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    Clinical Trial Results:
    A Dose-Blind Extension Study With Double-blind, Placebo-Controlled, Randomized Withdrawal Period to Evaluate the Safety and Explore the Pharmacokinetics and Pharmacodynamics of TAK-994 in Adults With Narcolepsy With Cataplexy (Narcolepsy Type 1)

    Summary
    EudraCT number
    		 2021-000251-39
    Trial protocol
    		 CZ   HU   FR   IT   ES  
    Global end of trial date
    03 Nov 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 Nov 2023
    First version publication date
    15 Dec 2022
    Other versions
    		 v1
    Version creation reason
    Summary report(s)
    		 TAK-994-1504_2021-000251-39_EudraCT PDF

    Trial information

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    Trial identification
    Sponsor protocol code
    TAK-994-1504
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04820842
    WHO universal trial number (UTN)
    		 -
    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
    03 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Nov 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the safety and tolerability of TAK-994 in the Active Drug Extension Period of the study over a period of up to 8 weeks.
    Protection of trial subjects
    Each participant signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Apr 2021
    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
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    26
    EEA total number of subjects
    14
    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)
    26
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in study at 13 investigative sites in Spain,Italy,Japan,Korea,United States from 30Apr2021-29Jun2022[LPLV].Study officially terminated in Nov2021,however,database lock and full data analysis significantly delayed as participants with serious hepatic safety events were being followed,respective data collected until Jun2022.

    Pre-assignment
    Screening details
    		 Participants with narcolepsy type 1 (NT 1) who completed Part B of TAK-994-1501(NCT04096560) were enrolled in this study to receive TAK-994 or placebo.

    Period 1
    Period 1 title
    Active Drug Extension Period (8 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active Drug Extension Period: TAK-99430 mg
    Arm description
    		 TAK-994 30 mg, twice daily (BID) tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 tablet, was administered orally, from Day 1 (Day 57 of previous study) to Day 56.

    Arm title
    		 Active Drug Extension Period: TAK-994 90 mg
    Arm description
    		 TAK-994 90 mg, BID, tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 tablet, was administered orally, from Day 1 (Day 57 of previous study) to Day 56.

    Arm title
    		 Active Drug Extension Period: TAK-994 180 mg
    Arm description
    		 TAK-994 180 mg, BID, tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 tablet, was administered orally, from Day 1 (Day 57 of previous study) to Day 56.

    Number of subjects in period 1
    		Active Drug Extension Period: TAK-99430 mg Active Drug Extension Period: TAK-994 90 mg Active Drug Extension Period: TAK-994 180 mg
    Started
    8
    9
    9
    Completed
    5
    1
    2
    Not completed
    3
    8
    7
         Consent withdrawn by subject
    -
    1
    -
         Adverse event, non-fatal
    -
    1
    2
         Study Terminated by Sponsor
    3
    6
    5
    Period 2
    Period 2 title
    Randomized Withdrawal Period (4 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-blind Randomized Withdrawal Period: TAK-994 30 mg
    Arm description
    		 Following the Active Drug Extension Period, participants randomized to active treatment 30 mg, BID, meeting eligibility specification and continued to receive same dose (TAK-994, 30 mg, BID, tablets, orally) from Day 57 to Day 84 in the Double-blind Randomized Withdrawal Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 tablet, was administered orally, from Day 57 to Day 84.

    Arm title
    		 Double-blind Randomized Withdrawal Period: TAK-994 90 mg
    Arm description
    		 Following the Active Drug Extension Period, participants randomized to active treatment 90 mg, BID, meeting eligibility specification and continued to receive same dose (TAK-994, 90 mg, BID, tablets, orally) from Day 57 to Day 84 in the Double-blind Randomized Withdrawal Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 tablet, was administered orally, from Day 57 to Day 84.

