The main aims of the study are: * To check for side effects from TAK-994 and check what dose of TAK-994 participants can tolerate. * To check what dose range provides adequate relief of narcolepsy symptoms. * To check how much TAK-994 stays in the blood of participants, over time. The study will have 4 parts. Participants can only join 1 of the parts. A. Participants with type 1 narcolepsy will take either TAK-994 or placebo tablets for 28 days. A placebo looks just like TAK-994 but will not have any medicine in it. B. Participants with type 1 narcolepsy will take 1 of 3 doses of TAK-994 or placebo tablets for 56 days. C. Participants with type 1 narcolepsy in China only will take TAK-994 or placebo tablets for 56 days. D. Participants with type 2 narcolepsy will take either TAK-994 or placebo tablets for 28 days.
The drug being tested in this study is called TAK-994. TAK-994 is being tested in participants with NT1 and NT2. The study will enroll up to approximately 202 participants. The study has 4 Parts: Parts A, B, C (China only) and D. Part A - Part A has 2 cohorts \[Cohorts (A1a and A1b) A2\] In both of these Cohorts, participants will be randomly assigned (by chance, like flipping a coin) in a 2:1 ratio to receive TAK-994 or placebo up to 28 days: * Part B: In Part B, participants will be randomized in 1:1:1:1 ratio in four parallel arms to receive TAK-994 Dose 1, 2 or 3 or placebo for 56 days. Depending upon their eligibility participants completing Part B of the study treatment will be enrolled to participate in an Extension study. * Part C: In Part C, participants only from China will be enrolled and randomized in a 2:1 ratio to receive TAK-994 and placebo for 56 days. * Part D: Participants will be included in two cohorts \[Cohorts (D1a and D1b) and D2\] and will be randomized in 2:1 ratio to receive TAK-994 or placebo for 28 days. The dose will be selected based on the safety and tolerability in Part A. This multi-center trial will be conducted in the United States, Japan, China, Italy, France, and European Union. The overall duration of the study is 63 days. Participants will be followed up for 7 days after the last dose of study drug.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
97
Wright Clinical Research
Alabaster, Alabama, United States
Mayo Clinic Arizona
Phoenix, Arizona, United States
CITrials - Bellflower
Bellflower, California, United States
Santa Monica Clinical Trials
Los Angeles, California, United States
Stanford School of Medicine
Redwood City, California, United States
Part A: Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) During the Study
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an AE with an onset that occurs after receiving study drug.
Time frame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study
Standard safety laboratory values (hematology, serum chemistry, urinalysis) were collected and compared to pre-specified criteria for markedly abnormal values. Markedly abnormal values criteria: Erythrocytes(10\^12/L:\<0.8xlower limit of normal(LLN), \>1.2xupper limit of normal(ULN); Hemoglobin grams per litre(g/L):\<0.8xLLN, \>1.2xULN; Hematocrit voltage/volts(V/V):\<0.8xLLN, \>1.2xULN; Platelets(10\^9/L):\<75, \>600; Leukocytes(10\^9/L):\<0.5xLLN, \>1.5xULN; Alanine Aminotransferase units/litre(U/L):\>3xULN, Aspartate Aminotransferase(U/L):\>3xULN; Bilirubin micromoles/litre (umol/L):\>1.5xULN; Alkaline Phosphatase(U/L):\>3xULN; Gamma Glutamyl Transferase(U/L):\>3 x ULN; Albumin(g/L):\<25; Protein Total(g/L):\<0.8xLLN, \>1.2xULN;Glucose millimoles/litre(mmol/L):\<2.8, \>19.4; Calcium(mmol/L):\<1.92, \>2.77; Creatinine(umol/L):\>1.5xULN; Urea(mmol/L):\>10.7; Sodium(mmol/L):\<130, \>150; Potassium(mmol/L):\<3.0, \>5.3. Only categories with at least one participant with event are reported.
Time frame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study
Vital signs (body temperature and sitting blood pressure) were collected and compared to pre-specified criteria for markedly abnormal values throughout the study. Markedly abnormal values criteria: Heart Rate (beats/min): \<40, \>115; Systolic Blood Pressure millimeters of mercury (mmHg): \<90, ≥160, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Diastolic Blood Pressure (mmHg): \<50, ≥100, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Respiratory Rate (breaths/min): \>21; Temperature Celsius (C): \>38.5. Only categories with at least one participant with event are reported.
Time frame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study
A 12 lead ECG was performed, the ECG values were compared to pre-specified criteria for markedly abnormal values. Markedly abnormal values criteria: ECG Mean Heart Rate (beats/min): \<40, \>115; PR Interval milliseconds (msec): ≤80, ≥200; corrected QT interval by Fredericia (QTcF) Interval (msec): ≤300, \>500, ≥30 change from baseline and \>450; QRS Duration (msec): ≤80, ≥180. Only categories with at least one participant with event are reported.
