Safety, Tolerability and Pharmacokinetic Study of Multiple Rising Doses of TAK- 063 in Participants With Stable Schizophrenia and Healthy Participants

Phase 1

Completed

• Conditions: Schizophrenia
• Interventions: Drug: TAK-063; Drug: TAK-063 Placebo

• Registration Number: NCT01879722
• Lead Sponsor: Takeda

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.

Study Timeline

• Study Start: 2013-06
• Study First Submitted: 2013-06-13
• Study First Submitted QC: 2013-06-13
• Study First Posted: 2013-06-18
• Primary Completion: 2014-06
• Study Completion: 2014-06
• Results First Submitted: 2015-06-25
• Status Verified: 2016-09
• Results First Submitted QC: 2016-09-09
• Last Update Submitted: 2016-09-09
• Results First Posted: 2016-10-28
• Last Update Posted: 2016-10-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 77

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TAK-063 30 mg	TAK-063	TAK-063 30 mg, tablets, orally, once daily for 7 days.
TAK-063 100 mg	TAK-063	TAK-063 100 mg, tablets, orally, once daily for 7 days.
TAK-063 3 mg	TAK-063	TAK-063 3 mg, tablets, orally, once daily for 7 days.
TAK-063 10 mg	TAK-063	TAK-063 10 mg, tablets, orally, once daily for 7 days.
TAK-063 20 mg	TAK-063	TAK-063 20 mg, tablets, orally, once daily for 7 days.
Placebo	TAK-063 Placebo	Placebo matching TAK-063, tablets, orally, once daily for 7 days.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Markedly Abnormal Safety Laboratory Tests	Day 1 to Day 8	The percentage of participants with any markedly abnormal standard safety laboratory values, including hematology, serum chemistries, and urinalysis, during the treatment period.
Percentage of Participants Who Experience at Least One Treatment-Emergent Adverse Event (TEAE) After 7 Days of Dosing	Day 1 to Day 14	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 (eg, 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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Percentage of Participants With Markedly Abnormal Vital Sign Measurements	Day 1 to Day 8	The percentage of participants who meet markedly abnormal criteria for vital signs, including oral body temperature, respiration rate, pulse, and resting blood pressure and after standing
Percentage of Participants With Markedly Abnormal Values of 12-Lead Electrocardiogram (ECG) Parameters	Day 1 to Day 8	The percentage of participants who meet markedly abnormal criteria specified by the protocol and statistical analysis plan during the treatment period.

Secondary Outcome Measures

Name	Time	Method
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	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	AUC(0-tlqc) is a measure of total plasma exposure to the drug from time 0 to time of the Last Quantifiable Concentration.
Average Plasma Concentration on Day 1 (Cav) and Day 7 (Cavss) for TAK-063 and TAK-063 Metabolite M-I	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	Cav is the Average plasma concentration on Day 1, calculated as AUC(0-24)/24 on Day 1. Cavss is the average plasma concentration on Day 7, calculated as AUC(0-24)/24 on Day 7.
AUC(0-24) Ratio: Ratio of TAK-063 Metabolite AUC(0-24) to TAK-063 AUC(0-24)	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	AUC(0-24) Ratio is the ratio of AUC(0-24) values of the metabolite compared to the parent calculated by dividing AUC(0-24) values of metabolite M-I with those of the parent drug TAK-063.
Cmax: Maximum Observed Plasma Concentration for TAK-063 and TAK-063 Metabolite M-I	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
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	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	AUC(0-24) is a measure of total plasma exposure to the drug from Time 0 to 24 hours post-dose.
Cmax Molar Ratio: Ratio of TAK-063 Metabolite Cmax to TAK-063 Cmax	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	Cmax Molar Ratio is the ratio of Cmax molar values of the metabolite compared to the parent calculated by dividing Cmax molar values of metabolite M-I with those of TAK-063.
Accumulation Ratios Between Day 7 AUC(0-24) and Day 1 AUC(0-24)	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	Accumulation ratios between Day 7 AUC(0-24) and Day 1 AUC(0-24), (Day 7/Day 1). Estimated Ratio (Day 7/Day 1) is the exponentiated results of the difference between Day 7 and Day 1 in log-transformed values which resolves to the ratio of Day 7/Day 1 estimates.
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	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	Ae(0-24) is a measure of the total amount of study drug excreted in the urine from time 0 to 24 hours postdose.
Fe: Fraction of Drug Excreted in Urine for TAK-063	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	Fe is a measure of the fraction of drug excreted in urine and is calculated as Fe = (total amount excreted in the urine from time 0 to 24 hours post-dose / dose)×100
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-063 and TAK-063 Metabolite M-I	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
CL/F: Oral Clearance of TAK-063	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided by area under the curve from time 0 to 24 hours post-dose, after multiple dosing (at steady state).
CLr: Renal Clearance of TAK-063 and TAK-063 Metabolite M-I	Days 1 and 7 pre-dose and multiple time-points post-dose (Up to 24 hours)	CLr is a measure of apparent clearance of the drug from the urine calculated as total amount excreted in the urine from time 0 to 24 hours postdose / plasma area under the curve from time 0 to 24 hours post-dose.