    Arm title
    		 Double-blind Randomized Withdrawal Period: TAK-994 180 mg
    Arm description
    		 Following the Active Drug Extension Period, participants randomized to active treatment 180 mg, BID, meeting eligibility specification and continued to receive same dose (TAK-994, 180 mg, BID, tablets, orally) from Day 57 to Day 84 in the Double-blind Randomized Withdrawal Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAK-994
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-994 tablet, was administered orally, from Day 57 to Day 84.

    Arm title
    		 Double-blind Randomized Withdrawal Period: Placebo
    Arm description
    		 Following the Active Drug Extension Period participants meeting eligibility specification and received placebo-matching tablets for 4 weeks (from Day 57 to Day 84) in the Double-blind Randomized Withdrawal Period.
    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 tablet, was administered orally, for 4 weeks (from Day 57 to Day 84).

    Number of subjects in period 2
    		Double-blind Randomized Withdrawal Period: TAK-994 30 mg Double-blind Randomized Withdrawal Period: TAK-994 90 mg Double-blind Randomized Withdrawal Period: TAK-994 180 mg Double-blind Randomized Withdrawal Period: Placebo
    Started
    3
    1
    1
    3
    Completed
    1
    1
    1
    2
    Not completed
    2
    0
    0
    1
         Study Terminated by Sponsor
    2
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active Drug Extension Period: TAK-99430 mg
    Reporting group description
    		 TAK-994 30 mg, twice daily (BID) tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.

    Reporting group title
    Active Drug Extension Period: TAK-994 90 mg
    Reporting group description
    		 TAK-994 90 mg, BID, tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.

    Reporting group title
    Active Drug Extension Period: TAK-994 180 mg
    Reporting group description
    		 TAK-994 180 mg, BID, tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.

    Reporting group values
    		 Active Drug Extension Period: TAK-99430 mg Active Drug Extension Period: TAK-994 90 mg Active Drug Extension Period: TAK-994 180 mg Total
    Number of subjects
    		 8 9 9
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.4 ± 12.13 31.3 ± 9.75 29.7 ± 11.08 -
    Gender categorical
    Units: Subjects
        Female
    		 7 4 3 14
        Male
    		 1 5 6 12
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 0 1
        Not Hispanic or Latino
    		 7 9 9 25
        Unknown or Not Reported
    		 0 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 1 1 1 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 2 1 3
        White
    		 6 6 6 18
        More than one race
    		 1 0 0 1
        Unknown or Not Reported
    		 0 0 1 1
    Region of Enrollment
    Units: Subjects
        Spain
    		 4 1 0 5
        Italy
    		 1 4 4 9
        Japan
    		 1 0 1 2
        Korea, South
    		 0 1 0 1
        United States
    		 2 3 4 9
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    		 163.9 ± 8.39 170.5 ± 8.24 174.4 ± 6.45 -
    Body Mass Index (BMI)
    BMI=weight (kg) / [height (m)]^2
    Units: kilograms per meter square (kg/m^2)
        arithmetic mean (standard deviation)
    		 28.3 ± 5.86 27.7 ± 5.45 25.9 ± 5.07 -
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    		 76.5 ± 18.52 81.8 ± 22.68 79.1 ± 16.15 -

    End points

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    End points reporting groups
    Reporting group title
    Active Drug Extension Period: TAK-99430 mg
    Reporting group description
    		 TAK-994 30 mg, twice daily (BID) tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.

    Reporting group title
    Active Drug Extension Period: TAK-994 90 mg
    Reporting group description
    		 TAK-994 90 mg, BID, tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.

    Reporting group title
    Active Drug Extension Period: TAK-994 180 mg
    Reporting group description
    		 TAK-994 180 mg, BID, tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.
    Reporting group title
    Double-blind Randomized Withdrawal Period: TAK-994 30 mg
    Reporting group description
    		 Following the Active Drug Extension Period, participants randomized to active treatment 30 mg, BID, meeting eligibility specification and continued to receive same dose (TAK-994, 30 mg, BID, tablets, orally) from Day 57 to Day 84 in the Double-blind Randomized Withdrawal Period.

