The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of TAK-041: 1. Following oral single and multiple doses in healthy participants. 2. As add-on therapy to antipsychotics in stable schizophrenia participants. 3. To determine the oral bioavailability of the TAK-041 tablet formulation compared to the oral suspension formulation in the fasted state. 4. To assess the effect of food on the PK of TAK-041 in healthy participants.
The drug being tested in this study is called TAK-041. TAK-041 is being tested to evaluate its safety, tolerability, and PK of single and multiple doses in healthy participants and as add-on therapy to antipsychotics in participants with stable schizophrenia. This study will also assess the oral bioavailability in healthy participants administered with tablet formulation compared to oral suspension formulation in fasted state, and effect of high-fat, high-calorie meal on the PK of single dose of TAK-041 tablet formulation. The study will enroll approximately 114 participants. The study is composed of 4 parts. Part 1 (single-rising dose \[SRD\], alternating panel design and a sequential panel design), Part 2 (multiple-rising dose \[MRD\], sequential panel design), Part 3 (open label parallel design), and Part 4 (single dose cohort). Part 1 consists of 5 cohorts, participants in Cohorts 1 and 2 will be randomly assigned (by chance, like flipping a coin) to treatment sequences of 2 periods and for Cohorts 3 to 5 participants will be assigned to a single dose sequential-panel: * TAK-041 5-160 mg * Placebo (inactive) - this is a similar formulation that looks like the study drug but has no active ingredient. Part 2 consists of 4 cohorts, participants will be randomly assigned to one of the two treatments: * TAK-041 * Placebo Dose levels for Part 2 cohort 1 will be based on emerging safety/tolerability and PK data from Part 1. The dose levels for Part 2 Cohorts 2 onwards will be based on emerging safety/tolerability and available PK data from Part 1 and from preceding cohorts in Part 2. Part 3 consists of 2 cohorts, participants will be randomly assigned to one of the two treatments under fasted state or fed state: * TAK-041 40 mg tablet (Fasted state) * TAK-041 40 mg tablet (Fed state) Part 4 consists of 1 cohort, participants will be randomly assigned to one of the two treatments: * TAK-041 * Placebo The dose levels for Part 4 will be based upon the emerging safety/tolerability and PK data of same dose in healthy participants from Part 2. This single center trial will be conducted in the United States. Participants will remain confined to the study site from check-in (Day -1) through Days 5 of each period in Part 1, on Days -2 to 3, Days 7 to 10, Days 14 to 17, Day 21 to 24 in Part 2, on Days 1 to 3 in Part 3, and on Days -2 to 3, Days 7 to 10, Days 14 to 17, Days 21 to 24 in Part 4. A final visit that completes the study will occur 12 to 16 days after the last safety and PK follow-up visit in Part 1, 2 and 4, and 18 days after dosing in Part 3.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
DOUBLE
Enrollment
114
TAK-041 tablets or oral suspension.
TAK-041 placebo-matching suspension or tablet.
Parexel Early Phase Clinic Unit- Los Angeles
Glendale, California, United States
Percentage of Participants Who Experienced at Least One Treatment-Emergent Adverse Event (TEAE)
An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug or due to a study procedure; it did not necessarily have to have a causal relationship with this treatment. A TEAE was defined as an AE that occurred or worsened after receiving the first dose of study drug and within 6 weeks after the last dose of study drug. A TEAE may also have been a pre-treatment AE or a concurrent medical condition diagnosed before the date of first dose of study drug that increased in severity after the start of dosing.
Time frame: From the first dose of study drug up to 42 days after the last dose of study drug (Up to 12 weeks)
Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug or due to a study procedure; it did not necessarily have to have a causal relationship with this treatment.
