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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Oral Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-994 in Patients With Narcolepsy With or Without Cataplexy (Narcolepsy Type 1 or Narcolepsy Type 2)

    Summary
    EudraCT number
    2020-000777-24
    Trial protocol
    HU   FR   CZ   NL   FI   IT  
    Global end of trial date
    05 Nov 2021

    Results information
    Results version number
    v3(current)
    This version publication date
    20 Oct 2024
    First version publication date
    15 Dec 2022
    Other versions
    v1 , v2
    Version creation reason
    • New data added to full data set
    Full data set
    Summary report(s)
    TAK-994-1501_2020-000777-24_EudraCT PDF_Update Nov 2023

    Trial information

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    Trial identification
    Sponsor protocol code
    TAK-994-1501
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04096560
    WHO universal trial number (UTN)
    U1111-1240-0346
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, United States, MA 02421
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Nov 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this study is to assess the safety and tolerability of TAK-994 following multiple oral doses in subjects with narcolepsy with or without cataplexy (NT1 or NT2) and to assess the efficacy of TAK-994 on reducing excessive daytime sleepiness as measured by MWT and ESS.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 May 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    China: 2
    Country: Number of subjects enrolled
    Japan: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    97
    EEA total number of subjects
    31
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    97
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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. 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.

    Pre-assignment
    Screening details
    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.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part A: Placebo
    Arm description
    TAK-994 placebo-matching tablets, orally, twice daily (BID) for 28 days, in participants with NT1.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 placebo-matching tablets, orally, twice daily (BID) for 28 days.

    Arm title
    Part A: TAK-994 120 mg
    Arm description
    TAK-994 120 mg, orally, BID for 28 days, in participants with NT1.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Firazorexton
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 120 mg, orally, BID for 28 days.

    Arm title
    Part A: TAK-994 180 mg
    Arm description
    TAK-994 180 mg, orally, BID for 28 days, in participants with NT1.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Firazorexton
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 180 mg, orally, BID for 28 days.

    Arm title
    Part B: Placebo
    Arm description
    TAK-994 placebo-matching tablets, orally, BID for 56 days, in participants with NT1.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 placebo-matching tablets, orally, BID for 56 days.

    Arm title
    Part B: TAK-994 30 mg
    Arm description
    TAK-994 30 mg tablets, orally, BID for 56 days, in participants with NT1.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Firazorexton
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 30 mg tablets, orally, BID for 56 days.

    Arm title
    Part B: TAK-994 90 mg
    Arm description
    TAK-994 90 mg tablets, orally, BID for 56 days, in participants with NT1.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Firazorexton
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 90 mg tablets, orally, BID for 56 days.

    Arm title
    Part B: TAK-994 180 mg
    Arm description
    TAK-994 180 mg tablets, orally, BID for 56 days, in participants with NT1.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Firazorexton
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 180 mg tablets, orally, BID for 56 days.

    Arm title
    Part C: TAK-994 180 mg
    Arm description
    TAK-994 180 mg tablets, orally, BID for 56 days, in Chinese participants with NT1.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Firazorexton
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 180 mg tablets, orally, BID for 56 days.

    Number of subjects in period 1
    Part A: Placebo Part A: TAK-994 120 mg Part A: TAK-994 180 mg Part B: Placebo Part B: TAK-994 30 mg Part B: TAK-994 90 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg
    Started
    7
    7
    8
    17
    17
    20
    19
    2
    Completed
    6
    7
    8
    12
    10
    12
    9
    0
    Not completed
    1
    0
    0
    5
    7
    8
    10
    2
         Met the Discontinuation Criteria of the Protocol
    -
    -
    -
    -
    -
    -
    -
    1
         Study terminated by sponsor
    -
    -
    -
    5
    6
    4
    6
    1
         Pretreatment event (Serious or other adverse event
    -
    -
    -
    -
    -
    3
    3
    -
         Reason not specified
    1
    -
    -
    -
    1
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Placebo
    Reporting group description
    TAK-994 placebo-matching tablets, orally, twice daily (BID) for 28 days, in participants with NT1.

    Reporting group title
    Part A: TAK-994 120 mg
    Reporting group description
    TAK-994 120 mg, orally, BID for 28 days, in participants with NT1.

    Reporting group title
    Part A: TAK-994 180 mg
    Reporting group description
    TAK-994 180 mg, orally, BID for 28 days, in participants with NT1.