    Reporting group title
    Double-blind Randomized Withdrawal Period: TAK-994 90 mg
    Reporting group description
    		 Following the Active Drug Extension Period, participants randomized to active treatment 90 mg, BID, meeting eligibility specification and continued to receive same dose (TAK-994, 90 mg, BID, tablets, orally) from Day 57 to Day 84 in the Double-blind Randomized Withdrawal Period.

    Reporting group title
    Double-blind Randomized Withdrawal Period: TAK-994 180 mg
    Reporting group description
    		 Following the Active Drug Extension Period, participants randomized to active treatment 180 mg, BID, meeting eligibility specification and continued to receive same dose (TAK-994, 180 mg, BID, tablets, orally) from Day 57 to Day 84 in the Double-blind Randomized Withdrawal Period.

    Reporting group title
    Double-blind Randomized Withdrawal Period: Placebo
    Reporting group description
    		 Following the Active Drug Extension Period participants meeting eligibility specification and received placebo-matching tablets for 4 weeks (from Day 57 to Day 84) in the Double-blind Randomized Withdrawal Period.

    Primary: Number of Participants with at Least One Treatment Emergent Adverse Event (TEAE) During the Active Drug Extension Period

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    End point title
    		 Number of Participants with at Least One Treatment Emergent Adverse Event (TEAE) During the Active Drug Extension Period [1]
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participants 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 for the Active Drug Extension Period included all participants who were randomized and received at least 1 dose of study drug in the Active Drug Extension Period.
    End point type
    Primary
    End point timeframe
    Up to 8 weeks in the Active Drug Extension Period (Weeks 1 to 8)
    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 statistics were planned to be analysed for this endpoint.
    End point values
    		 Active Drug Extension Period: TAK-99430 mg Active Drug Extension Period: TAK-994 90 mg Active Drug Extension Period: TAK-994 180 mg
    Number of subjects analysed
    8
    9
    9
    Units: participants
    5
    4
    3
    No statistical analyses for this end point

    Primary: Number of Participants with at Least One Post-dose Markedly Abnormal Value (MAV) in Laboratory Test During the Active Drug Extension Period

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    End point title
    		 Number of Participants with at Least One Post-dose Markedly Abnormal Value (MAV) in Laboratory Test During the Active Drug Extension Period [2]
    End point description
    Clinical laboratory tests included hematology,serum chemistry,urinalysis.MAV criteria:Hemoglobin<0.8×lower limit of normal(LLN),>1.2×upper limit of normal (ULN);Hematocrit<0.8×LLN,>1.2×ULN;Red blood cells(RBC) count<0.8×LLN,>1.2×ULN;White blood cells(WBC) count<0.5xLLN,>1.5xULN; Platelet count<75x10^9/liter(L),>600x10^9/L;alanine aminotransferase(ALT)>3xULN;aspartate aminotransferase(AST)>3xULN;gamma-glutamyl transferase(GGT)>3xULN;Alkaline phosphatase>3xULN;Total bilirubin>1.5xULN;Albumin<25 grams per liter(g/L);Total protein<0.8xLLN,>1.2xULN;Creatinine>1.5xULN;Blood urea nitrogen>40 milligrams per deciliters(mg/dL);Sodium<130 milliequivalents per liter (mEq/L),>150 mEq/L;Potassium <3.0 millimoles per liter(mmol/L),>5.3 mmol/L;creatine phosphokinase(CPK)>3xULN;Glucose<50 mg/dL,>300 mg/dL; Calcium <7.7 mg/dL,>11.1 mg/dL.Only categories with atleast 1 participant with event are reported.Safety Analysis Set=all randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 8 weeks in the Active Drug Extension Period (Weeks 1 to 8)
    Notes
    [2] - 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 statistics were planned to be analysed for this endpoint.
    End point values
    		 Active Drug Extension Period: TAK-99430 mg Active Drug Extension Period: TAK-994 90 mg Active Drug Extension Period: TAK-994 180 mg
    Number of subjects analysed
    8
    9
    9
    Units: participants
        ALT: >3 x ULN
    0
    1
    2
        AST: >3 x ULN
    0
    1
    2
        Bilirubin: >1.5 x ULN
    0
    1
    1
        GGT: >3 x ULN
    0
    1
    0
        Potassium: >5.3 mmol/L
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Participants with at Least One Post-dose MAV for Vital Signs During the Active Drug Extension Period

