Clinical trial NCT02748694: Phase 1 TAK-041 First-in-Human Safety, Tolerability, and Pharmacokinetics Study
Official title: A Randomized, Double -Blind, Placebo-Controlled, Phase 1, Ascending Oral Single and Multiple Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-041 in Healthy Subjects and Subjects With Stable Schizophrenia and a Randomized Open-Label, Single Dose, Parallel Design to Evaluate the Relative Bioavailability and Effect of Food on the Pharmacokinetics of TAK-041 Tablet Formulation in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Schizophrenia
Keywords: Drug Therapy
Lead sponsor: Neurocrine Biosciences
Sponsor class: INDUSTRY
Collaborators: name: Takeda
First posted: 2016-04-22
Enrollment: 114
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

Healthy Participants and Participants with Schizophrenia:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any participant procedures including requesting that a participant fast for any laboratory evaluations.
3. The participant is willing to comply with study restrictions described in the protocol.
4. The participant is a healthy adult man or woman (of non-childbearing potential as described in the protocol)
5. The participant is aged 18 to 55 years, inclusive, at the time of informed consent.
6. The participant weighs at least 45 kilogram (kg) (99 pound \[lb\]) with a body mass index from 18 to 32 kilogram per square meter (kg/m\^2) for healthy participants and up to 40.5 kg/m\^2 for participants with schizophrenia, inclusive at screening.
7. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception (as defined in the protocol)from signing of informed consent throughout the duration of the study and for 145 days have elapsed since the last dose of study drug.

Participants with schizophrenia only-:

1. Is on a stable dose of an antipsychotic medication for at least 2 months as documented by medical history and assessed by site staff.
2. Meets schizophrenia criteria as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) by the Mini International Neuropsychiatric Interview (MINI).
3. Has Positive and Negative Syndrome Scale (PANSS) total score less than or equal to (\<=) 90 and PANSS Negative Symptom Factor Score (NSFS; Sum of PANSS N1, N2, N3, N4, N6, G7, and G16) greater than or equal to (\>=) 15 at screening and baseline (Day-1).
4. Has stable screening and baseline (Day -1) PANSS and NSFS total scores (less than \[\<\] 20 percent (%) change).

Exclusion Criteria:

Healthy Participants:

1. The participant has received any investigational compound within 30 days prior to the first dose of study drug, or due to the half-life of the investigational drug is likely to still have detectable plasma levels of that compound.
2. The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (example spouse, parent, child, sibling) or may consent under duress
3. The participant has a known hypersensitivity to any component of the formulation of TAK-041.
4. The participant has a positive urine/blood drug result for drugs of abuse (defined as any illicit drug use) at Screening or Check-in (Day -1).
5. The participant taken any excluded medication, supplements, or food products during the time periods listed in the protocol.
6. The participant is lactose intolerant (Part3 only).
7. If female, the participant is of childbearing potential (example, premenopausal, not sterilized).
8. If male, the participant intends to donate sperm during the course of this study or for 145 days have elapsed since the last dose of study drug.
9. The participant has evidence of current active cardiovascular, central nervous system, hepatobiliary disease including history of biliary tree disorders, gallstones, endoscopic retrograde cholangio pancreatography (ERCP), and/or cholecystectomy, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma, hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the participant's medical history, physical examination, or safety laboratory test results (including elevated alkaline phosphatase (ALP), elevated bilirubin, elevated GGT, or elevated 5'-nucleotidase) that in the judgment of the principal investigator represents a reasonable suspicion of a disease that would contraindicate taking TAK-041, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, cholestasis, seizure disorders, and cardiac arrhythmias.
10. The participant has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (that is, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent \[more than once per week\] occurrence of heartburn, or any surgical intervention).
11. Had major surgery, or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to Screening.
12. The participant has a history of cancer, except basal cell carcinoma that has been in remission for at least 5 years prior to Day 1. Participant has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody at Screening or a known history of human immunodeficiency virus (HIV) infection.
13. The participant has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 21 days prior to Check-in on Day -1. Cotinine test is positive at Screening or Day -1.
14. The participant has poor peripheral venous access.
15. Had a transfusion of any blood product within 30 days prior to Day 1.
16. Participant has a Screening or Check-in abnormal (clinically significant) electrocardiogram (ECG). Entry of any participant with an abnormal (not clinically significant) ECG must be approved, and documented by signature of the principal investigator or a medically qualified sub-investigator.
17. The participant has a sustained resting heart rate outside the range 40 to 100 beats per minute (bpm), confirmed on repeat testing within a maximum of 30 minutes, at Screening or Check-in.
18. The participant has a QT interval with Fridericia correction method (QTcF) \>450 millisecond (ms) or PR outside the range 120 to 220 ms, confirmed on repeat testing within a maximum of 30 minutes, at the Screening Visit or Check-in.
19. The participant has abnormal Screening or Check-in laboratory values (\> upper limit of normal \[ULN\] for the respective serum chemistries) of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBILI), ALP, gamma-glutamyl transpeptidase (GGT), 5'nucleotidase (Screening only) and/or abnormal urine osmolality, confirmed upon repeat testing.
20. The participant has a clinically significant history of head injury or trauma associated with loss of consciousness for \>15 minutes.
21. Is considered by the investigator to be at an imminent risk of suicide injury to self, other, property, or participants who within the past year prior to Screening have attempted suicide. Participants having positive answer on item 4 or 5 on Columbia Suicide Severity Rating Scale (C-SSRS) (based on the past year) prior to randomization are excluded.
22. The participant has a history of significant skin reactions (hypersensitivity) to adhesives, metals or plastic; this criterion applies only to participants participating in the study of the two wearable digital devices.