Time frame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the Maintenance of Wakefulness Test (MWT)
MWT: validated, objective measure that evaluates person's ability to remain awake under soporific conditions for defined period. During each MWT session (1 session=40 minutes), participants were instructed to sit quietly and remain awake for as long as possible. Sleep latency in each session was recorded on electroencephalography (EEG). If no sleep had been observed according to these rules, then latency= 40 minutes. Mixed-effect model for repeated measures (MMRM) was used for analysis. Due to early termination of the study, no post-baseline efficacy data for this outcome measure was collected and analyzed for participants in Part C: TAK-994 180 mg.
Time frame: Baseline and Week 8 (Day 56) in Parts B and C
Part A: Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 at Day 1
Time frame: Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 1 in Part A
Part A: Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 at Day 1
Time frame: Pre-dose and at multiple time points (Up to 14 hours) post-dose at Day 1 in Part A
Part A: AUC(0-last): Area Under the Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration After Single Dose of TAK-994 at Day 1
Time frame: Pre-dose and at multiple time points (up to 24 hours) post-dose at Day 1 in Part A
Part A: Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 at Day 28
Time frame: Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 28 in Part A
Part A: Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 at Day 28
Time frame: Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 28 in Part A
Part A: AUC(0-t): Area Under the Concentration-time Curve From Time 0 to Time Tau Over a Dosing Interval of TAK-994 at Day 28
Time frame: Pre-dose and at multiple time points (Up to 12 hours) post-dose at Day 28 in Part A
Parts B and C: Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 8
The ESS is a subjective, self-administered, validated scale (scored 0 to 3) to respond to each of the 8 questions of daily life that asks participants how likely they are to fall asleep in those situations. The scores are summed to give an overall score of 0 to 24. Higher scores indicate stronger subjective daytime sleepiness, and scores below 10 are considered to be within the normal range. MMRM was used for analysis. Due to early termination of the study, no post-baseline secondary efficacy data for this outcome measure was collected and analyzed for participants in Part C: TAK-994 180 mg.
Time frame: Baseline and Week 8 (Day 56) in Parts B and C
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Pacific Research Network, Inc
San Diego, California, United States
SDS Clinical Trials, Inc.
Santa Ana, California, United States
Alpine Clinical Research Center
Boulder, Colorado, United States
Delta Waves Sleep Disorders and Research Center
Colorado Springs, Colorado, United States
St. Francis Medical Institute
Clearwater, Florida, United States
...and 68 more locations
Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) at Week 8
Participants will complete a daily patient-reported sleep diary to record self-reported narcolepsy symptoms. Participants will record episodes of cataplexy in the diary. The total number of events averaged for a week will be reported. WCR = (Total number of cataplexy over a number of non-missing diary days for a given duration/number of Non-missing diary days in that duration)\*7. MMRM was used for the analysis. Due to early termination of the study, no secondary efficacy data was collected and analyzed for participants in Part C: TAK-994 180 mg.
Time frame: Baseline and Week 8 (Day 56) in Parts B and C
Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an AE with an onset that occurs after receiving study drug.
Time frame: First dose of study drug to end of study follow-up (up to Day 63) in Parts B and C
Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study
Standard safety laboratory values (serum chemistry, hematology, and urine analysis) were collected and compared to pre-specified criteria for Markedly Abnormal Values throughout the study. Markedly abnormal values criteria: Alanine Aminotransferase (U/L):\>3xULN, Aspartate Aminotransferase(U/L):\>3xULN; Bilirubin micromoles/litre (umol/L):\>1.5xULN; Calcium(mmol/L):\<1.92, \>2.77; Potassium(mmol/L):\<3.0, \>5.3. Only categories with at least one participant with event are reported.
Time frame: Up to Day 63 in Parts B and C
Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study
Vital signs (body temperature and sitting blood pressure) were collected and compared to pre-specified criteria for markedly abnormal values throughout the study. Markedly abnormal values criteria: Systolic Blood Pressure millimeters of mercury (mmHg): \<90, ≥160, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Diastolic Blood Pressure (mmHg): \<50, ≥100, Change from Pre-Dose \>20, Change from Pre-Dose \>30, Time-matched Change from Baseline \> 20, Time-matched Change from Baseline \> 30; Respiratory Rate (breaths/min): \>21.Only categories with at least one participant with event are reported.
Time frame: Up to Day 63 in Parts B and C
Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study
A 12 lead ECG was performed, the ECG values were compared to pre-specified criteria for markedly abnormal values. Markedly abnormal values criteria: PR Interval (msec): ≤80, ≥200; QRS Duration (msec): ≤80, ≥180. Only categories with at least one participant with event are reported.
Time frame: Up to Day 63 in Parts B and C