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    End point title
    		 Number of Participants with at Least One Post-dose MAV for Vital Signs During the Active Drug Extension Period [3]
    End point description
    MAV criteria for vital signs were: Pulse <40 beats per minute (bpm), >115 bpm; Systolic blood pressure <90 millimeters of mercury (mmHg), ≥160 mmHg; Diastolic blood pressure <50 mmHg, ≥100 mmHg, Systolic or Diastolic blood pressure change of >20, >30 mmHg from Baseline, Body temperature >38.5 degree Celsius, Respiratory Rate >21 breath/minute. Only categories with at least one participant with event are reported. Baseline for this outcome measure is Day 1 of the Active Drug Extension Period.
    End point type
    Primary
    End point timeframe
    Up to 8 weeks in the Active Drug Extension Period (Weeks 1 to 8)
    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 statistics were planned to be analysed for this endpoint.
    End point values
    		 Active Drug Extension Period: TAK-99430 mg Active Drug Extension Period: TAK-994 90 mg Active Drug Extension Period: TAK-994 180 mg
    Number of subjects analysed
    8
    9
    9
    Units: participants
        Systolic Blood Pressure: <90 mmHg
    0
    1
    0
        Systolic Blood Pressure: >=160 mmHg
    0
    1
    0
        Systolic Blood Pressure: Change from Pre-Dose >20
    1
    1
    0
        Systolic Blood Pressure: Change from Pre-Dose >30
    0
    1
    0
        Diastolic Blood Pressure: >=100 mmHg
    0
    1
    0
        Diastolic Blood Pressure: Change from Pre-Dose >20
    2
    1
    1
        Diastolic Blood Pressure: Change from Pre-Dose >30
    0
    1
    0
        Respiratory Rate: >21 breaths/min
    1
    0
    2
    No statistical analyses for this end point

    Primary: Number of Participants with at Least One Post-dose MAV for Electrocardiogram (ECG) Parameters During the Active Drug Extension Period

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    End point title
    		 Number of Participants with at Least One Post-dose MAV for Electrocardiogram (ECG) Parameters During the Active Drug Extension Period [4]
    End point description
    MAV criteria for ECG were: Heart rate <40 bpm, >115 bpm; PR interval ≤80 milliseconds (msec), ≥200 msec; QT interval with Fridericia correction method (QTcF) Interval ≤300 msec, >500 msec or ≥30 msec change from baseline and >450 msec; QRS duration ≤80 msec, ≥180 msec. Only categories with at least one participant with event are reported. Safety Analysis Set for the Active Drug Extension Period included all participants who were randomized and received at least 1 dose of study drug in the Active Drug Extension Period.
    End point type
    Primary
    End point timeframe
    Up to 8 weeks in the Active Drug Extension Period (Weeks 1 to 8)
    Notes
    [4] - 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 statistics were planned to be analysed for this endpoint.
    End point values
    		 Active Drug Extension Period: TAK-99430 mg Active Drug Extension Period: TAK-994 90 mg Active Drug Extension Period: TAK-994 180 mg
    Number of subjects analysed
    8
    9
    9
    Units: participants
        Heart Rate: <40 bpm
    1
    0
    1
        PR Interval: ≥200 msec
    0
    1
    2
        QRS Duration: ≤80 msec
    3
    3
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with at Least One TEAE During the Double-blind Randomized Withdrawal Period

