Dose Finding Study
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to characterize the safety and tolerability profile of escalating dose levels of ENV8058 (TAK-058) solution when administered as a single oral dose in healthy adults.
Detailed description
The drug being tested in this study is called ENV8058 (also known as TAK-058). ENV8058 is being tested to find a safe and well-tolerated dose and to assess how ENV8058 moves throughout the body. This study will look at side effects and lab results in people who took ENV8058. This study was designed as a randomized, sequential-panel, single rising dose study. The study population will consist of 6 Cohorts with 8 participants in each Cohort; with 6 participants randomized to receive a single dose of ENV8058, and 2 participants to receive placebo. Participants in each Cohort will receive a single dose of study drug after a 10-hour fast. The starting dose is 15 mg followed by administrations of 30, 45, 15, 75 and 150 mg. * ENV8058 (Tak-058): 5, 15, 30, 45, 75 or 150 mg oral solution * Placebo (dummy inactive) - this oral solution looks like the study drug but has no active ingredient This single-centre trial will be conducted in the United States. The overall time to participate in this study is up to 14 days. Participants will make 2 visits to the clinic, including one 5-day period of confinement to the clinic. All participants will be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.
Interventions
DRUGTAK-058 (ENV8058)
TAK-058 (ENV8058) oral solution
DRUGPlacebo
TAK-058 (ENV8058) placebo-matching oral solution
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures including requesting that a participant fast for any laboratory evaluations. 3. Is a healthy male or female adult who is 18 to 55 years of age inclusive at the time of informed consent and study drug dosing. 4. Weighs at least 45 kg (99 lbs) and has a body mass index (BMI) between 18.0 and 30.0 kg/m\^2, inclusive at Screening. 5. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose. 6. A female participant with no childbearing potential, defined as the participant has been surgically sterilized (hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (defined as continuous amenorrhea of at least 2 years and follicle-stimulating hormone (FSH)\>40 IU/L).
Exclusion criteria
1. Has received any investigational compound within 30 days prior to the first dose of study medication. 2. Is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 3. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease, or psychiatric disorder, or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results. 4. Has a known hypersensitivity to any component of the formulation of ENV8058 (TAK-058). 5. Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -1). 6. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. 7. Has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products table. 8. If female, the participant is of childbearing potential (e.g premenopausal, not sterilized). 9. If male, the participant intends to donate sperm during the course of this study or for 12 weeks thereafter. 10. Has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the participant's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking ENV8058 (TAK-058), or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to seizure disorders and cardiac arrhythmias. 11. Has previously had a seizure or convulsion (lifetime), including absence seizure and febrile convulsion. 12. Has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, any surgical intervention known to impact absorption \[eg, bariatric surgery or bowel resection\], esophageal reflux, peptic ulcer disease, erosive esophagitis, or frequent \[more than once per week\] occurrence of heartburn). 13. Has a history of cancer or other malignancy, except basal cell carcinoma that has been in remission for at least 5 years prior to Day 1. 14. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or a known history of human immunodeficiency virus infection at Screening. 15. Has used nicotine-containing products (including but not limited to cigarettes, electronic cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in (Day -1). Cotinine test is positive at Screening or Check-in (Day -1). 16. Has poor peripheral venous access. 17. Has donated or lost 450 mL or more of his or her blood volume (including plasmapheresis), or had a transfusion of any blood product within 45 days prior to Day 1. 18. Has a Screening or Check-in (Day -1) abnormal (clinically significant) electrocardiogram (ECG). Entry of any participant with an abnormal (not clinically significant) ECG must be approved and documented by signature by the principal investigator or medically qualified subinvestigator. 