Participants with schizophrenia only:

1. Has an undetectable level of baseline antipsychotic medication at Screening.
2. Has a lifetime diagnosis of schizoaffective disorder; a lifetime diagnosis of bipolar disorder; or a lifetime diagnosis of obsessive compulsive disorder based on the Mini International Neuropsychiatric Interview (MINI) combined with the general psychiatric evaluation. As an exception, participants with a historical prior lifetime diagnosis of schizoaffective disorder may be enrolled in the study with sponsor or designee approval provided that the principal investigator can attest that the participant's overall history and current clinical presentation and history is most consistent with schizophrenia, not schizoaffective disorder.
3. Has a recent (within the last 6 months) diagnosis of panic disorder, depressive episode, or other comorbid psychiatric conditions requiring clinical attention based on the MINI for DSM-5 and the general psychiatric evaluation.
4. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as 4 or more alcoholic beverages per day) within 1 year prior to the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.
5. Has a diagnosis of substance use disorder (with the exception of nicotine dependence) within the preceding 6 months based on the MINI for DSM-5 and the general psychiatric evaluation.
6. Has evidence or history of current clinically significant cardiovascular disease, including uncontrolled hypertension (standing or supine diastolic blood pressure \>90 millimeter of mercury (mm Hg) and/or standing or supine systolic blood pressure \>145 mm Hg, with or without treatment), symptomatic ischemic heart disease, uncompensated heart failure or recent (past 12 months) acute myocardial infarction or bypass surgery. Controlled essential hypertension, non-clinically significant sinus bradycardia and sinus tachycardia will not be considered significant medical illnesses and would not exclude a participant from the study. Other well-controlled medical illnesses may be permitted that do not increase hepatic risks or other safety risks to the participant's participation in the judgement of the investigator in consultation with the sponsor or designee.
7. Has evidence of clinically significant extrapyramidal symptoms as measured by a Simson-Angus Scale (SAS) score \>6.
8. The participant has evidence of depression as measured by a Calgary Depression Score (CDSS) score \>9.
9. Has received TAK-041 in a previous clinical study; or has previously or is currently participating in this study; has received treatment with other experimental therapies within the preceding 60 days or \<5 half-lives prior to randomization, whichever is longer; has participated in 2 or more clinical studies within 12 months prior to Screening; or has participated in a clinical study for a psychiatric condition that is exclusionary per this protocol.

