time frame: Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Terminal Elimination Rate Constant for Midazolam | 0.1366 1/hour | Geometric Coefficient of Variation 18.7 |
| Part 1: Placebo - Fed | Part 2: Terminal Elimination Rate Constant for Midazolam | 0.1494 1/hour | Geometric Coefficient of Variation 32.4 |
| Part 1: 10 mg S-648414 | Part 2: Terminal Elimination Rate Constant for Midazolam | 0.1570 1/hour | Geometric Coefficient of Variation 41.1 |
| Part 1: 30 mg S-648414 | Part 2: Terminal Elimination Rate Constant for Midazolam | 0.1528 1/hour | Geometric Coefficient of Variation 39.5 |
Secondary
Part 2: Terminal Elimination Rate Constant (λz) of S-648414 Following Multiple-dose Administration
Terminal elimination rate constant, where λz is the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase on Day 14.
Time frame: Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Terminal Elimination Rate Constant (λz) of S-648414 Following Multiple-dose Administration | 0.0321 1/hours | Geometric Coefficient of Variation 12.5 |
| Part 1: Placebo - Fed | Part 2: Terminal Elimination Rate Constant (λz) of S-648414 Following Multiple-dose Administration | 0.0292 1/hours | Geometric Coefficient of Variation 11 |
Secondary
Part 2: Time to Maximum Plasma Concentration of Midazolam
The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A \[CYP3A\] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).
Time frame: Day -2 and Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose.
Population: The PK parameter population with available data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Time to Maximum Plasma Concentration of Midazolam | 0.76 hours |
| Part 1: Placebo - Fed | Part 2: Time to Maximum Plasma Concentration of Midazolam | 1.00 hours |
| Part 1: 10 mg S-648414 | Part 2: Time to Maximum Plasma Concentration of Midazolam | 0.50 hours |
| Part 1: 30 mg S-648414 | Part 2: Time to Maximum Plasma Concentration of Midazolam | 0.50 hours |
Secondary
Part 2: Time to Maximum Plasma Concentration (Tmax) of S-648414 Following Single and Multiple-dose Administration
Time frame: Day 1 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 hours postdose; Day 14 predose (0 hours), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, and 96 hours postdose.
Population: The PK parameter population with available data at each time point
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Placebo - Fasted | Part 2: Time to Maximum Plasma Concentration (Tmax) of S-648414 Following Single and Multiple-dose Administration | Day 1 | 3.02 hours |
| Part 1: Placebo - Fasted | Part 2: Time to Maximum Plasma Concentration (Tmax) of S-648414 Following Single and Multiple-dose Administration | Day 14 | 2.03 hours |
| Part 1: Placebo - Fed | Part 2: Time to Maximum Plasma Concentration (Tmax) of S-648414 Following Single and Multiple-dose Administration | Day 1 | 4.50 hours |
| Part 1: Placebo - Fed | Part 2: Time to Maximum Plasma Concentration (Tmax) of S-648414 Following Single and Multiple-dose Administration | Day 14 | 1.25 hours |
Secondary
Parts 1: Change From Baseline in Heart Rate (HR)
Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median HR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point. Baseline was defined as the average of the measured ECG values from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1. Change from Baseline in HR (ΔHR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline HR as covariate.
Time frame: Day 1: Predose at 3 time points (-45, -30 and -15 minutes), and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours postdose.
Population: The QT/QTc population with available data at each time point
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 6 hours postdose | 5.2 beats per minute | Standard Error 1.18 |
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 4 hours postdose | 0.2 beats per minute | Standard Error 1.41 |
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 24 hours postdose | 0.4 beats per minute | Standard Error 1.64 |
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 1 hour postdose | 1.5 beats per minute | Standard Error 1.16 |
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 2.5 hours postdose | 0.8 beats per minute | Standard Error 1.28 |
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 1.5 hours postdose | -0.4 beats per minute | Standard Error 1.18 |
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 0.5 hours postdose | 0.9 beats per minute | Standard Error 1.11 |
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 3 hours postdose | -0.9 beats per minute | Standard Error 1.38 |
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 12 hours postdose | 2.7 beats per minute | Standard Error 1.8 |
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 2 hours postdose | -0.5 beats per minute | Standard Error 1.3 |
| Part 1: Placebo - Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 8 hours postdose | 1.5 beats per minute | Standard Error 1.56 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 0.5 hours postdose | -0.2 beats per minute | Standard Error 1.58 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 12 hours postdose | 1.1 beats per minute | Standard Error 2.55 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 24 hours postdose | -1.7 beats per minute | Standard Error 2.33 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 2.5 hours postdose | -1.2 beats per minute | Standard Error 1.82 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 1 hour postdose | -2.7 beats per minute | Standard Error 1.64 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 4 hours postdose | -1.2 beats per minute | Standard Error 2 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 1.5 hours postdose | -3.0 beats per minute | Standard Error 1.67 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 3 hours postdose | -3.0 beats per minute | Standard Error 1.96 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 8 hours postdose | 1.7 beats per minute | Standard Error 2.21 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 2 hours postdose | -3.2 beats per minute | Standard Error 1.85 |
