Clinical trial NCT01879722: Safety, Tolerability and Pharmacokinetic Study of Multiple Rising Doses of TAK- 063 in Participants With Stable Schizophrenia and Healthy Participants
Official title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and Pharmacokinetic Study of Multiple Rising Doses of TAK- 063 in Subjects With Stable Schizophrenia and Healthy Japanese Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Schizophrenia
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2013-06-18
Enrollment: 77
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to characterize the safety and tolerability of TAK-063 when administered as multiple oral doses at escalating dose levels in participants with stable schizophrenia and in healthy Japanese participants.

Detailed description: The drug being tested in this study is called TAK-063. TAK-063 is being tested to find a well-tolerated dose and also to treat schizophrenia. This study will look at how well different doses of TAK-063 are tolerated in healthy people of Japanese descent and in people with stable schizophrenia.

Five dose levels will be examined, starting at the lowest, in each population with 10 participants in each dose level. These participants will be randomized to receive TAK-063 (8 subjects) and placebo (2 subjects) once daily (QD) for 7 days.

In total, approximately 60 participants will be enrolled in the study. This trial will be conducted in single site in the United States. The overall time to participate in this study is up to 42 days. Participants will make 2 visits to the clinic, including 8-10 days confinement to the clinic, and will be contacted by telephone 7 days after last dose of study drug for a follow-up assessment.

Dose escalation and the actual choice of the subsequent dose level will only occur following a review of the blinded data from the previous cohorts.

Eligibility criteria: Inclusion Criteria:

Healthy Participants:

1. Aged 20-55 years, inclusive, at the time of informed consent and first study medication dose.
2. Is a healthy adult male or female of Japanese descent (born to Japanese parents and grandparents and has lived outside of Japan for less than 5 years).
3. Weighs at least 45 kg and has a body mass index (BMI) between 18.0 and 28.0 kg/m\^2, inclusive, at Screening.

Participants with Stable Schizophrenia:

1. Is aged 18 to 55 years, inclusive, at the time of informed consent and first study medication dose.
2. Is an adult male or female with a diagnosis of schizophrenia or schizoaffective disorder.
3. Weighs at least 45 kg and has a BMI between 18.0 and 35.0 kg/m\^2, inclusive at Screening.
4. Has been receiving a stable dose of antipsychotic monotherapy for at least 1 month prior to Screening.
5. Has not had an acute exacerbation of psychosis or been hospitalization for the treatment of schizophrenia or schizoaffective disorder for at least 3 months prior to Screening.

Exclusion Criteria:

All Participants:

1. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality (other than the disease being studied), which may impact the ability of the participant to participate or potentially confound the study results.
2. If female, the participant is pregnant or lactating or intending to become pregnant, or intending to donate ova, before, during the course of the study or within 12 weeks after last dose.
3. Intends to donate sperm during the course of this study or for 12 weeks after last dose.
4. Has evidence of current cardiovascular, central nervous system, hepatic, 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 tests giving reasonable suspicion of a disease that would contraindicate taking TAK-063, or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias.

Healthy Participants:

1. Has a history or treatment of Axis I/II mental disorders according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) such as depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, anorexia nervosa, bulimia nervosa or schizophrenia within the past 3 years.
2. Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in Day -1. Cotinine test is positive at Screening or Check-in (Day -1).

Participants with Stable Schizophrenia:

1. Has a history of a primary DSM-IV axis I diagnosis other than schizophrenia or schizoaffective disorder.
2. Has not discontinued antipsychotic or other psychotropic medications or is unable to discontinue antipsychotic or other psychotropic medications at Day -7 (or five half-lives prior to Day -1).
3. Is taking a concomitant medication for a medical condition at a stable dose or regimen for less than two months or is taking a concomitant medication for a medical condition for less than two months and for which the discontinuation for the study period is not medically permissible.

Primary outcomes:
measure: Percentage of Participants Who Experience at Least One Treatment-Emergent Adverse Event (TEAE) After 7 Days of Dosing
timeFrame: Day 1 to Day 14
measure: Percentage of Participants With Markedly Abnormal Safety Laboratory Tests
timeFrame: Day 1 to Day 8
measure: Percentage of Participants With Markedly Abnormal Vital Sign Measurements
timeFrame: Day 1 to Day 8
measure: Percentage of Participants With Markedly Abnormal Values of 12-Lead Electrocardiogram (ECG) Parameters
timeFrame: Day 1 to Day 8
Secondary outcomes:
measure: Cmax: Maximum Observed Plasma Concentration for TAK-063 and TAK-063 Metabolite M-I
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-063 and TAK-063 Metabolite M-I
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-063 and TAK-063 Metabolite M-I
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose for TAK-063 and TAK-063 Metabolite M-I
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: CL/F: Oral Clearance of TAK-063
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: Average Plasma Concentration on Day 1 (Cav) and Day 7 (Cavss) for TAK-063 and TAK-063 Metabolite M-I
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: Cmax Molar Ratio: Ratio of TAK-063 Metabolite Cmax to TAK-063 Cmax
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: AUC(0-24) Ratio: Ratio of TAK-063 Metabolite AUC(0-24) to TAK-063 AUC(0-24)
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: Accumulation Ratios Between Day 7 AUC(0-24) and Day 1 AUC(0-24)
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: Ae(0-24): Total Amount Excreted in the Urine From Time 0 to 24 Hours Postdose for TAK-063 and TAK-063 Metabolite M-I
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: Fe: Fraction of Drug Excreted in Urine for TAK-063
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
measure: CLr: Renal Clearance of TAK-063 and TAK-063 Metabolite M-I
timeFrame: Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)
Other outcomes:
Locations:
city: Glendale
country: United States
state: California
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Goldsmith P, Affinito J, McCue M, Tsai M, Roepcke S, Xie J, Gertsik L, Macek TA. A Randomized Multiple Dose Pharmacokinetic Study of a Novel PDE10A Inhibitor TAK-063 in Subjects with Stable Schizophrenia and Japanese Subjects and Modeling of Exposure Relationships to Adverse Events. Drugs R D. 2017 Dec;17(4):631-643. doi: 10.1007/s40268-017-0214-8.