    Reporting group title
    Part B: Placebo
    Reporting group description
    TAK-994 placebo-matching tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part B: TAK-994 30 mg
    Reporting group description
    TAK-994 30 mg tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part B: TAK-994 90 mg
    Reporting group description
    TAK-994 90 mg tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part B: TAK-994 180 mg
    Reporting group description
    TAK-994 180 mg tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part C: TAK-994 180 mg
    Reporting group description
    TAK-994 180 mg tablets, orally, BID for 56 days, in Chinese participants with NT1.

    Reporting group values
    Part A: Placebo Part A: TAK-994 120 mg Part A: TAK-994 180 mg Part B: Placebo Part B: TAK-994 30 mg Part B: TAK-994 90 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg Total
    Number of subjects
    7 7 8 17 17 20 19 2 97
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    31.4 (22 to 36) 38.0 (23 to 53) 33.4 (18 to 45) 32.6 (18 to 47) 33.4 (18 to 55) 28.8 (18 to 48) 29.2 (19 to 43) 38.5 (25 to 52) -
    Gender categorical
    Units: Subjects
        Female
    4 2 5 8 12 10 12 1 54
        Male
    3 5 3 9 5 10 7 1 43
    Race
    Units: Subjects
        Asian
    2 0 4 1 6 6 3 2 24
        Black or African American
    0 3 1 3 1 4 0 0 12
        White
    5 3 3 11 7 8 15 0 52
        More than one race
    0 0 0 1 1 0 0 0 2
        Unknown or Not Reported
    0 1 0 1 2 2 1 0 7
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 0 0 0 2 0 0 0 2
        Not Hispanic or Latino
    7 7 8 17 14 19 18 2 92
        Unknown or Not Reported
    0 0 0 0 1 1 1 0 3
    Height
    Units: centimetres (cm)
        arithmetic mean (full range (min-max))
    168.07 (157.5 to 177.8) 176.61 (162.0 to 187.9) 164.01 (152.8 to 177.8) 171.00 (150.4 to 187.0) 164.24 (151.0 to 177.8) 168.38 (151.9 to 182.0) 171.66 (160.0 to 185.4) 169 (163.0 to 175.0) -
    Weight
    Units: kilograms (kg)
        arithmetic mean (full range (min-max))
    85.77 (74.2 to 92.7) 80.07 (56.7 to 102.5) 74.33 (60.0 to 91.9) 80.75 (46.3 to 126.5) 71.97 (48.0 to 108.0) 77.68 (52.3 to 102.0) 80.33 (56.7 to 102.0) 77 (66.0 to 88.0) -
    Body Mass Index (BMI)
    BMI= Weight (kg)/[height(m)^2
    Units: kilogram per square metre (kg/m^2)
        arithmetic mean (full range (min-max))
    30.529 (25.3 to 37.4) 25.629 (20.5 to 33.2) 27.575 (23.2 to 33.8) 27.48 (20.5 to 38.9) 26.56 (18.2 to 38.3) 27.29 (19.7 to 35.3) 27.21 (19.2 to 34.0) 26.75 (24.8 to 28.7) -
    Average Sleep Latency
    The Maintenance of Wakefulness Test (MWT) is a validated, objective measure that evaluates a person’s ability to remain awake under soporific conditions for a 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 was observed according to these rules, then the latency was defined as 40 minutes.
    Units: Minutes
        arithmetic mean (full range (min-max))
    3.30 (1.1 to 8.6) 4.41 (0.3 to 13.4) 2.75 (1.0 to 6.9) 6.0 (0 to 31) 6.1 (1 to 21) 6.1 (0 to 19) 4.9 (0 to 23) 17.87 (4.5 to 40) -
    Epworth Sleepiness Scale (ESS) Score
    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 them 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.
    Units: score on a scale
        arithmetic mean (full range (min-max))
    18.6 (13 to 21) 17.4 (13 to 24) 18.0 (11 to 23) 16.6 (8 to 21) 18.5 (12 to 23) 17.5 (10 to 23) 17.4 (11 to 23) 20 (16 to 24) -
    Weekly Cataplexy Rate (WCR)
    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. 999 represents data was not collected as 0 participants were analyzed in part C for endpoint WCR.
    Units: cataplexy attacks per week
        arithmetic mean (full range (min-max))
    19.9 (10 to 49) 19.1 (5 to 41) 12.0 (4 to 28) 15.94 (0.0 to 50.0) 14.98 (3.5 to 72.5) 11.68 (4.3 to 36.5) 15.37 (3.0 to 47.5) 999 (999 to 999) -

    End points

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    End points reporting groups
    Reporting group title
    Part A: Placebo
    Reporting group description
    TAK-994 placebo-matching tablets, orally, twice daily (BID) for 28 days, in participants with NT1.

    Reporting group title
    Part A: TAK-994 120 mg
    Reporting group description
    TAK-994 120 mg, orally, BID for 28 days, in participants with NT1.