| Part 1: Placebo - Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 6 hours postdose | 4.6 beats per minute | Standard Error 1.68 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 6 hours postdose | 2.4 beats per minute | Standard Error 1.7 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 1.5 hours postdose | -0.3 beats per minute | Standard Error 1.69 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 8 hours postdose | 0.7 beats per minute | Standard Error 2.22 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 0.5 hours postdose | -1.4 beats per minute | Standard Error 1.6 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 12 hours postdose | 1.9 beats per minute | Standard Error 2.56 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 1 hour postdose | -1.9 beats per minute | Standard Error 1.66 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 24 hours postdose | -0.4 beats per minute | Standard Error 2.34 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 4 hours postdose | 0.7 beats per minute | Standard Error 2.02 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 2 hours postdose | -2.4 beats per minute | Standard Error 1.87 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 3 hours postdose | -1.6 beats per minute | Standard Error 1.97 |
| Part 1: 10 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 2.5 hours postdose | -3.0 beats per minute | Standard Error 1.84 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 8 hours postdose | -0.2 beats per minute | Standard Error 1.91 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 6 hours postdose | 4.2 beats per minute | Standard Error 1.45 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 24 hours postdose | -1.4 beats per minute | Standard Error 2.01 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 0.5 hours postdose | -1.1 beats per minute | Standard Error 1.36 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 1 hour postdose | -2.1 beats per minute | Standard Error 1.41 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 1.5 hours postdose | -3.0 beats per minute | Standard Error 1.44 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 12 hours postdose | 1.1 beats per minute | Standard Error 2.21 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 2.5 hours postdose | -2.2 beats per minute | Standard Error 1.57 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 2 hours postdose | -2.5 beats per minute | Standard Error 1.6 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 3 hours postdose | -2.1 beats per minute | Standard Error 1.69 |
| Part 1: 30 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 4 hours postdose | -2.8 beats per minute | Standard Error 1.73 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 2 hours postdose | -1.7 beats per minute | Standard Error 1.85 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 1.5 hours postdose | -0.5 beats per minute | Standard Error 1.67 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 12 hours postdose | 2.4 beats per minute | Standard Error 2.55 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 8 hours postdose | 1.8 beats per minute | Standard Error 2.2 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 3 hours postdose | -1.8 beats per minute | Standard Error 1.95 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 6 hours postdose | 3.7 beats per minute | Standard Error 1.67 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 2.5 hours postdose | -0.7 beats per minute | Standard Error 1.81 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 1 hour postdose | 0.4 beats per minute | Standard Error 1.64 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 0.5 hours postdose | -0.1 beats per minute | Standard Error 1.57 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 24 hours postdose | 0.8 beats per minute | Standard Error 2.33 |
| Part 1: 100 mg S-648414 Fasted | Parts 1: Change From Baseline in Heart Rate (HR) | 4 hours postdose | 0.8 beats per minute | Standard Error 2 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 24 hours postdose | 0.3 beats per minute | Standard Error 2.32 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 2.5 hours postdose | 2.7 beats per minute | Standard Error 1.81 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 0.5 hours postdose | -0.7 beats per minute | Standard Error 1.57 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 1 hour postdose | -1.0 beats per minute | Standard Error 1.63 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 1.5 hours postdose | 0.2 beats per minute | Standard Error 1.67 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 4 hours postdose | 2.1 beats per minute | Standard Error 2 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 3 hours postdose | 2.0 beats per minute | Standard Error 1.95 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 6 hours postdose | 7.3 beats per minute | Standard Error 1.67 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 8 hours postdose | 4.6 beats per minute | Standard Error 2.2 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 12 hours postdose | 9.1 beats per minute | Standard Error 2.55 |
| Part 1: 100 mg S-648414 Fed | Parts 1: Change From Baseline in Heart Rate (HR) | 2 hours postdose | 0.4 beats per minute | Standard Error 1.85 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 4 hours postdose | 3.3 beats per minute | Standard Error 2 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 2.5 hours postdose | -0.7 beats per minute | Standard Error 1.81 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 2 hours postdose | -0.3 beats per minute | Standard Error 1.84 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 1.5 hours postdose | -0.4 beats per minute | Standard Error 1.66 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 1 hour postdose | -0.8 beats per minute | Standard Error 1.63 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 3 hours postdose | -0.6 beats per minute | Standard Error 1.95 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 12 hours postdose | 3.4 beats per minute | Standard Error 2.55 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 0.5 hours postdose | -1.6 beats per minute | Standard Error 1.57 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 6 hours postdose | 7.5 beats per minute | Standard Error 1.67 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 24 hours postdose | 3.3 beats per minute | Standard Error 2.59 |
| Part 1: 250 mg S-648414 | Parts 1: Change From Baseline in Heart Rate (HR) | 8 hours postdose | 3.5 beats per minute | Standard Error 2.2 |