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    End point title
    		 Number of Participants with at Least One TEAE During the Double-blind Randomized Withdrawal Period
    End point description
    An AE is defined as any untoward medical occurrence in a clinical investigation participants 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 for the Double-blind Randomized Withdrawal Period included all participants who were randomized and received at least 1 dose of study drug in the Double-blind Randomized Withdrawal Period.
    End point type
    Secondary
    End point timeframe
    Up to 4 weeks in the Double-blind Randomized Withdrawal Period (Weeks 9 to 12)
    End point values
    		 Double-blind Randomized Withdrawal Period: TAK-994 30 mg Double-blind Randomized Withdrawal Period: TAK-994 90 mg Double-blind Randomized Withdrawal Period: TAK-994 180 mg Double-blind Randomized Withdrawal Period: Placebo
    Number of subjects analysed
    3
    1
    1
    3
    Units: participants
    0
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with at Least One Post-dose MAV in Laboratory Test During the Double-blind Randomized Withdrawal Period

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    End point title
    		 Number of Participants with at Least One Post-dose MAV in Laboratory Test During the Double-blind Randomized Withdrawal Period
    End point description
    Clinical laboratory tests included hematology, serum chemistry, and urinalysis. MAV criteria: Hemoglobin <0.8×LLN, >1.2×ULN; Hematocrit <0.8×LLN, >1.2×ULN; RBC count <0.8×LLN, >1.2×ULN; WBC count <0.5xLLN, >1.5xULN; Platelet count <75x10^9/L, >600x10^9/L; ALT >3xULN; AST >3xULN; GGT >3xULN; Alkaline phosphatase >3xULN; Total bilirubin >1.5xULN; Albumin <25 g/L; Total protein <0.8x LLN, >1.2xULN; Creatinine >1.5xULN; Blood urea nitrogen >40 mg/dL; Sodium <130 mEq/L, >150 mEq/L; Potassium <3.0 mmol/L, >5.3 mmol/L; CPK >3xULN; Glucose <50 mg/dL, >300 mg/dL; Calcium <7.7 mg/dL, >11.1 mg/dL. Safety Analysis Set for the Double-blind Randomized Withdrawal Period included all participants who were randomized and received at least 1 dose of study drug in the Double-blind Randomized Withdrawal Period.
    End point type
    Secondary
    End point timeframe
    Up to 4 weeks in the Double-blind Randomized Withdrawal Period (Weeks 9 to 12)
    End point values
    		 Double-blind Randomized Withdrawal Period: TAK-994 30 mg Double-blind Randomized Withdrawal Period: TAK-994 90 mg Double-blind Randomized Withdrawal Period: TAK-994 180 mg Double-blind Randomized Withdrawal Period: Placebo
    Number of subjects analysed
    3
    1
    1
    3
    Units: participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with at Least One Post-dose MAV for Vital Signs During the Double-blind Randomized Withdrawal Period

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    End point title
    		 Number of Participants with at Least One Post-dose MAV for Vital Signs During the Double-blind Randomized Withdrawal Period
    End point description
    MAV criteria for vital signs were: Pulse <40 bpm, >115 bpm; Systolic blood pressure <90 mmHg, ≥160 mmHg; Diastolic blood pressure <50 mmHg, ≥100 mmHg, Systolic or Diastolic blood pressure change of >20, >30 mmHg from Baseline, Body temperature >38.5 degree Celsius, Respiratory Rate >21 breath/minute. Only categories with at least one participant with event are reported. Baseline for this outcome measure is Day 1 of the Double-blind Randomized Withdrawal Period (Day 57 of this study). Safety Analysis Set for the Double-blind Randomized Withdrawal Period included all participants who were randomized and received at least 1 dose of study drug in the Double-blind Randomized Withdrawal Period.
    End point type
    Secondary
    End point timeframe
    Up to 4 weeks in the Double-blind Randomized Withdrawal Period (Weeks 9 to 12)
    End point values
    		 Double-blind Randomized Withdrawal Period: TAK-994 30 mg Double-blind Randomized Withdrawal Period: TAK-994 90 mg Double-blind Randomized Withdrawal Period: TAK-994 180 mg Double-blind Randomized Withdrawal Period: Placebo
    Number of subjects analysed
    3
    1
    1
    3
    Units: participants
        Systolic Blood Pressure: <90 mmHg
    0
    0
    0
    1
        Systolic Blood Pressure: Change from Baseline >20
    1
    0
    0
    0
        Diastolic Blood Pressure:Change from Baseline>20
    1
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with at Least One Post-dose MAV for ECG Parameters During the Double-blind Randomized Withdrawal Period

