Narcolepsy Type 1 (NT1), Narcolepsy Type 2 (NT2)
Conditions
Keywords
Drug therapy
Brief summary
The main aims of the study are: * To check for side effects from TAK-994 and check what dose of TAK-994 participants can tolerate. * To check what dose range provides adequate relief of narcolepsy symptoms. * To check how much TAK-994 stays in the blood of participants, over time. The study will have 4 parts. Participants can only join 1 of the parts. A. Participants with type 1 narcolepsy will take either TAK-994 or placebo tablets for 28 days. A placebo looks just like TAK-994 but will not have any medicine in it. B. Participants with type 1 narcolepsy will take 1 of 3 doses of TAK-994 or placebo tablets for 56 days. C. Participants with type 1 narcolepsy in China only will take TAK-994 or placebo tablets for 56 days. D. Participants with type 2 narcolepsy will take either TAK-994 or placebo tablets for 28 days.
Detailed description
The drug being tested in this study is called TAK-994. TAK-994 is being tested in participants with NT1 and NT2. The study will enroll up to approximately 202 participants. The study has 4 Parts: Parts A, B, C (China only) and D. Part A - Part A has 2 cohorts \[Cohorts (A1a and A1b) A2\] In both of these Cohorts, participants will be randomly assigned (by chance, like flipping a coin) in a 2:1 ratio to receive TAK-994 or placebo up to 28 days: * Part B: In Part B, participants will be randomized in 1:1:1:1 ratio in four parallel arms to receive TAK-994 Dose 1, 2 or 3 or placebo for 56 days. Depending upon their eligibility participants completing Part B of the study treatment will be enrolled to participate in an Extension study. * Part C: In Part C, participants only from China will be enrolled and randomized in a 2:1 ratio to receive TAK-994 and placebo for 56 days. * Part D: Participants will be included in two cohorts \[Cohorts (D1a and D1b) and D2\] and will be randomized in 2:1 ratio to receive TAK-994 or placebo for 28 days. The dose will be selected based on the safety and tolerability in Part A. This multi-center trial will be conducted in the United States, Japan, China, Italy, France, and European Union. The overall duration of the study is 63 days. Participants will be followed up for 7 days after the last dose of study drug.
Interventions
DRUGTAK-994
TAK-994 tablets.
DRUGPlacebo
TAK-994 placebo-matching tablets.
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 65 Years
Healthy volunteers
No
Inclusion criteria
1. Has a diagnosis of narcolepsy type 1 (NT1) (Parts A-C) or NT2 (Part D) by polysomnography (PSG)/ multiple sleep latency test (MSLT) performed within the past 10 years meeting the minimal acceptable criteria for the proper performance of the PSG/MSLT as outlined by the International Classification of Sleep Disorders, 3rd edition criteria. 2. The participant's Epworth Sleepiness Scale (ESS) score must be greater than or equal to (\>=) 10 at Day -1. 3. Must be willing to discontinue all medications used for the treatment of NT1/NT2. 4. The human leukocyte antigen (HLA) genotype: Part A: should test positive for human leukocyte antigen (HLADQB1)\* 06:02 (PARTs A-C)- (positive results for either homozygous or heterozygous alleles will be considered positive and acceptable). However, if the HLA test is negative (i.e. negative for the heterozygous allele) and the PI feels strongly that the participant has narcolepsy with cataplexy (NT1) then a discussion should be initiated between the PI and the sponsor or designee about the advisability of doing a spinal tap to determine the participant's cerebrospinal fluid (CSF) orexin-1 (OX-1) level. If the CSF result shows the orexin 1 (OX-1) concentration is either less than or equal to\<110 pg/mL, or less than one-third of mean values obtained in normal participants with the same standardized assay, then the diagnosis of NT1 is established allowing the participant to be enrolled and randomized, If the CSF OX-1 concentration is \>110 pg/mL then the participant will not be allowed to continue in the study . 5. For Parts A, B, and C, during the screening period, participant, must have \>=4 partial or complete episodes of cataplexy/week (WCR), and \>=4 partial or complete episodes of cataplexy/week during the screening period when off of anticataplexy medications, averaged over 2 weeks (14 consecutive days) minimum. WCR recording taken during following period will be considered for study eligibility: after the participant has stopped taking anticataplexy medications for at least 7 days (minimum 7-day washout) and study Day -2.