Time frame: From the first dose of study drug up to 42 days after the last dose of study drug (Up to 12 weeks)
Percentage of Participants With Markedly Abnormal Value (MAV) Criteria for Safety Laboratory Tests At Least Once Post-dose
Clinical laboratory tests included serum chemistry, hematology and urinalysis. MAV criteria:Alanine aminotransferase(U/L) \>3 x upper limit of normal(ULN);albumin\<2.5g/dL,\<25g/L;alkaline phosphatase (U/L)\>3 x ULN; aspartate aminotransferase (U/L)\>3 x ULN;bicarbonate\<8.0 mmol/L; bilirubin\>2.0mg/dL, \>34.2 μmol/L;blood urea nitrogen\>30 mg/dL,\>10.7mmol/L;calcium\<7.0 mg/dL,\<1.75 mmol/L, \>11.5 mg/dL,\>2.88 mmol/L;chloride\<75 mmol/L,\>126 mmol/L;creatine kinase(U/L) \>5 xULN; creatinine\>2.0 mg/dL,\>177μmol/L;direct bilirubin\>2 x ULN;gamma glutamyl transferase (U/L)\>3 x ULN;glucose\<50 mg/dL,\<2.8 mmol/L,\>350 mg/dL,\>19.4 mmol/L;potassium\<3.0 mmol/L \>6.0 mmol/L; protein(g/L)\<0.8 x LLN \>1.2 x ULN;sodium\<130mmol/L \>150mmol/L;erythrocytes(10\^12erythrocytes/L) \<0.8 x LLN,\>1.2 x ULN;hematocrit(fraction of 1)\<0.8 x LLN,\>1.2xULN;hemoglobin(g/L)\<0.8 x LLN\>1.2 x ULN;leukocytes(10\^9 leukocytes/L)\<0.5 x LLN \>1.5 x ULN;platelets(10\^9 platelets/L)\<75-\>600. Categories with at least one participant are reported.
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Time frame: From the first dose of study drug up to 42 days after the last dose of study drug (Up to 12 weeks)
Percentage of Participants With Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post-dose
Vital signs included oral body temperature measurement, supine and standing blood pressure, respiration rate, and pulse. Pulse and blood pressure was measured after 5 minutes supine and again at 1 and 3 minutes after standing. The markedly abnormal value (MAV) criteria for vital signs included systolic blood pressure \< 85 mmHg, \> 180 mmHg; diastolic blood pressure \< 50 mmHg, \> 110 mmHg; pulse \< 50 beats/min, \> 120 beats/min; temperature \< 35.6 C \> 37.7 C. Categories with data in at least one arm group are reported.
Time frame: From the first dose of study drug up to 42 days after the last dose of study drug (Up to 12 weeks)
Percentage of Participants With Markedly Abnormal Criteria for 12-Lead Electrocardiogram (ECG) Parameters at Least Once Post-dose
The markedly abnormal value (MAV) criteria for 12-lead ECG parameters included ECG Mean Heart Rate \< 50 beats/min, \> 120 beats/min; PR Interval, Aggregate \<= 80 msec, \>= 200 msec; QRS Duration, Aggregate \<= 80 msec, \>= 180 msec; QTcB Interval, Aggregate \<= 300 msec, \>= 500 msec OR (\>= 30 msec change from baseline and \>= 450 msec); QTcF Interval, Aggregate \<= 300 msec, \>= 500 msec OR (\>= 30 msec change from baseline and \>= 450 msec). Categories with data in at least one arm group are reported.
Time frame: From the first dose of study drug up to 42 days after the last dose of study drug (Up to 12 weeks)
Part 2: Percentage of Participants Who Experienced Clinically Significant Abnormal Changes in Continuous 12-Lead Holter ECG Measurements at Least Once Post-Dose
The markedly abnormal value (MAV) criteria for continuous 12-lead Holter ECG parameters included ECG Mean Heart Rate \< 50 beats/min, \> 120 beats/min; PR Interval, Aggregate \<= 80 msec, \>= 200 msec; QRS Duration, Aggregate \<= 80 msec, \>= 180 msec; QTcB Interval, Aggregate \<= 300 msec, \>= 500 msec OR (\>= 30 msec change from baseline and \>= 450 msec); QTcF Interval, Aggregate \<= 300 msec, \>= 500 msec OR (\>= 30 msec change from baseline and \>= 450 msec). Categories with data in at least one arm group are reported.