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    End point title
    		 Number of Participants with at Least One Post-dose MAV for ECG Parameters During the Double-blind Randomized Withdrawal Period
    End point description
    MAV criteria for ECG were: Heart rate <40 bpm, >115 bpm; PR interval ≤80 msec, ≥200 msec; QTcF Interval ≤300 msec, >500 msec or ≥30 msec change from baseline and >450 msec; QRS duration ≤80 msec, ≥180 msec. Only categories with at least one participant with event are reported. Safety Analysis Set for the Double-blind Randomized Withdrawal Period included all participants who were randomized and received at least 1 dose of study drug in the Double-blind Randomized Withdrawal Period.
    End point type
    Secondary
    End point timeframe
    Up to 4 weeks in the Double-blind Randomized Withdrawal Period (Weeks 9 to 12)
    End point values
    		 Double-blind Randomized Withdrawal Period: TAK-994 30 mg Double-blind Randomized Withdrawal Period: TAK-994 90 mg Double-blind Randomized Withdrawal Period: TAK-994 180 mg Double-blind Randomized Withdrawal Period: Placebo
    Number of subjects analysed
    3
    1
    1
    3
    Units: participants
        QRS Duration ≤80 msec
    0
    0
    0
    1
        Heart Rate <40 bpm
    0
    0
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization up to two weeks post end of treatment (up to Week 14)
    Adverse event reporting additional description
    Safety Analysis Set for the Active Drug Extension Period and Double-blind Randomized Withdrawal Period included all participants who were randomized and received at least 1 dose of study drug in the Active Drug Extension Period and Double-blind Randomized Withdrawal Period respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Period 1: TAK-994 30 mg BID
    Reporting group description
    		 TAK-994 30 mg, BID tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.

    Reporting group title
    Period 1: TAK-994 90 mg BID
    Reporting group description
    		 TAK-994 90 mg, BID, tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.

    Reporting group title
    Period 1: TAK-994 180 mg BID
    Reporting group description
    		 TAK-994 180 mg, BID, tablets, orally, from Day 1 (Day 57 of previous study) to Day 56 in the Active Drug Extension Period.

    Reporting group title
    Period 2: Placebo
    Reporting group description
    		 Following the Active Drug Extension Period participants meeting eligibility specification and received placebo-matching tablets for 4 weeks (from Day 57 to Day 84) in the Double-blind Randomized Withdrawal Period.

    Reporting group title
    Period 2: TAK-994 90 mg BID
    Reporting group description
    		 Following the Active Drug Extension Period, participants randomized to active treatment 90 mg, BID, meeting eligibility specification and continued to receive same dose (TAK-994, 90 mg, BID, tablets, orally) from Day 57 to Day 84 in the Double-blind Randomized Withdrawal Period.

    Reporting group title
    Period 2: TAK-994 180 mg BID
    Reporting group description
    		 Following the Active Drug Extension Period, participants randomized to active treatment 180 mg, BID, meeting eligibility specification and continued to receive same dose (TAK-994, 180 mg, BID, tablets, orally) from Day 57 to Day 84 in the Double-blind Randomized Withdrawal Period.

    Reporting group title
    Period 2: TAK-994 30 mg BID
    Reporting group description
    		 Following the Active Drug Extension Period, participants randomized to active treatment 30 mg, BID, meeting eligibility specification and continued to receive same dose (TAK-994, 30 mg, BID, tablets, orally) from Day 57 to Day 84 in the Double-blind Randomized Withdrawal Period.