Exclusion criteria
1. Has a risk of suicide according to endorsement of Item 4 or 5 of the screening/baseline visit Columbia suicide severity rating scale (C-SSRS) or has made a suicide attempt in the previous 12 months. 2. Is an excessive (\>600 mg/day) caffeine user 1 week before to the study screening. 3. Has a history of cancer (except carcinoma in situ that has been resolved without further treatment or basal cell skin cancer); past or current epilepsy, seizure; a lifetime history of major psychiatric disorder other than depression or anxiety; a clinically significant history of head injury or head trauma; a history of cerebral ischemia, transient ischemic attack, intracranial aneurysm, or arteriovenous malformation; known coronary artery disease, a history of myocardial infarction, angina, cardiac rhythm abnormality, or heart failure; or current or recent (within 6 months) gastrointestinal disease expected to influence the absorption of drugs. Any history of Roux-en-Y gastric bypass is considered exclusionary and any other surgical intervention that may influence the absorption of drugs should be discussed and approved by the sponsor or designee before enrolling the participants. 4. Has a medical disorder, other than narcolepsy, associated with EDS. This includes clinically significant moderate to severe obstructive sleep apnea and/or with or without treatment with mandibular advanced device hypoglossal nerve stimulation and/or positive airway pressure (PAP) therapy) and/or restless legs syndrome (RLS)/periodic limb movement disorder that has a significant impact on daytime sleepiness. This is evidenced by a clinical history of sleep apnea syndrome (loud snoring with observed respiratory pauses in the absence of nPSG) and/or RLS causing historical sleep onset/maintenance insomnia with resultant insufficient sleep. Or any as evaluated during the clinical interview at screening. pPast PSG data demonstrating any of the following sleep disturbances: apnea Hypopnea Index ≥15 or apnea index ≥10, an oxygen saturation of \<80 for \>10 seconds, periodic leg movement arousal index of ≥15/h) or as evaluated on interview at the time of screening. Asshould be considered exclusionary unless, based on a clinical evaluation by the investigator, a meaningful change in clinical status has occurred that would impact the results. Because nPSG data is obtained on Day -2, subjects may fail screening if criteria are not meet on the Day -2 nPSG. 5. Has a usual bedtime later than 2400 (12:00 AM, midnight) or an occupation requiring nighttime shift work or variable shift work within the past 6 months or travel within more than 3 time zones, within 14 days before Study Day -2. 6. Has a nicotine dependence that is likely to have an effect on sleep (e.g., a participant who routinely awakens at night to smoke) and/or an unwillingness to discontinue all smoking and nicotine use during the confinement portions of the study. Participants undergoing optional CSF collection. 7. Has a local infection at the puncture site. 8. Has developed signs of lumbar radiculopathy, including lower extremity pain and paresthesia. 9. Has any known focal neurological deficit that might suggest an increase in intracranial pressure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) During the Study | First dose of study treatment to end of study follow-up (up to Day 35) in Part A | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an AE with an onset that occurs after receiving study drug. |
| Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | First dose of study treatment to end of study follow-up (up to Day 35) in Part A | Standard safety laboratory values (hematology, serum chemistry, urinalysis) were collected and compared to pre-specified criteria for markedly abnormal values. Markedly abnormal values criteria: Erythrocytes(10\^12/L:\<0.8xlower limit of normal(LLN), \>1.2xupper limit of normal(ULN); Hemoglobin grams per litre(g/L):\<0.8xLLN, \>1.2xULN; Hematocrit voltage/volts(V/V):\<0.8xLLN, \>1.2xULN; Platelets(10\^9/L):\<75, \>600; Leukocytes(10\^9/L):\<0.5xLLN, \>1.5xULN; Alanine Aminotransferase units/litre(U/L):\>3xULN, Aspartate Aminotransferase(U/L):\>3xULN; Bilirubin micromoles/litre (umol/L):\>1.5xULN; Alkaline Phosphatase(U/L):\>3xULN; Gamma Glutamyl Transferase(U/L):\>3 x ULN; Albumin(g/L):\<25; Protein Total(g/L):\<0.8xLLN, \>1.2xULN;Glucose millimoles/litre(mmol/L):\<2.8, \>19.4; Calcium(mmol/L):\<1.92, \>2.77; Creatinine(umol/L):\>1.5xULN; Urea(mmol/L):\>10.7; Sodium(mmol/L):\<130, \>150; Potassium(mmol/L):\<3.0, \>5.3. Only categories with at least one participant with event are reported. |
| Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | First dose of study treatment to end of study follow-up (up to Day 35) in Part A | Vital signs (body temperature and sitting blood pressure) were collected and compared to pre-specified criteria for markedly abnormal values throughout the study. Markedly abnormal values criteria: Heart Rate (beats/min): \<40, \>115; Systolic Blood Pressure millimeters of mercury (mmHg): \<90, ≥160, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Diastolic Blood Pressure (mmHg): \<50, ≥100, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Respiratory Rate (breaths/min): \>21; Temperature Celsius (C): \>38.5. Only categories with at least one participant with event are reported. |
| Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study | First dose of study treatment to end of study follow-up (up to Day 35) in Part A | A 12 lead ECG was performed, the ECG values were compared to pre-specified criteria for markedly abnormal values. Markedly abnormal values criteria: ECG Mean Heart Rate (beats/min): \<40, \>115; PR Interval milliseconds (msec): ≤80, ≥200; corrected QT interval by Fredericia (QTcF) Interval (msec): ≤300, \>500, ≥30 change from baseline and \>450; QRS Duration (msec): ≤80, ≥180. Only categories with at least one participant with event are reported. |
| Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the Maintenance of Wakefulness Test (MWT) | Baseline and Week 8 (Day 56) in Parts B and C | MWT: validated, objective measure that evaluates person's ability to remain awake under soporific conditions for defined period. During each MWT session (1 session=40 minutes), participants were instructed to sit quietly and remain awake for as long as possible. Sleep latency in each session was recorded on electroencephalography (EEG). If no sleep had been observed according to these rules, then latency= 40 minutes. Mixed-effect model for repeated measures (MMRM) was used for analysis. Due to early termination of the study, no post-baseline efficacy data for this outcome measure was collected and analyzed for participants in Part C: TAK-994 180 mg. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: AUC(0-t): Area Under the Concentration-time Curve From Time 0 to Time Tau Over a Dosing Interval of TAK-994 at Day 28 | Pre-dose and at multiple time points (Up to 12 hours) post-dose at Day 28 in Part A | — |
| Parts B and C: Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 8 | Baseline and Week 8 (Day 56) in Parts B and C | The ESS is a subjective, self-administered, validated scale (scored 0 to 3) to respond to each of the 8 questions of daily life that asks participants how likely they are to fall asleep in those situations. The scores are summed to give an overall score of 0 to 24. Higher scores indicate stronger subjective daytime sleepiness, and scores below 10 are considered to be within the normal range. MMRM was used for analysis. Due to early termination of the study, no post-baseline secondary efficacy data for this outcome measure was collected and analyzed for participants in Part C: TAK-994 180 mg. |
| Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) at Week 8 | Baseline and Week 8 (Day 56) in Parts B and C | Participants will complete a daily patient-reported sleep diary to record self-reported narcolepsy symptoms. Participants will record episodes of cataplexy in the diary. The total number of events averaged for a week will be reported. WCR = (Total number of cataplexy over a number of non-missing diary days for a given duration/number of Non-missing diary days in that duration)\*7. MMRM was used for the analysis. Due to early termination of the study, no secondary efficacy data was collected and analyzed for participants in Part C: TAK-994 180 mg. |
| Part A: Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 at Day 1 | Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 1 in Part A | — |
| Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Up to Day 63 in Parts B and C | Standard safety laboratory values (serum chemistry, hematology, and urine analysis) were collected and compared to pre-specified criteria for Markedly Abnormal Values throughout the study. Markedly abnormal values criteria: Alanine Aminotransferase (U/L):\>3xULN, Aspartate Aminotransferase(U/L):\>3xULN; Bilirubin micromoles/litre (umol/L):\>1.5xULN; Calcium(mmol/L):\<1.92, \>2.77; Potassium(mmol/L):\<3.0, \>5.3. Only categories with at least one participant with event are reported. |
| Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Up to Day 63 in Parts B and C | Vital signs (body temperature and sitting blood pressure) were collected and compared to pre-specified criteria for markedly abnormal values throughout the study. Markedly abnormal values criteria: Systolic Blood Pressure millimeters of mercury (mmHg): \<90, ≥160, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Diastolic Blood Pressure (mmHg): \<50, ≥100, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Respiratory Rate (breaths/min): \>21.Only categories with at least one participant with event are reported. |
| Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | Up to Day 63 in Parts B and C | A 12 lead ECG was performed, the ECG values were compared to pre-specified criteria for markedly abnormal values. Markedly abnormal values criteria: PR Interval (msec): ≤80, ≥200; QRS Duration (msec): ≤80, ≥180. Only categories with at least one participant with event are reported. |
| Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study | First dose of study drug to end of study follow-up (up to Day 63) in Parts B and C | An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an AE with an onset that occurs after receiving study drug. |
| Part A: Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 at Day 1 | Pre-dose and at multiple time points (Up to 14 hours) post-dose at Day 1 in Part A | — |
| Part A: AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration After Single Dose of TAK-994 at Day 1 | Pre-dose and at multiple time points (up to 24 hours) post-dose at Day 1 in Part A | — |
| Part A: Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 at Day 28 | Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 28 in Part A | — |
| Part A: Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 at Day 28 | Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 28 in Part A | — |
Countries
Canada, China, Czechia, Finland, France, Hungary, Italy, Japan, Netherlands, South Korea, Spain, United States
Participant flow
Recruitment details
Participants took part in the study at 35 investigative sites in Canada, China, France, Hungary, Italy, Japan, South Korea, Spain and United States from 27 May 2020 to 05 November 2021. The study was early terminated due to a safety signal that had emerged in the phase 2 studies of firazorexton.