Primary outcomes:
measure: Percentage of Participants Who Experienced at Least One Treatment-Emergent Adverse Event (TEAE)
timeFrame: From the first dose of study drug up to 42 days after the last dose of study drug (Up to 12 weeks)
measure: Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (AE)
timeFrame: From the first dose of study drug up to 42 days after the last dose of study drug (Up to 12 weeks)
measure: Percentage of Participants With Markedly Abnormal Value (MAV) Criteria for Safety Laboratory Tests At Least Once Post-dose
timeFrame: From the first dose of study drug up to 42 days after the last dose of study drug (Up to 12 weeks)
measure: Percentage of Participants With Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post-dose
timeFrame: From the first dose of study drug up to 42 days after the last dose of study drug (Up to 12 weeks)
measure: Percentage of Participants With Markedly Abnormal Criteria for 12-Lead Electrocardiogram (ECG) Parameters at Least Once Post-dose
timeFrame: From the first dose of study drug up to 42 days after the last dose of study drug (Up to 12 weeks)
measure: Part 2: Percentage of Participants Who Experienced Clinically Significant Abnormal Changes in Continuous 12-Lead Holter ECG Measurements at Least Once Post-Dose
timeFrame: Part 2: from first dose up to Day 66
measure: Part 3: Cmax: Maximum Observed Plasma Concentration for TAK-041 in RBA/Food Effect Participants [Day 1]
timeFrame: Part 3: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose
measure: 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]
timeFrame: Part 3: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose
Secondary outcomes:
measure: Part 1: Cmax: Maximum Observed Plasma Concentration for TAK-041 in SRD Participants [Day 1]
timeFrame: 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
measure: Part 1: Cmax: Maximum Observed Plasma Concentration for TAK-041 in SRD Participants [Day 8], Cohorts 1 (20 mg) and 2 (40 mg) Only
timeFrame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
measure: Parts 2 and 4: Cmax: Maximum Observed Plasma Concentration for TAK-041 in MRD Participants [Day 1]
timeFrame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
measure: Part 1: Tmax: Time to Reach the Cmax for TAK-041 in SRD Participants [Day 1]
timeFrame: 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
measure: 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
timeFrame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
measure: Parts 2 and 4: Tmax: Time to Reach the Cmax for TAK-041 in MRD Participants [Day 1]
timeFrame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
measure: Part 3: Tmax: Time to Reach the Cmax for TAK-041 in RBA/Food Effect Participants [Day 1]
timeFrame: Part 3: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose
measure: Part 1: AUC24: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours for TAK-041 in SRD Participants [Day 1]
timeFrame: 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
measure: 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
timeFrame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
measure: 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]
timeFrame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
measure: 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]
timeFrame: Part 3: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose
measure: Part 1: AUC96: Area Under the Plasma Concentration-Time Curve From Time 0 to 96 Hours for TAK-041 in SRD Participants [Day 1]
timeFrame: 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
measure: 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
timeFrame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
measure: 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]
timeFrame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
measure: Part 1: AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to Time t for TAK-041 in SRD Participants [Day 1]
timeFrame: 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
measure: 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
timeFrame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
measure: 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]
timeFrame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
measure: 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]
timeFrame: Part 3: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose
measure: Part 1: AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for TAK-041 in SRD Participants [Day 1]
timeFrame: 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
measure: 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
timeFrame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
measure: 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]
timeFrame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
measure: Part 1: T1/2z: Terminal Disposition Phase Half-Life for TAK-041 in SRD Participants [Day 1]
timeFrame: 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
measure: 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
timeFrame: Part 1: Pre-dose on Day 8 and at multiple timepoints (Up to 96 hours) post-dose
measure: Parts 2 and 4: T1/2z: Terminal Disposition Phase Half-Life for TAK-041 in MRD Participants [Day 1]
timeFrame: Parts 2 and 4: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Parexel Early Phase Clinic Unit- Los Angeles
state: California
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References:
citation: Yin W, Han D, Khudyakov P, Behrje R, Posener J, Laurenza A, Arkilo D. A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia. Br J Clin Pharmacol. 2022 Aug;88(8):3872-3882. doi: 10.1111/bcp.15305. Epub 2022 Apr 17.