    Serious adverse events
    		 Period 1: TAK-994 30 mg BID Period 1: TAK-994 90 mg BID Period 1: TAK-994 180 mg BID Period 2: Placebo Period 2: TAK-994 90 mg BID Period 2: TAK-994 180 mg BID Period 2: TAK-994 30 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    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
    		 Period 1: TAK-994 30 mg BID Period 1: TAK-994 90 mg BID Period 1: TAK-994 180 mg BID Period 2: Placebo Period 2: TAK-994 90 mg BID Period 2: TAK-994 180 mg BID Period 2: TAK-994 30 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 8 (62.50%)
    4 / 9 (44.44%)
    3 / 9 (33.33%)
    1 / 3 (33.33%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    General disorders and administration site conditions
    Temperature intolerance
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Nervousness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Migraine
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    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
    08 Jul 2021
    The following changes were implemented as per Amendment 1: 1. The duration of the randomized withdrawal period was shortened from 4 to 2 weeks. 2. An open-label extension period was added to evaluate safety of the TAK-994 regimen following the randomized withdrawal period. 3. An objective and endpoint related to microsleeps was added. 4. Low, middle, and high doses information was added to the protocol. 5. Ambulatory blood pressure monitoring and guidance was added. 6. Karolinska Sleepiness Scale and Narcolepsy Severity Scale for Clinical Trials scales have been added to the objectives and endpoints. 7. The possibility for participants to roll over to an optional open-label extension study was added to the study design. 8. The number of sites estimated to be included was updated from 70 to 81. 9. Stratification by Epworth Sleepiness Scale total score (<10, ≥10) and total number of cataplexy episodes in the last 7 days (≤3, >3) was added for the randomized withdrawal period. 10. The study title was updated. 11. The Overactive Bladder Questionnaire – Long Form (OAB-q-LF) and Patient Perception of Bladder Control (PPBC) have been added to objectives and endpoints. 12. The overnight stay at Day 56 to monitor possible withdrawal effect was replaced by a telephone call 24 hours after the last dose in the active drug extension period. As a result, pharmacokinetics (PK) and renin/aldosterone samples to be taken before discharge will be taken at Day 56 rather than 57.
    08 Jul 2021
    The following changes were implemented as per Amendment 1: 13. The clinical study experience and benefit-risk information was updated with the most recent information. 14. Open-label wording was removed from the figure on study design schematics. 15. The Columbia Suicide Severity Assessment scale was added at each visit. 16. The threshold for Maintenance of Wakefulness Test (MWT) was corrected to 7 minutes. 17. Statements with regard to the need to consult the sponsor and/or designee before the initiation of any concomitant medication was removed. 18. The excluded medications were updated to differentiate between prior use of medications resulting in exclusion and prior use of medications resulting in exclusion at the discretion of the investigator. 19. Relaxation of study restrictions due to the long duration of this study. 20. The instruction that breakfast and lunch should be standard meals each containing approximately 30% fat (relative total calories) was removed. 21. A partially unblinded safety physician, separate from the study team, was added. 22. Addition to include available information on coronavirus disease 2019 (COVID-19) vaccination. 23. Orthostatic blood pressure measuring was added. 24. A physical examination was added at Baseline 2. 25. Update to have PK samples close to MWT measurement for the potential PK/pharmacodynamic analysis. 26. The planned pregnancy test on Day 55 was moved to Day 56. 27. It was updated that pregnancy avoidance counselling should continue through follow-up. 28. An additional pregnancy test 30 days after the last intake of study drug was added.
    23 Sep 2021
    The following changes were implemented as per Amendment 2: 1. It was clarified that liver function test results should be available to check participant eligibility before enrollment. 2. Glutamate dehydrogenase (GLDH) and fluoride assessments have been added. 3. Additional safety assessments were added at increased frequency. 4. A criterion was added to assess participant suitability based on blood pressure data. 5. Orthostatic blood pressure measurement was added.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    03 Nov 2021
    A safety signal has emerged in Phase 2 studies of TAK-994. As an immediate precautionary measure, Takeda has suspended dosing of patients 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.
    None reported
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