Pre-assignment details
Participants with Narcolepsy Type 1 or Type 2 were planned to be enrolled in study in Parts A, B, C and D to receive TAK-994 or placebo. Due to the early termination of the study, data was not collected for Part C: placebo and was insufficient for Part C: TAK-994 180 mg to allow the pre-planned analyses. Similarly, for Part D, the prespecified sample size at Week 4 was not reached and therefore the pre-planned analyses cannot be adequately interpreted.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Placebo TAK-994 placebo-matching tablets, orally, BID for 28 days, in participants with NT1. | 7 |
| Part A: TAK-994 120 mg TAK-994 120 mg, orally, BID for 28 days, in participants with NT1. | 7 |
| Part A: TAK-994 180 mg TAK-994 120 mg, orally, BID for 28 days, in participants with NT1 | 8 |
| Part B: Placebo TAK-994 placebo-matching tablets, orally, BID for 56 days, in participants with NT1. | 17 |
| Part B: TAK-994 30 mg TAK-994 30 mg tablets, orally, BID for 56 days, in participants with NT1. | 17 |
| Part B: TAK-994 90 mg TAK-994 90 mg tablets, orally, BID for 56 days, in participants with NT1. | 20 |
| Part B: TAK-994 180 mg TAK-994 180 mg tablets, orally, BID for 56 days, in participants with NT1. | 19 |
| Part C: TAK-994 180 mg TAK-994 180 mg tablets, orally, BID for 56 days, in Chinese participants with NT1. | 2 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Met the Discontinuation Criteria of the Protocol | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Pretreatment Event, Serious Adverse Event, or Adverse Event | 0 | 0 | 0 | 0 | 0 | 3 | 3 | 0 |
| Overall Study | Reason not Specified | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 0 | 5 | 6 | 4 | 6 | 1 |
Baseline characteristics
| Characteristic | Total | Part A: TAK-994 180 mg | Part B: Placebo | Part B: TAK-994 30 mg | Part A: Placebo | Part B: TAK-994 90 mg | Part B: TAK-994 180 mg | Part A: TAK-994 120 mg | Part C: TAK-994 180 mg |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 33.16 years | 33.4 years | 32.6 years | 33.4 years | 31.4 years | 28.8 years | 29.2 years | 38.0 years | 38.5 years |
| Average Sleep Latency (MWT) | 6.43 minutes | 2.75 minutes | 6.0 minutes | 6.1 minutes | 3.30 minutes | 6.1 minutes | 4.9 minutes | 4.41 minutes | 17.87 minutes |
| Body Mass Index (BMI) | 27.37 kilogram per square meter (kg/m^2) | 27.575 kilogram per square meter (kg/m^2) | 27.48 kilogram per square meter (kg/m^2) | 26.56 kilogram per square meter (kg/m^2) | 30.529 kilogram per square meter (kg/m^2) | 27.29 kilogram per square meter (kg/m^2) | 27.21 kilogram per square meter (kg/m^2) | 25.629 kilogram per square meter (kg/m^2) | 26.75 kilogram per square meter (kg/m^2) |
| Epworth Sleepiness Scale (ESS) Score | 18 score on a scale | 18.0 score on a scale | 16.6 score on a scale | 18.5 score on a scale | 18.6 score on a scale | 17.5 score on a scale | 17.4 score on a scale | 17.4 score on a scale | 20 score on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 92 Participants | 8 Participants | 17 Participants | 14 Participants | 7 Participants | 19 Participants | 18 Participants | 7 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Height | 169.12 centimeters (cm) | 164.01 centimeters (cm) | 171.00 centimeters (cm) | 164.24 centimeters (cm) | 168.07 centimeters (cm) | 168.38 centimeters (cm) | 171.66 centimeters (cm) | 176.61 centimeters (cm) | 169 centimeters (cm) |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 24 Participants | 4 Participants | 1 Participants | 6 Participants | 2 Participants | 6 Participants | 3 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 4 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 52 Participants | 3 Participants | 11 Participants | 7 Participants | 5 Participants | 8 Participants | 15 Participants | 3 Participants | 0 Participants |
| Sex: Female, Male Female | 54 Participants | 5 Participants | 8 Participants | 12 Participants | 4 Participants | 10 Participants | 12 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 43 Participants | 3 Participants | 9 Participants | 5 Participants | 3 Participants | 10 Participants | 7 Participants | 5 Participants | 1 Participants |
| Weekly Cataplexy Rate (WCR) | 13.62 cataplexy attacks per week | 12.0 cataplexy attacks per week | 15.94 cataplexy attacks per week | 14.98 cataplexy attacks per week | 19.9 cataplexy attacks per week | 11.68 cataplexy attacks per week | 15.37 cataplexy attacks per week | 19.1 cataplexy attacks per week | — |
| Weight | 78.48 kilograms (kg) | 74.33 kilograms (kg) | 80.75 kilograms (kg) | 71.97 kilograms (kg) | 85.77 kilograms (kg) | 77.68 kilograms (kg) | 80.33 kilograms (kg) | 80.07 kilograms (kg) | 77 kilograms (kg) |
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 |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 | 0 / 8 | 0 / 17 | 0 / 17 | 0 / 20 | 0 / 19 | 0 / 2 |
| other Total, other adverse events | 2 / 7 | 6 / 7 | 7 / 8 | 4 / 17 | 13 / 17 | 17 / 20 | 14 / 19 | 2 / 2 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 | 0 / 8 | 0 / 17 | 0 / 17 | 0 / 20 | 1 / 19 | 0 / 2 |
Outcome results
Primary
Part A: Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) During the Study
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an AE with an onset that occurs after receiving study drug.
Time frame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
Population: Safety Analysis Set included all participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo | Part A: Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) During the Study | 2 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) During the Study | 6 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) During the Study | 7 Participants |
Primary
Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study
A 12 lead ECG was performed, the ECG values were compared to pre-specified criteria for markedly abnormal values. Markedly abnormal values criteria: ECG Mean Heart Rate (beats/min): \<40, \>115; PR Interval milliseconds (msec): ≤80, ≥200; corrected QT interval by Fredericia (QTcF) Interval (msec): ≤300, \>500, ≥30 change from baseline and \>450; QRS Duration (msec): ≤80, ≥180. Only categories with at least one participant with event are reported.