    Reporting group title
    Part A: TAK-994 180 mg
    Reporting group description
    TAK-994 180 mg, orally, BID for 28 days, in participants with NT1.

    Reporting group title
    Part B: Placebo
    Reporting group description
    TAK-994 placebo-matching tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part B: TAK-994 30 mg
    Reporting group description
    TAK-994 30 mg tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part B: TAK-994 90 mg
    Reporting group description
    TAK-994 90 mg tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part B: TAK-994 180 mg
    Reporting group description
    TAK-994 180 mg tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part C: TAK-994 180 mg
    Reporting group description
    TAK-994 180 mg tablets, orally, BID for 56 days, in Chinese participants with NT1.

    Primary: Part A: Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) During the Study

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    End point title
    Part A: Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) During the Study [1] [2]
    End point description
    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. Safety Analysis Set included all participants who were randomised and received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    First dose of study treatment to end of study follow-up (up to Day 35) in Part A
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Part A were to be analysed for this endpoint.
    End point values
    Part A: Placebo Part A: TAK-994 120 mg Part A: TAK-994 180 mg
    Number of subjects analysed
    7
    7
    8
    Units: Participants
    2
    6
    7
    No statistical analyses for this end point

    Primary: Part A: Number of Participants Who Meet the Markedly Abnormal Value (MAV) Criteria for Safety Laboratory Tests at Least Once Postdose During the Study

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    End point title
    Part A: Number of Participants Who Meet the Markedly Abnormal Value (MAV) Criteria for Safety Laboratory Tests at Least Once Postdose During the Study [3] [4]
    End point description
    Standard safety laboratory values(hematology,serum chemistry,urinalysis)were collected & compared to pre-specified criteria for MAVs: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 1 participant with event are reported. Safety Analysis set included all participants who were randomised & received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    First dose of study treatment to end of study follow-up (up to Day 35) in Part A
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Part A were to be analysed for this endpoint.
    End point values
    Part A: Placebo Part A: TAK-994 120 mg Part A: TAK-994 180 mg
    Number of subjects analysed
    7
    7
    8
    Units: Participants
        Calcium (mmol/L): <1.92
    0
    1
    0
        Sodium (mmol/L): <130
    0
    1
    0
        Potassium (mmol/L): >5.3
    1
    0
    0
    No statistical analyses for this end point

    Primary: Part A: Number of Participants Who Meet the Markedly Abnormal Value (MAV) Criteria for Vital Sign Measurements at Least Once Postdose During the Study

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    End point title
    Part A: Number of Participants Who Meet the Markedly Abnormal Value (MAV) Criteria for Vital Sign Measurements at Least Once Postdose During the Study [5] [6]
    End point description
    Vital signs (body temperature and sitting blood pressure) were collected and compared to pre-specified criteria for MAVs throughout the study. MAV criteria: Heart Rate (beats/min): <40, >115; Systolic Blood Pressure (SBP) millimeters of mercury (mmHg): <90, ≥160, Change from Pre-Dose >20, Change from Pre-Dose >30, Time-matched Change from Baseline (CFB) > 20, Time-matched CFB > 30; Diastolic Blood Pressure (DBP) (mmHg): <50, ≥100, Change from Pre-Dose >20, Change from Pre-Dose >30, Time-matched CFB > 20, Time-matched CFB > 30; Respiratory Rate (breaths/min): >21; Temperature Celsius (C): >38.5. Only categories with at least one participant with event are reported. Safety Analysis Set included all participants who were randomised and received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    First dose of study treatment to end of study follow-up (up to Day 35) in Part A
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Part A were to be analysed for this endpoint.
    End point values
    Part A: Placebo Part A: TAK-994 120 mg Part A: TAK-994 180 mg
    Number of subjects analysed
    7
    7
    8
    Units: Participants
        SBP (mmHg)<90
    2
    0
    0
        SBP (mmHg): Change From Pre-Dose >20
    2
    3
    2
        SBP (mmHg): Change From Pre-Dose >30
    1
    1
    0
        SBP (mmHg): Time matched CFB>20
    4
    7
    6
        SBP (mmHg): Time matched CFB>30
    0
    3
    0
        DBP (mmHg): Change From Pre-Dose >20
    1
    3
    0
        DBP (mmHg): Time matched CFB>30
    1
    4
    3
        Temperature (C): >38.5
    0
    1
    0
    No statistical analyses for this end point

    Primary: Part A: Number of Participants Who Meet the Markedly Abnormal Value (MAV) Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study

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    End point title
    Part A: Number of Participants Who Meet the Markedly Abnormal Value (MAV) Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study [7] [8]
    End point description
    A 12 lead ECG was performed, the ECG values were compared to pre-specified criteria for MAVs. MAV 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 CFB and >450; QRS Duration (msec): ≤80, ≥180. Only categories with at least one participant with event are reported. Safety Analysis Set included all participants who were randomised and received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    First dose of study treatment to end of study follow-up (up to Day 35) in Part A
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Part A were to be analysed for this endpoint.
    End point values
    Part A: Placebo Part A: TAK-994 120 mg Part A: TAK-994 180 mg
    Number of subjects analysed
    7
    7
    8
    Units: participants
        PR Interval (msec): ≥200
    0
    1
    2
        QTcF Interval (msec): ≥30 CFB and >450
    1
    0
    0
        QRS Duration (msec): ≤80
    4
    0
    5
    No statistical analyses for this end point

    Primary: Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the Maintenance of Wakefulness Test (MWT)

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    End point title
    Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the Maintenance of Wakefulness Test (MWT) [9]
    End point description
    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 analysed for participants in Part C: TAK-994 180 mg. 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. Number of subjects analysed is the number of participants available for analyses.
    End point type
    Primary
    End point timeframe
    Baseline and Week 8 (Day 56) in Parts B and C
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Parts B and C were to be analysed for this endpoint.
    End point values
    Part B: Placebo Part B: TAK-994 30 mg Part B: TAK-994 90 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg
    Number of subjects analysed
    12
    9
    11
    9
    0 [10]
    Units: minutes (mins)
        least squares mean (standard error)
    -2.5 ( 2.19 )
    23.9 ( 2.27 )
    27.4 ( 2.17 )
    32.6 ( 2.25 )
    ( )
    Notes
    [10] - Due to early termination of the study no data was collected and analysed.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Part B: TAK-994 30 mg v Part B: Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [11]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    26.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.07
         upper limit
    32.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.15
    Notes
    [11] - The analysis used a linear MMRM with fixed effects for baseline (Day -1 mean values), treatment, visit, and treatment-by-visit interaction. Visit was repeated factor in the model. The unstructured covariance structure was used for repeated statement.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Part B: Placebo v Part B: TAK-994 90 mg
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [12]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    29.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.68
         upper limit
    36.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.08
    Notes
    [12] - The analysis used a linear MMRM with fixed effects for baseline (Day -1 mean values), treatment, visit, and treatment-by-visit interaction. Visit was repeated factor in the model. The unstructured covariance structure was used for repeated statement.
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Part B: Placebo v Part B: TAK-994 180 mg
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [13]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.73
         upper limit
    41.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.14
    Notes
    [13] - The analysis used a linear MMRM with fixed effects for baseline (Day -1 mean values), treatment, visit, and treatment-by-visit interaction. Visit was repeated factor in the model. The unstructured covariance structure was used for repeated statement.

    Secondary: Part A: Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 at Day 1

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    End point title
    Part A: Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 at Day 1 [14]
    End point description
    Pharmacokinetic (PK) Analysis Set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration. Number of subjects analysed is the number of participants available for analyses.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 1 in Part A
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Part A were to be analysed for this endpoint.
    End point values
    Part A: TAK-994 120 mg Part A: TAK-994 180 mg
    Number of subjects analysed
    6
    8
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cmax (ng/mL); Following First (AM) Dose at Day 1
    305.5 ( 68.3 )
    679.1 ( 24.5 )
        Cmax (ng/mL); Following Second (PM) Dose at Day 1
    437.1 ( 46.9 )
    1127 ( 26.4 )
    No statistical analyses for this end point

    Secondary: Part A: Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 at Day 1

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    End point title
    Part A: Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 at Day 1 [15]
    End point description
    PK Analysis Set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration. Number of subjects analysed is the number of participants available for analyses.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at multiple time points (Up to 14 hours) post-dose at Day 1 in Part A
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Part A were to be analysed for this endpoint.
    End point values
    Part A: TAK-994 120 mg Part A: TAK-994 180 mg
    Number of subjects analysed
    6
    8
    Units: hours (h)
    median (full range (min-max))
        Tmax (h): Following First (AM) Dose at Day 1
    1.19 (1.00 to 5.03)
    1.00 (1.00 to 5.00)
        Tmax (h): Following Second (PM) Dose at Day 1
    2.04 (1.02 to 4.00)
    1.75 (1.42 to 2.08)
    No statistical analyses for this end point

