Single-Dose Phase 1 Study of TAK-792

Study Overview
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Brief Summary
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The purpose of this study is to characterize the safety and tolerability profile of TAK-792 when administered as a single oral dose in healthy Japanese and Caucasian male participants.

Detailed Description
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This study will be double-blind and placebo-controlled to avoid subjective bias in the assessment of safety and tolerability of TAK-792. Sentinel dosing will be used in the first cohort (cohort 1) to ensure adequate safety and tolerability evaluation prior to administering TAK-792 to the remainder of participants within the cohort. The dose escalation to the next cohort for Cohorts 2 to 6 will occur after full review of safety and tolerability of the current cohort, and available pharmacokinetic data up to 24 hours in the preceding cohorts. The planned dose levels are 30, 100, 250, 500, 750 and 1250 mg, to be administered in the morning after a fast of at least 10 hours.

Official Title
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A Randomized, Single-Center, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Single Oral Dose of TAK-792 in Healthy Subjects

Conditions
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Healthy Male Adults Participants

Intervention / Treatment
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* Drug: TAK-792 30 mg
* Drug: TAK-792 30 mg placebo
* Drug: TAK-792 100 mg
* Drug: TAK-792 100 mg placebo
* Drug: TAK-792 250 mg
* Drug: TAK-792 250 mg placebo
* Drug: TAK-792 500 mg
* Drug: TAK-792 500 mg placebo
* Drug: TAK-792 750 mg
* Drug: TAK-792 750 mg placebo
* Drug: TAK-792 1250 mg
* Drug: TAK-792 1250 mg placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In the opinion of the investigator or sub-investigator, the participant is capable of understanding and complying with protocol requirements. The participant signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. The participant is a healthy male of Japanese descent (born to Japanese parents and grandparents) or Caucasian descent (born to Caucasian parents and grandparents). The participant is aged 20 to 45 years, inclusive, at the time of informed consent. The participant weighs at least 50 kilogram (kg) and has a body mass index (BMI) between 18.5 kilogram per square meter (kg/m^2) and 25.0 kg/m^2 for Japanese, BMI between 18.5 kg/m^2 and 30.0 kg/m^2 for Caucasian, inclusive at Screening and Day -1. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose. Exclusion Criteria:. The participant has received any investigational compound within 16 weeks (112 days) prior to the dose of study medication. The participant is an immediate family member, study site employee, or in a dependent relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. The participant has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urological, or endocrine disease or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results. The participant has a positive urine drug result for drugs of abuse at Screening. The participant has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 2 years prior to the Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. Participant has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products table. The participant intends to donate sperm during the course of this study or for 12 weeks thereafter. Participant 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. Participant has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis frequent [more than once per week] occurrence of heartburn, or any surgical intervention [eg, cholecystectomy]). Participant has a history of cancer, except basal cell carcinoma which 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 antibody (HCV), human immunodeficiency virus (HIV) antibody/antigen, or serological reactions for syphilis at Screening. Participant 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. The participant has poor peripheral venous access. The participant has undergone whole blood collection of at least 200 milliliter (mL) within 4 weeks (28 days) or at least 400 mL within 12 weeks (84 days) prior to the start of study drug administration. The participant has undergone whole blood collection of at least 800 mL in total within 52 weeks (364 days) prior to the start of study drug administration. The participant has undergone blood component collection within 2 weeks (14 days) prior to the start of study drug administration. Participant has a Screening abnormal (clinically significant) electrocardiogram (ECG). Participant has abnormal Screening laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than (>)1.5 the upper limits of normal. Participant who, in the opinion of the investigator or sub-investigator, is unlikely to comply with the protocol or is unsuitable for any other reason.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1-active<br>Single oral administration of TAK-792 30 milligram (mg) in Japanese participants | Drug: TAK-792 30 mg<br>* TAK-792 30 mg was administered in the morning after a fast.<br>|
| Placebo Comparator: Cohort 1-placebo<br>Single oral administration of TAK-792 30 mg placebo in Japanese participants | Drug: TAK-792 30 mg placebo<br>* TAK-792 30 mg placebo was administered in the morning after a fast.<br>|
| Experimental: Cohort 2-active<br>Single oral administration of TAK-792 100 mg in Japanese participants | Drug: TAK-792 100 mg<br>* TAK-792 100 mg was administered in the morning after a fast.<br>|
| Placebo Comparator: Cohort 2-placebo<br>Single oral administration of TAK-792 100 mg placebo in Japanese participants | Drug: TAK-792 100 mg placebo<br>* TAK-792 100 mg placebo was administered in the morning after a fast.<br>|
| Experimental: Cohort 3-active<br>Single oral administration of TAK-792 250 mg in Japanese participants | Drug: TAK-792 250 mg<br>* TAK-792 250 mg was administered in the morning after a fast.<br>|
| Placebo Comparator: Cohort 3-placebo<br>Single oral administration of TAK-792 250 mg placebo in Japanese participants | Drug: TAK-792 250 mg placebo<br>* TAK-792 250 mg placebo was administered in the morning after a fast.<br>|
| Experimental: Cohort 4-active<br>Single oral administration of TAK-792 500 mg in Japanese and Caucasian participants | Drug: TAK-792 500 mg<br>* TAK-792 500 mg was administered in the morning after a fast or after breakfast.<br>|
| Placebo Comparator: Cohort 4-placebo<br>Single oral administration of TAK-792 500 mg placebo in Japanese and Caucasian participants | Drug: TAK-792 500 mg placebo<br>* TAK-792 500 mg placebo was administered in the morning after a fast or after breakfast.<br>|
| Experimental: Cohort 5-active<br>Single oral administration of TAK-792 750 mg in Japanese and Caucasian participants | Drug: TAK-792 750 mg<br>* TAK-792 750 mg was administered in the morning after a fast.<br>|
| Placebo Comparator: Cohort 5-placebo<br>Single oral administration of TAK-792 750 mg placebo in Japanese and Caucasian participants | Drug: TAK-792 750 mg placebo<br>* TAK-792 750 mg placebo was administered in the morning after a fast.<br>|
| Experimental: Cohort 6-active<br>Single oral administration of TAK-792 1250 mg in Japanese and Caucasian participants | Drug: TAK-792 1250 mg<br>* TAK-792 1250 mg was administered in the morning after a fast.<br>|
| Placebo Comparator: Cohort 6-placebo<br>Single oral administration of TAK-792 1250 mg placebo in Japanese and Caucasian participants | Drug: TAK-792 1250 mg placebo<br>* TAK-792 1250 mg placebo was administered in the morning after a fast.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) |  | Baseline up to Day 8 | 
| Number of Participants With TEAE Related to Vital Signs | Vital signs included body temperature (infra-axillary measurement), supine blood pressure (systolic and diastolic) after the participant has rested for at least 5 minutes, respiratory rate, and pulse (beats per minute [bpm]). | Baseline up to Day 5 | 
| Number of Participants With TEAE Related to Body Weight |  | Baseline up to Day 5 | 
| Number of Participants With TEAE Related to Electrocardiograms (ECG) |  | Baseline up to Day 5 | 
| Number of Participants With TEAEs Related to Laboratory Tests | Reported TEAE Related to Laboratory Tests are following; Occult blood positive, Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood bilirubin increased, Blood creatine phosphokinase increased, Blood glucose increased, Blood triglycerides increased, Blood urine present, Protein urine present, and White blood cell count increased. | Baseline up to Day 5 | 
| Number of Participants With TEAE Related to Gastrointestinal Symptom Rating Scale (GSRS) | The gastrointestinal (GI) symptoms (abdominal pain, heartburn, acid regurgitation, hunger pains, nausea, borborygmus, abdominal distension, eructation, increased flatus, constipation, diarrhoea, loose stools, hard stools, urgent need for defecation, and feeling of incomplete evacuation) using GSRS questionnaires at each assessment point. The GSRS a 15-item self-administered questionnaire that assesses the impact of GI symptoms during the past week on a scale from 1 (no discomfort at all) to 7 (very severe discomfort). Possible overall scores range from 1 to 7, with lower scores indicating a better quality of life with respect to GI symptoms. TEAEs related to GSRS were reported as follows: Diarrhoea, Constipation, Faeces hard, and Faeces soft. | Baseline up to Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Postdose for TAK-792F and Its Metabolites M-I and M-II |  | Day 1: pre-dose and at multiple timepoints (0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 hours post dose; up to 96 hours) post-dose | 
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for TAK-792F and Its Metabolites M-I and M-II |  | Day 1: pre-dose and at multiple timepoints (0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 hours post dose; up to 96 hours) post-dose | 
| Cmax: Maximum Observed Plasma Concentration for TAK-792F and Its Metabolites M-I and M-II |  | Day 1: pre-dose and at multiple timepoints (0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 hours post dose; up to 96 hours) post-dose | 
| Tmax: Time to Reach the Cmax for TAK-792F and Its Metabolites M-I and M-II |  | Day 1: pre-dose and at multiple timepoints (0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96 hours post dose; up to 96 hours) post-dose | 
| Urinary Excretion Ratio of TAK-792F and Its Metabolites M-I and M-II as Percentage of TAK-792 Dose From 0 to 96 Hours Postdose |  | Day 1: pre-dose and at multiple timepoints (6, 12, 24, 36, 48, 72, 96 hours post dose; up to 96 hours) post-dose | 
| AUC(0-2.5): Area Under the Plasma Concentration-time Curve From Time 0 to 2.5 Hours Postdose for Total Branched Chain Amino Acids (BCAA) Parameter in Cohorts 4a-2, 4b-2, 5a-2 and 5b-2 |  | Day -1: pre-dose and Day 1 (2.5 hours post dose) | 
| Cmax: Maximum Observed Plasma Concentration for Total BCAA Parameter in Cohorts 4a-2, 4b-2, 5a-2 and 5b-2 |  | Day -1: pre-dose and Day 1 at multiple time points (0.5, 1, 1.5, 2, 2.5, 4, 5, 6, 10, 11, 12, 24 hours; up to 24 hours) post-dose | 
| Tmax: Time to Reach the Cmax for Total BCAA Parameter in Cohorts 4a-2, 4b-2, 5a-2 and 5b-2 |  | Day -1: pre-dose and Day 1 at multiple time points (0.5, 1, 1.5, 2, 2.5, 4, 5, 6, 10, 11, 12, 24 hours; up to 24 hours) post-dose |