Time frame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
Population: Safety Analysis Set included all participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study | QTcF Interval (msec): ≥30 change from baseline and >450 | 1 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study | PR Interval (msec): ≥200 | 0 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study | QRS Duration (msec): ≤80 | 4 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study | QTcF Interval (msec): ≥30 change from baseline and >450 | 0 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study | PR Interval (msec): ≥200 | 1 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study | QRS Duration (msec): ≤80 | 0 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study | PR Interval (msec): ≥200 | 2 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study | QRS Duration (msec): ≤80 | 5 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study | QTcF Interval (msec): ≥30 change from baseline and >450 | 0 Participants |
Primary
Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study
Standard safety laboratory values (hematology, serum chemistry, urinalysis) were collected and compared to pre-specified criteria for markedly abnormal values. Markedly abnormal values criteria: Erythrocytes(10\^12/L:\<0.8xlower limit of normal(LLN), \>1.2xupper limit of normal(ULN); Hemoglobin grams per litre(g/L):\<0.8xLLN, \>1.2xULN; Hematocrit voltage/volts(V/V):\<0.8xLLN, \>1.2xULN; Platelets(10\^9/L):\<75, \>600; Leukocytes(10\^9/L):\<0.5xLLN, \>1.5xULN; Alanine Aminotransferase units/litre(U/L):\>3xULN, Aspartate Aminotransferase(U/L):\>3xULN; Bilirubin micromoles/litre (umol/L):\>1.5xULN; Alkaline Phosphatase(U/L):\>3xULN; Gamma Glutamyl Transferase(U/L):\>3 x ULN; Albumin(g/L):\<25; Protein Total(g/L):\<0.8xLLN, \>1.2xULN;Glucose millimoles/litre(mmol/L):\<2.8, \>19.4; Calcium(mmol/L):\<1.92, \>2.77; Creatinine(umol/L):\>1.5xULN; Urea(mmol/L):\>10.7; Sodium(mmol/L):\<130, \>150; Potassium(mmol/L):\<3.0, \>5.3. Only categories with at least one participant with event are reported.
Time frame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
Population: Safety Analysis Set included all participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Sodium (mmol/L): <130 | 0 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Calcium (mmol/L): <1.92 | 0 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): >5.3 | 1 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Sodium (mmol/L): <130 | 1 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Calcium (mmol/L): <1.92 | 1 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): >5.3 | 0 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Calcium (mmol/L): <1.92 | 0 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): >5.3 | 0 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Sodium (mmol/L): <130 | 0 Participants |
Primary
Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study
Vital signs (body temperature and sitting blood pressure) were collected and compared to pre-specified criteria for markedly abnormal values throughout the study. Markedly abnormal values criteria: Heart Rate (beats/min): \<40, \>115; Systolic Blood Pressure millimeters of mercury (mmHg): \<90, ≥160, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Diastolic Blood Pressure (mmHg): \<50, ≥100, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Respiratory Rate (breaths/min): \>21; Temperature Celsius (C): \>38.5. Only categories with at least one participant with event are reported.
Time frame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
Population: Safety Analysis Set included all participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg) <90 | 2 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Change from Pre-Dose >20 | 2 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Change from Pre-Dose >30 | 1 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Time-matched Change from Baseline > 20 | 4 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Time-matched Change from Baseline > 30 | 0 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Pre-Dose >20 | 1 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline > 20 | 1 Participants |
| Part A: Placebo | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Temperature (C): >38.5 | 0 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Change from Pre-Dose >30 | 1 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline > 20 | 4 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Time-matched Change from Baseline > 20 | 7 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Time-matched Change from Baseline > 30 | 3 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Pre-Dose >20 | 3 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg) <90 | 0 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Change from Pre-Dose >20 | 3 Participants |
| Part A: TAK-994 120 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Temperature (C): >38.5 | 1 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Change from Pre-Dose >30 | 0 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Change from Pre-Dose >20 | 2 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg) <90 | 0 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Time-matched Change from Baseline > 20 | 6 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline > 20 | 3 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Pre-Dose >20 | 0 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic Blood Pressure (mmHg): Time-matched Change from Baseline > 30 | 0 Participants |
| Part A: TAK-994 180 mg | Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Temperature (C): >38.5 | 0 Participants |
Primary
Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the Maintenance of Wakefulness Test (MWT)
MWT: validated, objective measure that evaluates person's ability to remain awake under soporific conditions for defined period. During each MWT session (1 session=40 minutes), participants were instructed to sit quietly and remain awake for as long as possible. Sleep latency in each session was recorded on electroencephalography (EEG). If no sleep had been observed according to these rules, then latency= 40 minutes. Mixed-effect model for repeated measures (MMRM) was used for analysis. Due to early termination of the study, no post-baseline efficacy data for this outcome measure was collected and analyzed for participants in Part C: TAK-994 180 mg.