    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

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    End point title
    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 [16]
    End point description
    PK Analysis Set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration. Number of subjects analysed is the number of participants available for analyses.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at multiple time points (up to 24 hours) post-dose at Day 1 in Part A
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Part A were to be analysed for this endpoint.
    End point values
    Part A: TAK-994 120 mg Part A: TAK-994 180 mg
    Number of subjects analysed
    6
    8
    Units: nanograms*hour per milliliter (ng*h/mL)
        geometric mean (geometric coefficient of variation)
    3700 ( 63.0 )
    8559 ( 26.7 )
    No statistical analyses for this end point

    Secondary: Part A: Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 at Day 28

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    End point title
    Part A: Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 at Day 28 [17]
    End point description
    PK Analysis Set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 28 in Part A
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Part A were to be analysed for this endpoint.
    End point values
    Part A: TAK-994 120 mg Part A: TAK-994 180 mg
    Number of subjects analysed
    7
    8
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cmax (ng/mL); Following First (AM) Dose at Day 28
    377.5 ( 36.6 )
    856.9 ( 31.6 )
        Cmax (ng/mL); Following Second (PM) Dose at Day 28
    416.0 ( 40.9 )
    829.4 ( 28.4 )
    No statistical analyses for this end point

    Secondary: Part A: Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 at Day 28

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    End point title
    Part A: Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 at Day 28 [18]
    End point description
    PK analysis set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 28 in Part A
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Part A were to be analysed for this endpoint.
    End point values
    Part A: TAK-994 120 mg Part A: TAK-994 180 mg
    Number of subjects analysed
    7
    8
    Units: hours (h)
    median (full range (min-max))
        Tmax (h): Following First (AM) Dose at Day 28
    1.03 (0.93 to 3.10)
    1.00 (0.90 to 1.00)
        Tmax (h): Following Second (PM) Dose at Day 28
    2.15 (2.00 to 4.05)
    3.46 (1.50 to 7.00)
    No statistical analyses for this end point

    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

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    End point title
    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 [19]
    End point description
    PK analysis set included all participants who received at least 1 dose of TAK-994 and had at least 1 measurable plasma concentration.
    End point type
    Secondary
    End point timeframe
    Pre-dose and at multiple time points (Up to 12 hours) post-dose at Day 28 in Part A
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Part A were to be analysed for this endpoint.
    End point values
    Part A: TAK-994 120 mg Part A: TAK-994 180 mg
    Number of subjects analysed
    7
    8
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    2968 ( 33.1 )
    6438 ( 22.6 )
    No statistical analyses for this end point

    Secondary: Parts B and C: Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 8

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    End point title
    Parts B and C: Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 8 [20]
    End point description
    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 efficacy data for this outcome measure was collected and analysed for participants in Part C: TAK-994 180 mg. 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. Number of subjects analysed is the number of participants available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8 (Day 56) in Parts B and C
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Parts B and C were to be analysed for this endpoint.
    End point values
    Part B: Placebo Part B: TAK-994 30 mg Part B: TAK-994 90 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg
    Number of subjects analysed
    12
    10
    11
    9
    0 [21]
    Units: score on a scale
        least squares mean (standard error)
    -2.1 ( 1.35 )
    -12.2 ( 1.41 )
    -13.5 ( 1.32 )
    -15.1 ( 1.41 )
    ( )
    Notes
    [21] - Due to early termination of the study, no data was collected and analyzed.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Part B: Placebo v Part B: TAK-994 30 mg
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [22]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -10.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.07
         upper limit
    -6.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.96
    Notes
    [22] - The analysis used a linear MMRM with fixed effects for baseline (Day -1 mean values), treatment, visit, and treatment-by-visit interaction. Visit was repeated factor in the model. The unstructured covariance structure was used for repeated statement.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Part B: Placebo v Part B: TAK-994 90 mg
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [23]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -11.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.2
         upper limit
    -7.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.89
    Notes
    [23] - The analysis used a linear MMRM with fixed effects for baseline (Day -1 mean values), treatment, visit, and treatment-by-visit interaction. Visit was repeated factor in the model. The unstructured covariance structure was used for repeated statement.
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Part B: Placebo v Part B: TAK-994 180 mg
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [24]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.96
         upper limit
    -9.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.95
    Notes
    [24] - The analysis used a linear MMRM with fixed effects for baseline (Day -1 mean values), treatment, visit, and treatment-by-visit interaction. Visit was repeated factor in the model. The unstructured covariance structure was used for repeated statement.