19. Subject had a supine blood pressure outside the ranges of 90 to 140 mm Hg for systolic and 60 to 90 mm Hg (males) and 50 to 90 mm Hg (females) for diastolic, confirmed with 1repeat testing, at the Screening Visit or Check-in (Day -1). 20. Has a resting heart rate outside the range 40 to 90 bpm, confirmed with one repeat testing, at the Screening Visit or Check-in (Day -1). 21. Has a QT interval with Fridericia's correction method (QTcF) \>430 ms (males) or \>450 ms (females) or PR outside the range of 120 to 220 ms, confirmed with one repeat testing, at the Screening Visit or Check-in (Day -1) Visit. 22. Has abnormal Screening or Check-in (Day -1) laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>1.5 the upper limits of normal. 23. Has a risk of suicide according to the Investigator's clinical judgment (eg, per Columbia-Suicide Severity Rating Scale \[CSSRS\] or has made a suicide attempt in the previous 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) | Baseline up to Day 30 | Treatment-emergent adverse events are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug. |
| Percentage of Participants With Markedly Abnormal Safety Laboratory Tests | Baseline up to Day 14 | The percentage of participants with any markedly abnormal standard safety laboratory values, including hematology, serum chemistries, and urinalysis, during the treatment period. |
| Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Baseline up to Day 14 | The percentage of participants who meet markedly abnormal criteria for vital signs, including oral body temperature, respiration rate, pulse \[beats per minute (bpm)\], and resting blood pressure and after standing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Observed Plasma Concentration for ENV8058 (TAK-058) | Predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. |
| AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for ENV8058 (TAK-058) | Predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose | (AUC(0-tlqc) is a measure of total plasma exposure to the drug from time 0 to time of the last quantifiable concentration (AUC\[0-tlqc\]). |
| AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for ENV8058 (TAK-058) | Predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose | AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity. |
| Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for ENV8058 (TAK-058) | Predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose | Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in the United States from 14 May 2014 (signing of informed consent) to 13 November 2014.
Pre-assignment details
Healthy Volunteers were enrolled in 1 of 6 Dose Cohorts: (5 mg, 15 mg, 30 mg, 45 mg, 75 mg, 150 mg TAK-058) or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 4: TAK-058 5 mg TAK-058 5 mg, 100 mL oral solution, once on Day 1. | 6 |
| Cohort 1: TAK-058 15 mg TAK-058 15 mg, 100 mL oral solution, once on Day 1. | 6 |
| Cohort 2: TAK-058 30 mg TAK-058 30 mg, 100 mL oral solution, once on Day 1. | 6 |
| Cohort 3: TAK-058 45 mg TAK-058 45 mg, 100 mL oral solution, once on Day 1. | 6 |
| Cohort 5: TAK-058 75 mg TAK-058 75 mg, 100 mL oral solution, once on Day 1. | 6 |
| Cohorts 6: TAK-058 150 mg TAK-058 150 mg, 100 mL oral solution, once on Day 1. | 6 |
| Cohort 1-6: Placebo TAK-058 placebo-matching, 100 mL oral solution, once on Day 1. | 12 |
| Total | 48 |
Baseline characteristics
| Characteristic | Cohort 1-6: Placebo | Cohorts 6: TAK-058 150 mg | Cohort 4: TAK-058 5 mg | Cohort 5: TAK-058 75 mg | Total | Cohort 3: TAK-058 45 mg | Cohort 1: TAK-058 15 mg | Cohort 2: TAK-058 30 mg |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 34.2 years STANDARD_DEVIATION 9.11 | 30.8 years STANDARD_DEVIATION 8.54 | 33.7 years STANDARD_DEVIATION 11.38 | 41.5 years STANDARD_DEVIATION 10.93 | 35.1 years STANDARD_DEVIATION 10.09 | 34.2 years STANDARD_DEVIATION 7.78 | 37.0 years STANDARD_DEVIATION 14.01 | 35.3 years STANDARD_DEVIATION 10.71 |
| Body Mass Index (BMI) | 23.42 kg/m^2 STANDARD_DEVIATION 2.533 | 25.89 kg/m^2 STANDARD_DEVIATION 2.728 | 24.79 kg/m^2 STANDARD_DEVIATION 3.11 | 26.86 kg/m^2 STANDARD_DEVIATION 1.989 | 25.40 kg/m^2 STANDARD_DEVIATION 2.77 | 27.39 kg/m^2 STANDARD_DEVIATION 2.44 | 25.11 kg/m^2 STANDARD_DEVIATION 1.674 | 26.35 kg/m^2 STANDARD_DEVIATION 3.086 |
| Caffeine Consumption No | 6 participants | 3 participants | 3 participants | 2 participants | 21 participants | 2 participants | 3 participants | 2 participants |
| Caffeine Consumption Yes | 6 participants | 3 participants | 3 participants | 4 participants | 27 participants | 4 participants | 3 participants | 4 participants |
| Female Reproductive Status Female of Childbearing Potential | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Female Reproductive Status Postmenopausal | 0 participants | 0 participants | 1 participants | 0 participants | 3 participants | 0 participants | 1 participants | 1 participants |
| Female Reproductive Status Subject is Male | 10 participants | 6 participants | 5 participants | 5 participants | 39 participants | 4 participants | 5 participants | 4 participants |
| Female Reproductive Status Surgically Sterile | 2 participants | 0 participants | 0 participants | 1 participants | 6 participants | 2 participants | 0 participants | 1 participants |
| Height | 176.1 cm STANDARD_DEVIATION 12.91 | 175.5 cm STANDARD_DEVIATION 8.69 | 171.2 cm STANDARD_DEVIATION 4.4 | 178.7 cm STANDARD_DEVIATION 8.78 | 173.8 cm STANDARD_DEVIATION 10.49 | 170.2 cm STANDARD_DEVIATION 10.42 | 167.7 cm STANDARD_DEVIATION 6.44 | 174.7 cm STANDARD_DEVIATION 15.2 |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants | 0 participants | 3 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 3 participants | 1 participants | 2 participants | 3 participants | 12 participants | 1 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 participants | 2 participants | 0 participants | 1 participants | 12 participants | 3 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Non-Hispanic or non-Latino | 10 participants | 4 participants | 6 participants | 5 participants | 36 participants | 3 participants | 3 participants | 5 participants |
| Race/Ethnicity, Customized White | 7 participants | 5 participants | 3 participants | 3 participants | 32 participants | 4 participants | 5 participants | 5 participants |
| Region of Enrollment North America | 12 participants | 6 participants | 6 participants | 6 participants | 48 participants | 6 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 9 Participants | 2 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 5 Participants | 5 Participants | 39 Participants | 4 Participants | 5 Participants | 4 Participants |
| Smoking Status Current smoker | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Smoking Status Ex-smoker | 1 participants | 1 participants | 1 participants | 1 participants | 6 participants | 0 participants | 1 participants | 1 participants |
| Smoking Status Never smoked | 11 participants | 5 participants | 5 participants | 5 participants | 42 participants | 6 participants | 5 participants | 5 participants |
| Weight | 72.77 kg STANDARD_DEVIATION 12.359 | 80.50 kg STANDARD_DEVIATION 16.471 | 72.73 kg STANDARD_DEVIATION 10.683 | 86.17 kg STANDARD_DEVIATION 12.796 | 77.09 kg STANDARD_DEVIATION 13.514 | 79.38 kg STANDARD_DEVIATION 10.86 | 70.65 kg STANDARD_DEVIATION 6.763 | 81.72 kg STANDARD_DEVIATION 20.142 |
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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 6 | 0 / 6 | 3 / 6 | 0 / 6 | 1 / 6 | 0 / 6 | 1 / 12 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 12 |
Outcome results
Primary
Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE)
Treatment-emergent adverse events are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug.
Time frame: Baseline up to Day 30
Population: Safety population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 4: TAK-058 5 mg | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) | 16.7 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) | 50.0 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) | 16.7 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) | 8.3 percentage of participants |
Primary
Percentage of Participants With Markedly Abnormal Safety Laboratory Tests
The percentage of participants with any markedly abnormal standard safety laboratory values, including hematology, serum chemistries, and urinalysis, during the treatment period.
Time frame: Baseline up to Day 14
Population: Safety population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Safety Laboratory Tests | 0 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Safety Laboratory Tests | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Safety Laboratory Tests | 0 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Safety Laboratory Tests | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Safety Laboratory Tests | 0 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Safety Laboratory Tests | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Safety Laboratory Tests | 0 percentage of participants |
Primary
Percentage of Participants With Markedly Abnormal Vital Sign Measurements
The percentage of participants who meet markedly abnormal criteria for vital signs, including oral body temperature, respiration rate, pulse \[beats per minute (bpm)\], and resting blood pressure and after standing.
Time frame: Baseline up to Day 14
Population: Safety population included all enrolled participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure >110 mmHg | 0 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure >180 mmHg | 0 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal High | 0 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse - Any Abnormality | 50.0 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse <50 bpm | 50.0 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature <35.6 degrees Celsius | 16.7 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure <85 mmHg | 16.7 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal Low | 66.7 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure <50 mmHg | 0 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature - Any Abnormality | 16.7 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure - Any Abnormality | 16.7 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse >120 bpm | 0 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure - Any Abnormality | 0 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature >37.7 degrees Celsius | 0 percentage of participants |
| Cohort 4: TAK-058 5 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Any Abnormality | 66.7 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure >110 mmHg | 0 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure - Any Abnormality | 0 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal High | 16.7 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature >37.7 degrees Celsius | 0 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Any Abnormality | 33.3 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal Low | 16.7 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature <35.6 degrees Celsius | 0 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure <85 mmHg | 0 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse - Any Abnormality | 33.3 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure >180 mmHg | 0 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature - Any Abnormality | 0 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse >120 bpm | 16.7 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure - Any Abnormality | 0 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse <50 bpm | 16.7 percentage of participants |
| Cohort 1: TAK-058 15 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure <50 mmHg | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure >180 mmHg | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure <50 mmHg | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse >120 bpm | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure >110 mmHg | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature >37.7 degrees Celsius | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal Low | 33.3 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure - Any Abnormality | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure - Any Abnormality | 33.3 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure <85 mmHg | 33.3 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature - Any Abnormality | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse - Any Abnormality | 16.7 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal High | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature <35.6 degrees Celsius | 0 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Any Abnormality | 33.3 percentage of participants |
| Cohort 2: TAK-058 30 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse <50 bpm | 16.7 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure >110 mmHg | 0 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal Low | 33.3 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal High | 0 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Any Abnormality | 33.3 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure <85 mmHg | 0 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure >180 mmHg | 0 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure - Any Abnormality | 0 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure <50 mmHg | 16.7 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure - Any Abnormality | 16.7 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse <50 bpm | 16.7 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse >120 bpm | 0 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse - Any Abnormality | 16.7 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature <35.6 degrees Celsius | 0 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature >37.7 degrees Celsius | 0 percentage of participants |
| Cohort 3: TAK-058 45 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature - Any Abnormality | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure >110 mmHg | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal High | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature <35.6 degrees Celsius | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse <50 bpm | 50.0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure <85 mmHg | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature - Any Abnormality | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse - Any Abnormality | 50.0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure <50 mmHg | 16.7 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Any Abnormality | 50.0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature >37.7 degrees Celsius | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure - Any Abnormality | 16.7 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure - Any Abnormality | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure >180 mmHg | 0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal Low | 50.0 percentage of participants |
| Cohort 5: TAK-058 75 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse >120 bpm | 0 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature - Any Abnormality | 0 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure - Any Abnormality | 0 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure - Any Abnormality | 16.7 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal Low | 16.7 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse <50 bpm | 0 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure >180 mmHg | 0 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse >120 bpm | 16.7 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure <85 mmHg | 16.7 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse - Any Abnormality | 16.7 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Any Abnormality | 33.3 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature <35.6 degrees Celsius | 0 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal High | 16.7 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature >37.7 degrees Celsius | 0 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure >110 mmHg | 0 percentage of participants |
| Cohorts 6: TAK-058 150 mg | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure <50 mmHg | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature <35.6 degrees Celsius | 25.0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal High | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure <50 mmHg | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse >120 bpm | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure >180 mmHg | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse <50 bpm | 33.3 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Abnormal Low | 50.0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature >37.7 degrees Celsius | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure - Any Abnormality | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Any Vital Sign - Any Abnormality | 50.0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure - Any Abnormality | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Pulse - Any Abnormality | 33.3 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Temperature - Any Abnormality | 25.0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Systolic Blood Pressure <85 mmHg | 0 percentage of participants |
| Cohort 1-6: Placebo | Percentage of Participants With Markedly Abnormal Vital Sign Measurements | Diastolic Blood Pressure >110 mmHg | 0 percentage of participants |
Secondary
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for ENV8058 (TAK-058)
AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Time frame: Predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose
Population: PK Population included all enrolled participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 4: TAK-058 5 mg | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for ENV8058 (TAK-058) | 620.5 ng*hr/mL | Standard Deviation 334.86 |
| Cohort 1: TAK-058 15 mg | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for ENV8058 (TAK-058) | 2305.5 ng*hr/mL | Standard Deviation 678.59 |
| Cohort 2: TAK-058 30 mg | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for ENV8058 (TAK-058) | 3252.1 ng*hr/mL | Standard Deviation 1264.03 |
| Cohort 3: TAK-058 45 mg | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for ENV8058 (TAK-058) | 5038.9 ng*hr/mL | Standard Deviation 998.48 |
| Cohort 5: TAK-058 75 mg | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for ENV8058 (TAK-058) | 6292.1 ng*hr/mL | Standard Deviation 1546.9 |
| Cohorts 6: TAK-058 150 mg | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for ENV8058 (TAK-058) | 9407.9 ng*hr/mL | Standard Deviation 3402.5 |
Secondary
AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for ENV8058 (TAK-058)
(AUC(0-tlqc) is a measure of total plasma exposure to the drug from time 0 to time of the last quantifiable concentration (AUC\[0-tlqc\]).