Time frame: Baseline and Week 8 (Day 56) in Parts B and C
Population: Full Analysis Set included participants who received at least 1 dose of study drug, had baseline measure and at least 1 evaluable post-dose value. Overall number of participants analyzed is the number of participants available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the Maintenance of Wakefulness Test (MWT) | -2.5 minutes (min) | Standard Error 2.19 |
| Part A: TAK-994 120 mg | Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the Maintenance of Wakefulness Test (MWT) | 23.9 minutes (min) | Standard Error 2.27 |
| Part A: TAK-994 180 mg | Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the Maintenance of Wakefulness Test (MWT) | 27.4 minutes (min) | Standard Error 2.17 |
| Part B: TAK-994 180 mg | Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the Maintenance of Wakefulness Test (MWT) | 32.6 minutes (min) | Standard Error 2.25 |
p-value: <0.00195% CI: [20.07, 32.73]MMRM
p-value: <0.00195% CI: [23.68, 36.07]MMRM
p-value: <0.00195% CI: [28.73, 41.34]MMRM
Secondary
Part A: AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration After Single Dose of TAK-994 at Day 1
Time frame: Pre-dose and at multiple time points (up to 24 hours) post-dose at Day 1 in Part A
Population: PK Analysis Set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration After Single Dose of TAK-994 at Day 1 | 3700 nanograms*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 63 |
| Part A: TAK-994 120 mg | Part A: AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration After Single Dose of TAK-994 at Day 1 | 8559 nanograms*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 26.7 |
Secondary
Part A: AUC(0-t): Area Under the Concentration-time Curve From Time 0 to Time Tau Over a Dosing Interval of TAK-994 at Day 28
Time frame: Pre-dose and at multiple time points (Up to 12 hours) post-dose at Day 28 in Part A
Population: PK Analysis Set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: AUC(0-t): Area Under the Concentration-time Curve From Time 0 to Time Tau Over a Dosing Interval of TAK-994 at Day 28 | 2968 ng*h/mL | Geometric Coefficient of Variation 33.1 |
| Part A: TAK-994 120 mg | Part A: AUC(0-t): Area Under the Concentration-time Curve From Time 0 to Time Tau Over a Dosing Interval of TAK-994 at Day 28 | 6438 ng*h/mL | Geometric Coefficient of Variation 22.6 |
Secondary
Part A: Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 at Day 28
Time frame: Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 28 in Part A
Population: PK Analysis Set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part A: Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 at Day 28 | Cmax (ng/mL); Following First (AM) Dose at Day 28 | 377.5 ng/mL | Geometric Coefficient of Variation 36.6 |
| Part A: Placebo | Part A: Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 at Day 28 | Cmax (ng/mL); Following Second (PM) Dose at Day 28 | 416.0 ng/mL | Geometric Coefficient of Variation 40.9 |
| Part A: TAK-994 120 mg | Part A: Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 at Day 28 | Cmax (ng/mL); Following First (AM) Dose at Day 28 | 856.9 ng/mL | Geometric Coefficient of Variation 31.6 |
| Part A: TAK-994 120 mg | Part A: Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 at Day 28 | Cmax (ng/mL); Following Second (PM) Dose at Day 28 | 829.4 ng/mL | Geometric Coefficient of Variation 28.4 |
Secondary
Part A: Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 at Day 1
Time frame: Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 1 in Part A
Population: Pharmacokinetic (PK) Analysis Set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration. Overall number of participants analyzed is the number of participants available for analyses.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part A: Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 at Day 1 | Cmax (ng/mL); Following First (AM) Dose at Day 1 | 305.5 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 68.3 |
| Part A: Placebo | Part A: Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 at Day 1 | Cmax (ng/mL); Following Second (PM) Dose at Day 1 | 437.1 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 46.9 |
| Part A: TAK-994 120 mg | Part A: Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 at Day 1 | Cmax (ng/mL); Following First (AM) Dose at Day 1 | 679.1 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 24.5 |
| Part A: TAK-994 120 mg | Part A: Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 at Day 1 | Cmax (ng/mL); Following Second (PM) Dose at Day 1 | 1127 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 26.4 |
Secondary
Part A: Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 at Day 28
Time frame: Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 28 in Part A
Population: PK Analysis Set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Placebo | Part A: Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 at Day 28 | Tmax (h): Following First (AM) Dose at Day 28 | 1.03 hours (h) |
| Part A: Placebo | Part A: Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 at Day 28 | Tmax (h): Following Second (PM) Dose at Day 28 | 2.15 hours (h) |
| Part A: TAK-994 120 mg | Part A: Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 at Day 28 | Tmax (h): Following First (AM) Dose at Day 28 | 1.00 hours (h) |
| Part A: TAK-994 120 mg | Part A: Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 at Day 28 | Tmax (h): Following Second (PM) Dose at Day 28 | 3.46 hours (h) |
Secondary
Part A: Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 at Day 1
Time frame: Pre-dose and at multiple time points (Up to 14 hours) post-dose at Day 1 in Part A
Population: PK Analysis Set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration. Overall number of participants analyzed is the number of participants available for analyses.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Placebo | Part A: Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 at Day 1 | Tmax (h): Following First (AM) Dose at Day 1 | 1.19 hours (h) |
| Part A: Placebo | Part A: Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 at Day 1 | Tmax (h): Following Second (PM) Dose at Day 1 | 2.04 hours (h) |
| Part A: TAK-994 120 mg | Part A: Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 at Day 1 | Tmax (h): Following First (AM) Dose at Day 1 | 1.00 hours (h) |
| Part A: TAK-994 120 mg | Part A: Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 at Day 1 | Tmax (h): Following Second (PM) Dose at Day 1 | 1.75 hours (h) |
Secondary
Parts B and C: Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 8
The ESS is a subjective, self-administered, validated scale (scored 0 to 3) to respond to each of the 8 questions of daily life that asks participants how likely they are to fall asleep in those situations. The scores are summed to give an overall score of 0 to 24. Higher scores indicate stronger subjective daytime sleepiness, and scores below 10 are considered to be within the normal range. MMRM was used for analysis. Due to early termination of the study, no post-baseline secondary efficacy data for this outcome measure was collected and analyzed for participants in Part C: TAK-994 180 mg.