    Secondary: Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) at Week 8

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    End point title
    Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) at Week 8 [25]
    End point description
    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 analysed for participants in Part C: TAK-994 180 mg. 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. Number of subjects analysed is the number of participants available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8 (Day 56) in Parts B and C
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Parts B and C were to be analysed for this endpoint.
    End point values
    Part B: Placebo Part B: TAK-994 30 mg Part B: TAK-994 90 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg
    Number of subjects analysed
    10
    10
    11
    8
    0 [26]
    Units: cataplexy attacks per week
        arithmetic mean (standard deviation)
    -6.58 ( 7.433 )
    -16.17 ( 20.979 )
    -11.91 ( 10.174 )
    -15.74 ( 9.978 )
    ( )
    Notes
    [26] - Due to early termination of the study, no data was collected and analysed.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Part B: Placebo v Part B: TAK-994 30 mg
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002 [27]
    Method
    MMRM
    Parameter type
    IRR
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.007
         upper limit
    0.317
    Notes
    [27] - Incidence rate was the exponentiated LS means and the incidence rate ratio (IRR) was exponentiated LS mean differences from generalized estimating equation (GEE) Poisson regression model which with natural log link was on count of cataplexy per week.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Part B: Placebo v Part B: TAK-994 90 mg
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.019 [28]
    Method
    MMRM
    Parameter type
    IRR
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.05
         upper limit
    0.767
    Notes
    [28] - The incidence rate was the exponentiated LS means and the IRR was the exponentiated LS mean differences from the GEE Poisson regression model. The Poisson regression with natural log link was on the count of cataplexy per week.
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Part B: Placebo v Part B: TAK-994 180 mg
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [29]
    Method
    MMRM
    Parameter type
    IRR
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.047
         upper limit
    0.482
    Notes
    [29] - The incidence rate was the exponentiated LS means and the IRR was the exponentiated LS mean differences from the GEE Poisson regression model. The Poisson regression with natural log link was on the count of cataplexy per week.

    Secondary: Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study

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    End point title
    Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study [30]
    End point description
    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. Safety Analysis Set included all participants who were randomised and received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    First dose of study drug to end of study follow-up (up to Day 63) in Parts B and C
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Parts B and C were to be analysed for this endpoint.
    End point values
    Part B: Placebo Part B: TAK-994 30 mg Part B: TAK-994 90 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg
    Number of subjects analysed
    17
    17
    20
    19
    2
    Units: participants
    4
    13
    17
    14
    2
    No statistical analyses for this end point

    Secondary: Parts B and C: Number of Participants Who Met the Markedly Abnormal Value (MAV) Criteria for Safety Laboratory Tests at Least Once Postdose During the Study

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    End point title
    Parts B and C: Number of Participants Who Met the Markedly Abnormal Value (MAV) Criteria for Safety Laboratory Tests at Least Once Postdose During the Study [31]
    End point description
    Standard safety laboratory values (serum chemistry, hematology, and urine analysis) were collected and compared to pre-specified criteria for MAV throughout the study. MAV criteria: Alanine Aminotransferase (ALT) [(U/L)]:>3xULN, Aspartate Aminotransferase (AST) [(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. Safety Analysis Set included all participants who were randomised and received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Up to Day 63 in Parts B and C
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Parts B and C were to be analysed for this endpoint.
    End point values
    Part B: Placebo Part B: TAK-994 30 mg Part B: TAK-994 90 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg
    Number of subjects analysed
    17
    17
    20
    19
    2
    Units: participants
        ALT [U/L)]: >3 × ULN
    0
    0
    3
    2
    0
        AST (U/L): >3 × ULN
    0
    0
    1
    2
    0
        Bilirubin (µmol/L): >1.5 × ULN
    0
    0
    0
    1
    0
        Calcium (mmol/L): <1.92
    1
    0
    0
    0
    0
        Potassium (mmol/L): <3.0
    1
    0
    0
    0
    0
        Potassium (mmol/L): >5.3
    1
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Parts B and C: Number of Participants Who Met the Markedly Abnormal Value (MAV) Criteria for Vital Sign Measurements at Least Once Postdose During the Study

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    End point title
    Parts B and C: Number of Participants Who Met the Markedly Abnormal Value (MAV) Criteria for Vital Sign Measurements at Least Once Postdose During the Study [32]
    End point description
    Vital signs (body temperature and sitting blood pressure) were collected and compared to pre-specified criteria for MAVs throughout the study. MAV criteria: SBP (mmHg): <90, ≥160, Change from Pre-Dose >20, Change from Pre-Dose >30, Time-matched CFB > 20, Time-matched CFB > 30; DBP (mmHg): <50, ≥100, Change from Pre-Dose >20, Change from Pre-Dose >30, Time-matched CFB > 20, Time-matched CFB > 30; Respiratory Rate (breaths/min): >21. Only categories with at least one participant with event are reported. Safety Analysis Set included all participants who were randomised and received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Up to Day 63 in Parts B and C
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Parts B and C were to be analysed for this endpoint.
    End point values
    Part B: Placebo Part B: TAK-994 30 mg Part B: TAK-994 90 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg
    Number of subjects analysed
    17
    17
    20
    19
    2
    Units: participants
        SBP (mmHg): <90
    2
    3
    1
    1
    1
        SBP (mmHg): >= 160
    1
    0
    0
    1
    0
        SBP (mmHg): Change from Predose > 20
    5
    7
    10
    10
    0
        SBP (mmHg): Change from Predose >30
    2
    2
    6
    5
    0
        SBP (mmHg): Time-matched CFB >20
    2
    11
    13
    14
    1
        SBP (mmHg): Time-matched CFB >30
    1
    4
    3
    5
    0
        DBP (mmHg): <50
    0
    1
    1
    2
    0
        DBP (mmHg): >=100
    1
    1
    2
    2
    1
        DBP (mmHg): Change from Predose >20
    0
    3
    5
    9
    0
        DBP (mmHg): Change from Predose >30
    0
    0
    1
    3
    0
        DBP (mmHg): Time-matched CFB >20
    2
    5
    7
    7
    0
        DBP (mmHg): Time-matched CFB >30
    0
    0
    1
    2
    0
        Respiratory Rate (breaths/minute): >21
    0
    2
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Parts B and C: Number of Participants Who Met the Markedly Abnormal Value (MAV) Criteria for ECG Parameters at Least Once Postdose During the Study

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    End point title
    Parts B and C: Number of Participants Who Met the Markedly Abnormal Value (MAV) Criteria for ECG Parameters at Least Once Postdose During the Study [33]
    End point description
    A 12 lead ECG was performed, the ECG values were compared to pre-specified criteria for markedly abnormal values. MAV criteria: PR Interval (msec): ≤80, ≥200; QRS Duration (msec): ≤80, ≥180. Only categories with at least one participant with event are reported. Safety Analysis Set included all participants who were randomised and received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Up to Day 63 in Parts B and C
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only the drug-treated arms for Parts B and C were to be analysed for this endpoint.
    End point values
    Part B: Placebo Part B: TAK-994 30 mg Part B: TAK-994 90 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg
    Number of subjects analysed
    17
    17
    20
    19
    2
    Units: participants
        PR Interval (msec): >=200
    2
    2
    1
    3
    0
        QRS Duration (msec):<=80
    4
    3
    7
    4
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study treatment to end of study follow-up (up to Day 35 in Part A and up to Day 63 in Parts B and C)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Part A: Placebo
    Reporting group description
    TAK-994 placebo-matching tablets, orally, BID for 28 days, in participants with NT1.

    Reporting group title
    Part A: TAK-994 120 mg
    Reporting group description
    TAK-994 120 mg, orally, BID for 28 days, in participants with NT1.

    Reporting group title
    Part A: TAK-994 180 mg
    Reporting group description
    TAK-994 180 mg, orally, BID for 28 days, in participants with NT1.

    Reporting group title
    Part B: Placebo
    Reporting group description
    TAK-994 placebo-matching tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part B: TAK-994 90 mg
    Reporting group description
    TAK-994 90 mg tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part B: TAK-994 30 mg
    Reporting group description
    TAK-994 30 mg tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part B: TAK-994 180 mg
    Reporting group description
    TAK-994 180 mg tablets, orally, BID for 56 days, in participants with NT1.

    Reporting group title
    Part C: TAK-994 180 mg
    Reporting group description
    TAK-994 180 mg tablets, orally, BID for 56 days, in Chinese participants with NT1.