Time frame: Predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose
Population: PK Population included all enrolled participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 4: TAK-058 5 mg | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for ENV8058 (TAK-058) | 617.8 ng*hr/mL | Standard Deviation 334.31 |
| Cohort 1: TAK-058 15 mg | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for ENV8058 (TAK-058) | 2297.8 ng*hr/mL | Standard Deviation 678.69 |
| Cohort 2: TAK-058 30 mg | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for ENV8058 (TAK-058) | 3243.9 ng*hr/mL | Standard Deviation 1261.96 |
| Cohort 3: TAK-058 45 mg | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for ENV8058 (TAK-058) | 5027.3 ng*hr/mL | Standard Deviation 1001.82 |
| Cohort 5: TAK-058 75 mg | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for ENV8058 (TAK-058) | 6275.4 ng*hr/mL | Standard Deviation 1535.27 |
| Cohorts 6: TAK-058 150 mg | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for ENV8058 (TAK-058) | 9385.8 ng*hr/mL | Standard Deviation 3398.36 |
Secondary
Cmax: Maximum Observed Plasma Concentration for ENV8058 (TAK-058)
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time frame: Predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose
Population: Pharmacokinetic (PK) Population included all enrolled participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 4: TAK-058 5 mg | Cmax: Maximum Observed Plasma Concentration for ENV8058 (TAK-058) | 142.4 ng/mL | Standard Deviation 43.68 |
| Cohort 1: TAK-058 15 mg | Cmax: Maximum Observed Plasma Concentration for ENV8058 (TAK-058) | 565.0 ng/mL | Standard Deviation 112.07 |
| Cohort 2: TAK-058 30 mg | Cmax: Maximum Observed Plasma Concentration for ENV8058 (TAK-058) | 824.7 ng/mL | Standard Deviation 297.45 |
| Cohort 3: TAK-058 45 mg | Cmax: Maximum Observed Plasma Concentration for ENV8058 (TAK-058) | 1248.2 ng/mL | Standard Deviation 254.06 |
| Cohort 5: TAK-058 75 mg | Cmax: Maximum Observed Plasma Concentration for ENV8058 (TAK-058) | 1563.3 ng/mL | Standard Deviation 339.51 |
| Cohorts 6: TAK-058 150 mg | Cmax: Maximum Observed Plasma Concentration for ENV8058 (TAK-058) | 2136.7 ng/mL | Standard Deviation 818.04 |
Secondary
Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for ENV8058 (TAK-058)
Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Time frame: Predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose
Population: PK population included all enrolled participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 4: TAK-058 5 mg | Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for ENV8058 (TAK-058) | 2.814 hours | Standard Deviation 1.0871 |
| Cohort 1: TAK-058 15 mg | Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for ENV8058 (TAK-058) | 5.300 hours | Standard Deviation 2.2727 |
| Cohort 2: TAK-058 30 mg | Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for ENV8058 (TAK-058) | 5.925 hours | Standard Deviation 4.578 |
| Cohort 3: TAK-058 45 mg | Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for ENV8058 (TAK-058) | 9.611 hours | Standard Deviation 7.3329 |
| Cohort 5: TAK-058 75 mg | Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for ENV8058 (TAK-058) | 10.486 hours | Standard Deviation 7.1865 |
| Cohorts 6: TAK-058 150 mg | Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for ENV8058 (TAK-058) | 8.601 hours | Standard Deviation 7.9332 |