Time frame: Baseline and Week 8 (Day 56) in Parts B and C
Population: Full Analysis Set included participants who received at least 1 dose of study drug, had baseline measure and at least 1 evaluable post-dose value. Overall number of participants analyzed is the number of participants available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Parts B and C: Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 8 | -2.1 score on a scale | Standard Error 1.35 |
| Part A: TAK-994 120 mg | Parts B and C: Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 8 | -12.2 score on a scale | Standard Error 1.41 |
| Part A: TAK-994 180 mg | Parts B and C: Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 8 | -13.5 score on a scale | Standard Error 1.32 |
| Part B: TAK-994 180 mg | Parts B and C: Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 8 | -15.1 score on a scale | Standard Error 1.41 |
p-value: <0.00195% CI: [-14.07, -6.16]MMRM
p-value: <0.00195% CI: [-15.2, -7.56]MMRM
p-value: <0.00195% CI: [-16.96, -9.09]MMRM
Secondary
Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) at Week 8
Participants will complete a daily patient-reported sleep diary to record self-reported narcolepsy symptoms. Participants will record episodes of cataplexy in the diary. The total number of events averaged for a week will be reported. WCR = (Total number of cataplexy over a number of non-missing diary days for a given duration/number of Non-missing diary days in that duration)\*7. MMRM was used for the analysis. Due to early termination of the study, no secondary efficacy data was collected and analyzed for participants in Part C: TAK-994 180 mg.
Time frame: Baseline and Week 8 (Day 56) in Parts B and C
Population: Full Analysis Set included participants who received at least 1 dose of study drug, had baseline measure and at least 1 evaluable post-dose value. Overall number of participants analyzed is the number of participants available for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) at Week 8 | -6.58 cataplexy attacks per week | Standard Deviation 7.433 |
| Part A: TAK-994 120 mg | Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) at Week 8 | -16.17 cataplexy attacks per week | Standard Deviation 20.979 |
| Part A: TAK-994 180 mg | Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) at Week 8 | -11.91 cataplexy attacks per week | Standard Deviation 10.174 |
| Part B: TAK-994 180 mg | Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) at Week 8 | -15.74 cataplexy attacks per week | Standard Deviation 9.978 |
p-value: =0.00295% CI: [0.007, 0.317]MMRM
p-value: =0.01995% CI: [0.05, 0.767]MMRM
p-value: =0.00195% CI: [0.047, 0.482]MMRM
Secondary
Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an AE with an onset that occurs after receiving study drug.
Time frame: First dose of study drug to end of study follow-up (up to Day 63) in Parts B and C
Population: Safety Analysis Set included all participants who were randomized and received at least 1 dose of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Placebo | Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study | 4 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study | 13 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study | 17 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study | 14 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study | 2 Participants |
Secondary
Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study
A 12 lead ECG was performed, the ECG values were compared to pre-specified criteria for markedly abnormal values. Markedly abnormal values criteria: PR Interval (msec): ≤80, ≥200; QRS Duration (msec): ≤80, ≥180. Only categories with at least one participant with event are reported.
Time frame: Up to Day 63 in Parts B and C
Population: Safety Analysis Set included all participants who were randomized and received at least 1 dose of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | PR Interval (msec): >=200 | 2 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | QRS Duration (msec):<=80 | 4 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | PR Interval (msec): >=200 | 2 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | QRS Duration (msec):<=80 | 3 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | PR Interval (msec): >=200 | 1 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | QRS Duration (msec):<=80 | 7 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | QRS Duration (msec):<=80 | 4 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | PR Interval (msec): >=200 | 3 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | PR Interval (msec): >=200 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study | QRS Duration (msec):<=80 | 0 Participants |
Secondary
Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study
Standard safety laboratory values (serum chemistry, hematology, and urine analysis) were collected and compared to pre-specified criteria for Markedly Abnormal Values throughout the study. Markedly abnormal values criteria: Alanine Aminotransferase (U/L):\>3xULN, Aspartate Aminotransferase(U/L):\>3xULN; Bilirubin micromoles/litre (umol/L):\>1.5xULN; Calcium(mmol/L):\<1.92, \>2.77; Potassium(mmol/L):\<3.0, \>5.3. Only categories with at least one participant with event are reported.
Time frame: Up to Day 63 in Parts B and C
Population: Safety Analysis Set included all participants who were randomized and received at least 1 dose of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Alanine Aminotransferase (ALT) [U/L)]: >3 × Upper limit normal (ULN) | 0 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Aspartate Aminotransferase (AST) [(U/L)]: >3 × ULN | 0 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Bilirubin (µmol/L): >1.5 × ULN | 0 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Calcium (mmol/L): <1.92 | 1 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): <3.0 | 1 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): >5.3 | 1 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): <3.0 | 0 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): >5.3 | 1 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Alanine Aminotransferase (ALT) [U/L)]: >3 × Upper limit normal (ULN) | 0 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Bilirubin (µmol/L): >1.5 × ULN | 0 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Calcium (mmol/L): <1.92 | 0 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Aspartate Aminotransferase (AST) [(U/L)]: >3 × ULN | 0 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Calcium (mmol/L): <1.92 | 0 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): <3.0 | 0 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Alanine Aminotransferase (ALT) [U/L)]: >3 × Upper limit normal (ULN) | 3 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Bilirubin (µmol/L): >1.5 × ULN | 0 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Aspartate Aminotransferase (AST) [(U/L)]: >3 × ULN | 1 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): >5.3 | 0 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Calcium (mmol/L): <1.92 | 0 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Aspartate Aminotransferase (AST) [(U/L)]: >3 × ULN | 2 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Bilirubin (µmol/L): >1.5 × ULN | 1 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): >5.3 | 0 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): <3.0 | 0 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Alanine Aminotransferase (ALT) [U/L)]: >3 × Upper limit normal (ULN) | 2 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): <3.0 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Bilirubin (µmol/L): >1.5 × ULN | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Aspartate Aminotransferase (AST) [(U/L)]: >3 × ULN | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Potassium (mmol/L): >5.3 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Calcium (mmol/L): <1.92 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study | Alanine Aminotransferase (ALT) [U/L)]: >3 × Upper limit normal (ULN) | 0 Participants |
Secondary
Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study
Vital signs (body temperature and sitting blood pressure) were collected and compared to pre-specified criteria for markedly abnormal values throughout the study. Markedly abnormal values criteria: Systolic Blood Pressure millimeters of mercury (mmHg): \<90, ≥160, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Diastolic Blood Pressure (mmHg): \<50, ≥100, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Respiratory Rate (breaths/min): \>21.Only categories with at least one participant with event are reported.
Time frame: Up to Day 63 in Parts B and C
Population: Safety Analysis Set included all participants who were randomized and received at least 1 dose of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline >30 | 0 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): <50 | 0 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Time-matched Change from Baseline >20 | 2 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline >20 | 2 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Time-matched Change from Baseline >30 | 1 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): <90 | 2 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Predose >30 | 0 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg):>=160 | 1 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Respiratory Rate [Breaths per minute (breaths/min)]: >21 | 0 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Predose >20 | 0 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Change from Predose >20 | 5 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): >=100 | 1 Participants |
| Part A: Placebo | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Change from Predose >30 | 2 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Change from Predose >30 | 2 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): <50 | 1 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Change from Predose >20 | 7 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg):>=160 | 0 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Time-matched Change from Baseline >20 | 11 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Respiratory Rate [Breaths per minute (breaths/min)]: >21 | 2 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Time-matched Change from Baseline >30 | 4 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Predose >20 | 3 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline >30 | 0 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): >=100 | 1 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): <90 | 3 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline >20 | 5 Participants |
| Part A: TAK-994 120 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Predose >30 | 0 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Predose >30 | 1 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline >30 | 1 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Respiratory Rate [Breaths per minute (breaths/min)]: >21 | 0 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): <90 | 1 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg):>=160 | 0 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Change from Predose >20 | 10 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Change from Predose >30 | 6 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Time-matched Change from Baseline >20 | 13 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Time-matched Change from Baseline >30 | 3 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): <50 | 1 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): >=100 | 2 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Predose >20 | 5 Participants |
| Part A: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline >20 | 7 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Predose >20 | 9 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Change from Predose >20 | 10 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline >20 | 7 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): <90 | 1 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): >=100 | 2 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Predose >30 | 3 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): <50 | 2 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Respiratory Rate [Breaths per minute (breaths/min)]: >21 | 1 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Change from Predose >30 | 5 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Time-matched Change from Baseline >20 | 14 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg):>=160 | 1 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Time-matched Change from Baseline >30 | 5 Participants |
| Part B: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline >30 | 2 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Time-matched Change from Baseline >30 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): <50 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Change from Predose >20 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): >=100 | 1 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg):>=160 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline >20 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Predose >20 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): <90 | 1 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Respiratory Rate [Breaths per minute (breaths/min)]: >21 | 1 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Change from Predose >30 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Time-matched Change from Baseline >20 | 1 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Diastolic blood pressure (mmHg): Time-matched Change from Baseline >30 | 0 Participants |
| Part C: TAK-994 180 mg | Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study | Systolic blood pressure (mmHg): Change from Predose >30 | 0 Participants |