    Serious adverse events
    Part A: Placebo Part A: TAK-994 120 mg Part A: TAK-994 180 mg Part B: Placebo Part B: TAK-994 90 mg Part B: TAK-994 30 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part A: Placebo Part A: TAK-994 120 mg Part A: TAK-994 180 mg Part B: Placebo Part B: TAK-994 90 mg Part B: TAK-994 30 mg Part B: TAK-994 180 mg Part C: TAK-994 180 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 7 (28.57%)
    6 / 7 (85.71%)
    7 / 8 (87.50%)
    4 / 17 (23.53%)
    17 / 20 (85.00%)
    13 / 17 (76.47%)
    14 / 19 (73.68%)
    2 / 2 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pleomorphic adenoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Feeling jittery
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Puncture site erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Social circumstances
    Ex-tobacco user
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Vulvovaginal inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Sneezing
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    1 / 17 (5.88%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    3 / 19 (15.79%)
    2 / 2 (100.00%)
         occurrences all number
    0
    1
    2
    1
    2
    0
    3
    4
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Agitation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Hypervigilance
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Initial insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Middle insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Investigations
    Glutamate dehydrogenase increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    4 / 20 (20.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    2 / 20 (10.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Blood urea increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Heart rate increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Skin laceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Vaccination complication
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    4 / 17 (23.53%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    7
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    2
    Paraesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Tension headache
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Blood and lymphatic system disorders
    Granulocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Blepharospasm
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Salivary hypersecretion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    3 / 8 (37.50%)
    0 / 17 (0.00%)
    3 / 20 (15.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    3
    0
    3
    0
    2
    1
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    3 / 20 (15.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    1
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Faeces discoloured
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Faeces hard
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Abdominal mass
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    2 / 2 (100.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    2
    Papule
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Rash papular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 7 (42.86%)
    5 / 8 (62.50%)
    1 / 17 (5.88%)
    10 / 20 (50.00%)
    5 / 17 (29.41%)
    6 / 19 (31.58%)
    2 / 2 (100.00%)
         occurrences all number
    0
    4
    5
    1
    10
    5
    7
    2
    Micturition urgency
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    1 / 17 (5.88%)
    10 / 20 (50.00%)
    5 / 17 (29.41%)
    8 / 19 (42.11%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    2
    1
    10
    5
    9
    1
    Polyuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Hypertonic bladder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Muscle twitching
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Bacterial disease carrier
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 20 (5.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Giardiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    1 / 19 (5.26%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    2 / 19 (10.53%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    0
    Increased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 20 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Mar 2020
    The updates in Amendment 01 include: • The title of the study was updated to include both participants with narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). • The EudraCT number and study phase were added to the protocol title page. • The number of participating sites was updated. • The baseline period was added to the study duration overview. • Separate study schematics, outlining key study assessments, were added for Cohorts 4 and Cohorts 5 and 6. • Separate schedules of study procedures, outlining all study assessments, were added for Cohorts 4 and Cohorts 5 and 6. • A collection window of 10 minutes was added for the 5-hour PK sampling/assessments on Days 1, 14, and 28. • The information on disease background was updated. • Data from ongoing Study TAK-994-1001 were updated. • “other exploratory objectives” were removed. • Three additional cohorts were included, 1 consisting of 12 to 18 Chinese subjects with NT1 (Cohort 4) and 2, each consisting of 18 subjects with NT2 (Cohorts 5 and 6). • In inclusion criteria, it was specified that screening labs may be repeated once. • In exclusion criteria, the usual bedtime for subjects was changed from 0100 to no later than 2400 (12:00 AM, midnight). • Instructions related to caffeine use were updated. • BP and heart rate limits leading to discontinuation of subjects were updated. • Procedures around study drug blinding were corrected. • Procedures around randomization code creation and storage were corrected. • A strong recommendation for the same clinician to administer the clinical global impression scales at every visit was added. • Instructions of body position and lighting during the MWT were added. • Analysis methods for Cohorts 1 to 6 were updated. • Description of the planned interim analyses was updated. • Determination of sample size was updated enumerating the range of subjects and randomization ratio (study drug: placebo) in Cohorts 4 (China-specific), 5, and 6.
    05 Jun 2020
    The updates in Amendment 02 include: • Overall study description changed due to the study design. • Overall number of participants to be enrolled has increased. • Schematics for different parts of the study have been updated according to the updated design. • BMI criteria was updated to in acknowledgment of the comorbidity of obesity in this subject population. • Study objectives and endpoints have been revised to align with the revised design. • Clinical information has been updated based on emerging data from the study TAK-994-1001, including the blinded safety and preliminary PK data. • Instructions related to excluded medications have been revised to accommodate revised study population. • Text has been revised for criteria for discontinuation or withdrawal of a subject. • Text has been revised for study drug supply, randomization, blinding and storage.
    15 Jan 2021
    The updates in Amendment 03 include: • Updated to include recent clinical and nonclinical study data. • Change the study eligibility criteria to better define how the presence of cataplexy is established for participants in Part B and C cohorts. • Revised several protocol sections, including the Schedule of Study Procedures to allow more flexibility for the study participants and the site personnel. • Revise the statistical analysis strategy to reduce the number of times the sponsor unblinded team reviews the data.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    05 Nov 2021
    A safety signal has emerged in Phase 2 studies of TAK-994. As an immediate precautionary measure, Takeda has suspended dosing of participants and has decided to stop Phase 2 studies early.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    A safety signal has emerged in Phase 2 studies of TAK-994. As an immediate precautionary measure, Takeda has suspended dosing of participants and has decided to stop Phase 2 studies early.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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