Time frame: Part 2: from first dose up to Day 66
Part 3: Cmax: Maximum Observed Plasma Concentration for TAK-041 in RBA/Food Effect Participants [Day 1]
Time frame: Part 3: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose
Part 3: AUC96: Area Under the Plasma Concentration-Time Curve From Time 0 to 96 Hours (AUC96) for TAK-041 in RBA/Food Effect Participants [Day 1]
Time frame: Part 3: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose
Part 1: Cmax: Maximum Observed Plasma Concentration for TAK-041 in SRD Participants [Day 1]
Time frame: Part 1: Day 1 pre-dose and at multiple time points post dose, up to 96 hours for Cohorts 1 and 2; up to 168 hours for Cohorts 3-5
Part 1: Cmax: Maximum Observed Plasma Concentration for TAK-041 in SRD Participants [Day 8], Cohorts 1 (20 mg) and 2 (40 mg) Only
Time frame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
Parts 2 and 4: Cmax: Maximum Observed Plasma Concentration for TAK-041 in MRD Participants [Day 1]
Time frame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part 1: Tmax: Time to Reach the Cmax for TAK-041 in SRD Participants [Day 1]
Time frame: Part 1: Day 1 pre-dose and at multiple time points post dose, up to 96 hours for Cohorts 1 and 2; up to 168 hours for Cohorts 3-5
Part 1: Tmax: Time to Reach the Cmax for TAK-041 in SRD Participants [Day 8], Cohorts 1 (20 mg) and 2 (40 mg) Only
Time frame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
Parts 2 and 4: Tmax: Time to Reach the Cmax for TAK-041 in MRD Participants [Day 1]
Time frame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part 3: Tmax: Time to Reach the Cmax for TAK-041 in RBA/Food Effect Participants [Day 1]
Time frame: Part 3: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose
Part 1: AUC24: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours for TAK-041 in SRD Participants [Day 1]
Time frame: Part 1: Day 1 pre-dose and at multiple time points post dose, up to 96 hours for Cohorts 1 and 2; up to 168 hours for Cohorts 3-5
Part 1: AUC24: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours for TAK-041 in SRD Participants [Day 8], Cohorts 1 (20 mg) and 2 (40 mg) Only
Time frame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
Parts 2 and 4: AUC24: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours for TAK-041 in MRD Participants [Day 1]
Time frame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part 3: AUC24: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours for TAK-041 in RBA/Food Effect Participants [Day 1]
Time frame: Part 3: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose
Part 1: AUC96: Area Under the Plasma Concentration-Time Curve From Time 0 to 96 Hours for TAK-041 in SRD Participants [Day 1]
Time frame: Part 1: Day 1 pre-dose and at multiple time points post dose, up to 96 hours for Cohorts 1 and 2; up to 168 hours for Cohorts 3-5
Part 1: AUC96: Area Under the Plasma Concentration-Time Curve From Time 0 to 96 Hours for TAK-041 in SRD Participants [Day 8], Cohorts 1 (20 mg) and 2 (40 mg) Only
Time frame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
Parts 2 and 4: AUC96: Area Under the Plasma Concentration-Time Curve From Time 0 to 96 Hours for TAK-041 in MRD Participants [Day 1]
Time frame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part 1: AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to Time t for TAK-041 in SRD Participants [Day 1]
Time frame: Part 1: Day 1 pre-dose and at multiple time points post dose, up to 96 hours for Cohorts 1 and 2; up to 168 hours for Cohorts 3-5
Part 1: AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to Time t for TAK-041 in SRD Participants [Day 8], Cohorts 1 (20 mg) and 2 (40 mg) Only
Time frame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
Parts 2 and 4: AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to Time t for TAK-041 in MRD Participants [Day 1]
Time frame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part 3: AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to Time t for TAK-041 in RBA/Food Effect Participants [Day 1]
Time frame: Part 3: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose
Part 1: AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for TAK-041 in SRD Participants [Day 1]
Time frame: Part 1: Day 1 pre-dose and at multiple time points post dose, up to 96 hours for Cohorts 1 and 2; up to 168 hours for Cohorts 3-5
Part 1: AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for TAK-041 in SRD Participants [Day 8], Cohorts 1 (20 mg) and 2 (40 mg) Only
Time frame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
Parts 2 and 4: AUCtau: Area Under the Plasma Concentration-Time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-041 in MRD Participants [Day 1]
Time frame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part 1: T1/2z: Terminal Disposition Phase Half-Life for TAK-041 in SRD Participants [Day 1]
Time frame: Part 1: Day 1 pre-dose and at multiple time points post dose, up to 96 hours for Cohorts 1 and 2; up to 168 hours for Cohorts 3-5
Part 1: T1/2z: Terminal Disposition Phase Half-Life for TAK-041 in SRD Participants [Day 8], Cohorts 1 (20 mg) and 2 (40 mg) Only
Time frame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
Parts 2 and 4: T1/2z: Terminal Disposition Phase Half-Life for TAK-041 in MRD Participants [Day 1]
Time frame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose