Safety, Tolerability and Pharmacokinetics of Escalating Single Doses of TAK-828 in Healthy Participants

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of single oral doses of TAK-828 in healthy non-Japanese and Japanese participants.

Detailed Description
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The drug being tested in this study is called TAK-828. TAK-828 is being tested to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single oral doses of TAK-828 in healthy non-Japanese and Japanese participants. The study enrolled 36 healthy participants. An interleaving crossover design with placebo substitution was used for Cohorts 1 and 2, and a crossover design was used in Cohort 3. Each cohort consisted of 12 participants, and participants were randomized to treatment sequence to receive TAK-828 or placebo after undergoing a fasting stage of at least 8 hours through intervention periods 1-4 for Cohorts 1 and 2 and through intervention periods 1 - 3 for Cohort 3. The assigned treatment sequence will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need). An additional interventional period 5 (fed state) is planned to be conducted in either cohort 1 or 2, based on the dose of TAK-828 that will be chosen to be studied under fed conditions. Cohorts 1 and 2 were conducted in non-Japanese participants and Cohort 3 in Japanese participants. This multi-center trial was conducted in the United States. Participants remained confined to the study site from check-in (Day -1) through Day 4 of each intervention period and returned 7 to 10 days after last dose of study drug for a follow-up assessment.

Official Title
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A Randomized, Double-Blind (Sponsor-Open), Placebo-Controlled, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Escalating Single Doses of TAK-828 in Healthy Non-Japanese and Japanese Subjects

Conditions
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Dose Finding Study

Intervention / Treatment
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* Drug: TAK-828
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Is a healthy male and female (non-child bearing potential) participants. Cohorts 1 and 2: non-Japanese participants aged 18 to 55 years, inclusive, with body mass index (BMI) of 18 to 30 kilogram per square meter (kg/m^ 2), inclusive, and body weight greater than or equal (>=) 50 kilograms (kg). Cohort 3: Japanese participants (born to Japanese parents and grandparents) aged 20 to 55 years, inclusive, with BMI of 18.5 to 25 kg/m^ 2, inclusive, and body weight >= 45 kg. Exclusion Criteria: - 1. Has used prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to Check-in (Day -1). Herbal supplements and hormone replacement therapy (HRT) must be discontinued 28 days prior to Check-in (Day -1). As an exception, acetaminophen may be used at doses of less than equal to (<=) 1 gram per day (g/day). Limited use of nonprescription medications that are not believed to affect participant safety or the overall results of the study may be permitted on a case-by-case basis following approval by the sponsor.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1, Sequence I<br>Non-Japanese participants. TAK-828 0.1 mg, oral solution, fasted (after an 8 hour fast), on Day 1 of Period 1; followed by, TAK-828 0.5 mg, oral solution, fasted, on Day 1 of Period 2; followed by, TAK-828 15 mg, oral solution, fasted, on Day 1 of Period 3; followed by, placebo-matching TAK-828, oral solution, fasted, on Day 1 of Period 4; followed by, TAK-828 100 mg, oral solution, fed (high-fat, high-calorie meal 30 minutes prior to administration of study drug), on Day 1 of Period 5. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|
| Experimental: Cohort 1, Sequence II<br>Non-Japanese participants. TAK-828 0.1 mg, oral solution, fasted (after an 8 hour fast) on Day 1 of Period 1; followed by, TAK-828 0.5 mg, oral solution, fasted, on Day 1 of Period 2; followed by, placebo-matching, oral solution, fasted, on Day 1 of Period 3; followed by, TAK-828 100 mg, oral solution, fasted, on Day 1 of Period 4; followed by, TAK-828 100 mg, oral solution, fed (high-fat, high-calorie meal 30 minutes prior to administration of study drug), on Day 1 of Period 5. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|
| Experimental: Cohort 1, Sequence III<br>Non-Japanese participants. TAK-828 0.1 mg, oral solution, fasted (after an 8 hour fast), on Day 1 of Period 1; followed by, placebo-matching TAK-828, oral solution, fasted, on Day 1 of Period 2; followed by, TAK-828 15 mg, oral solution, fasted, on Day 1 of Period 3; followed by, TAK-828 100 mg, oral solution, fasted, on Day 1 of Period 4; followed by, TAK-828 100 mg, oral solution, fed (high-fat, high-calorie meal 30 minutes prior to administration of study drug), on Day 1 of Period 5. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|
| Experimental: Cohort 1, Sequence IV<br>Non-Japanese participants. Placebo-matching TAK-828, oral solution, fasted (after an 8 hour fast), on Day 1 of Period 1; followed by, TAK-828 0.5 mg, oral solution, fasted, on Day 1 of Period 2; followed by, TAK-828 15 mg, oral solution, fasted, on Day 1 of Period 3; followed by, TAK-828 100 mg, oral solution, fasted, on Day 1 of Period 4; followed by, TAK-828 100 mg, oral solution, fed (high-fat, high-calorie meal 30 minutes prior to administration of study drug), on Day 1 of Period 5. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|
| Experimental: Cohort 2, Sequence I<br>Non-Japanese participants. TAK-828 3 mg, oral solution, fasted (after an 8 hour fast), on Day 1 of Period 1; followed by, TAK-828 50 mg, oral solution, fasted, on Day 1 of Period 2; followed by, TAK-828 200 mg, oral solution, fasted, on Day 1 of Period 3; followed by, placebo-matching TAK-828, oral solution, fasted, on Day 1 of Period 4; followed by, TAK-828 100 mg, oral solution, fed (high-fat, high-calorie meal 30 minutes prior to administration of study drug), on Day 1 of Period 5. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|
| Experimental: Cohort 2, Sequence II<br>Non-Japanese participants. TAK-828 3 mg, oral solution, fasted (after an 8 hour fast) on Day 1 of Period 1; followed by, TAK-828 50 mg, oral solution, fasted, on Day 1 of Period 2; followed by, placebo-matching TAK-828, oral solution, fasted, on Day 1 of Period 3; followed by, TAK-828 100 mg, oral solution, fasted, on Day 1 of Period 4; followed by, TAK-828 100 mg, oral solution, fed (high-fat, high-calorie meal 30 minutes prior to administration of study drug), on Day 1 of Period 5. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|
| Experimental: Cohort 2, Sequence III<br>Non-Japanese participants. TAK-828 3 mg, oral solution, fasted (after an 8 hour fast) on Day 1 of Period 1; followed by, placebo-matching TAK-828, oral solution, fasted, on Day 1 of Period 2; followed by, TAK-828 200 mg, oral solution, fasted, on Day 1 of Period 3; followed by, TAK-828 100 mg, oral solution, fasted, on Day 1 of Period 4; followed by, TAK-828 100 mg, oral solution, fed (high-fat, high-calorie meal 30 minutes prior to administration of study drug), on Day 1 of Period 5. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|
| Experimental: Cohort 2, Sequence IV<br>Non-Japanese participants. Placebo-matching TAK-828, oral solution, fasted (after an 8 hour fast), on Day 1 of Period 1; followed by, TAK-828 50 mg, oral solution, fasted, on Day 1 of Period 2; followed by, TAK-828 200 mg, oral solution, fasted, on Day 1 of Period 3; followed by, TAK-828 100 mg, oral solution, fasted, on Day 1 of Period 4; followed by, TAK-828 100 mg, oral solution, fed (high-fat, high-calorie meal 30 minutes prior to administration of study drug), on Day 1 of Period 5. There was a 7-day washout period between each period. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|
| Experimental: Cohort 3, Sequence I<br>Japanese participants. TAK-828 15 mg, oral solution, fasted (after an 8 hour fast), on Day 1 of Period 1; followed by, TAK-828 100 mg, oral solution, fasted, on Day 1 of Period 2; followed by, placebo-matching TAK-828, oral solution, fasted, on Day 1 of Period 3. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|
| Experimental: Cohort 3, Sequence II<br>Japanese participants. TAK-828 15 mg, oral solution, fasted (after an 8 hour fast), on Day 1 of Period 1; followed by, placebo-matching TAK-828, oral solution, fasted, on Day 1 of Period 2; followed by, TAK-828 150 mg, oral solution, fasted, on Day 1 of Period 3. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|
| Experimental: Cohort 3, Sequence III<br>Japanese participants. Placebo-matching TAK-828, oral solution, fasted (after an 8 hour fast), on Day 1 of Period 1; followed by, TAK-828 100 mg, oral solution, fasted, on Day 1 of Period 2; followed by, TAK-828 150 mg, oral solution, fasted, on Day 1 of Period 3. Each period lasted 4 days with a 7-day washout period between periods. | Drug: TAK-828<br>* TAK-828 oral solution<br>Drug: Placebo<br>* TAK-828 placebo-matching oral solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event (TEAE) | 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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | Day 1 up to 30 days after last dose of study drug (up to 85 days) | 
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) |  | Day 1 up to 30 days after last dose of study drug (up to 85 days) | 
| Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post-dose | Hematology and Chemistry values that met the following criteria were considered to be markedly abnormal: Erythrocytes, Hematocrit and Hemoglobin <0.8*Lower Limit of Normal (LLN) or >1.2*Upper Limit of Normal ULN.; Leukocytes <0.5*LLN or >1.5*ULN; Platelet <75 or >600 10^9/liter (L). Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Gamma Glutamyl Transferase >3*ULN; Albumin <25 g/L; Bilirubin > 34.2 umol/L; Blood Urea Nitrogen >10.7 mmol/L; Chloride <75 or >126 mmol/L; Creatinine >177 umol/L; Direct Bilirubin >2*ULN; Glucose <2.8 or >19.4 mmol/L; Potassium <3.0 or >6.0 mmol/L; Protein <0.8*LLN or >1.2*ULN; Sodium <130 or >150 mmol/L. | Day 1 up to 7 days after last dose of study drug (up to 52 days) | 
| Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post-dose | Vital signs measurements that met the following criteria were considered to be markedly abnormal: Systolic Blood Pressure (SBP) <85 mmHg or >180 mmHg supine laying face upward) or standing; Diastolic Blood Pressure (DBP) <50 mmHg or >110 mmHg supine or standing; Pulse Rate (PR) <50 beats/minute (bpm) or >120 bpm supine or standing; Temperature <35.6 degrees Celsius (C) or >37.7 degrees C. | Day 1 up to 7 days after last dose of study drug (up to 52 days) | 
| Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety 12-lead Electrocardiogram (ECG) Measurements at Least Once Post-dose | Heart Rate <50 beats per minute (bpm) >120 bpm; QTcB (Bazett's Correction Formula) ≤50 milliseconds (msec) or ≥500 msec OR ≥30 msec change from Baseline and ≥450 msec; QTcF (Fridericia's Correction Formula) ≤50 msec or ≥500 msec OR ≥30 msec change from Baseline (CFB) and ≥450 msec. | Day 1 up to 7 days after last dose of study drug (up to 52 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration for TAK-828F (Free Base of TAK-828) |  | Day 1 pre-dose and at multiple timepoints (up to 72 hours) post-dose | 
| Tmax: Time of First Occurrence of Cmax for TAK-828F (Free Base of TAK-828) |  | Day 1 pre-dose and at multiple timepoints (up to 72 hours) post-dose | 
| t1/2z: Terminal Disposition Phase Half-Life for TAK-828F (Free Base of TAK-828) |  | Day 1 pre-dose and at multiple timepoints (up to 72 hours) post-dose | 
| AUC∞: Area Under the Concentration-Time Curve From Time 0 to Infinity Calculated Using the Observed Value of the Last Quantifiable Concentration for TAK-828F (Free Base of TAK-828) |  | Day 1 pre-dose and at multiple timepoints (up to 72 hours) post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy