Safety, Tolerability and Pharmacokinetics of TAK-438 in Healthy Male Participants

Study Overview
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Brief Summary
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The primary purpose of this study was to evaluate the single dose safety and pharmacokinetics of TAK-438 in healthy Japanese men.

Detailed Description
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The drug being tested in this study is called TAK-438. TAK-438 is being tested to find a safe and well-tolerated dose and to assess how TAK-438 moves throughout the body. This study will look at lab results and side effects in people who took TAK-438. This study consisted of 2 sequential studies: a single rising dose study (Steps 1 to 7) and a food-effect study (Steps 8 and 9). The study population for Steps 1 to 7 consisted of 12 participants; with 9 participants randomized to receive a single dose of TAK-438, and 3 participants to receive placebo. Participants in Steps 1 to 7 received a single dose of study drug after a 10-hour fast. The starting dose was 1 mg followed by administrations of 5, 10, 20, 40, 80, and 120 mg. Steps 8 and 9 consisted of 12 participants in a 2-sequence, 2-period crossover design. Four participants were to receive a single dose of TAK-438 and 2 participants were to receive a single dose of placebo on Day 1, in the fasted state, and 4 participants were to receive a single dose of TAK-438 and 2 participants were to receive a single dose of placebo on Day 1 in the fed state, followed by a second single dose of TAK-438 or placebo in the alternative fed state after a 13 day minimum washout period. Participants in Steps 8 randomized to receive TAK-438 will receive 10 mg and participants in Step 9 will receive 40 mg. This single-centre trial was conducted in Japan. The overall time to participate in this study was up to 32 days depending on the Step assignment. Participants made 3 to 5 visits to the clinic, including one or two 8-day periods of confinement to the clinic, also depending on Step assignment. All participants made a final visit 15 days after last dose of study drug for a follow-up assessment.

Official Title
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A Phase I, Randomized, Double-Blind, Placebo-Controlled, Ascending Single Dose Study of the Safety, Tolerability and Pharmacokinetics of TAK-438 in Healthy Male Subjects

Conditions
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Ascending Single Dose Study

Intervention / Treatment
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* Drug: TAK-438
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Japanese healthy adult male volunteer. Is between 20 and 45 years old when giving their informed consent. Is able to understand the consents of the study and to follow them. Provides their written informed consent prior to their participation in this study. Weighs at least 50 kg and has a body mass index (BMI) of 18.5 to 25.0 kg/m^2 at screening. Has negative results for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antigen/antibody, and serological tests for syphilis. Participant whom the investigator or subinvestigator judged to be eligible on the basis of subjective symptoms, objective findings, vital signs, electrocardiogram (ECG) findings, and results of laboratory tests obtained until before the study drug administration. Exclusion Criteria: Has undergone upper gastrointestinal resectioning or vagotomy. Has hypoacidity or anacidity: intragastric pH ≥ 5.5 at X-ray fluoroscopic confirmation of detained position of a pH probe inserted to measure baseline intragastric pH values. Has a history of previous and current acid-related diseases including reflux esophagitis, gastric ulcer, duodenal ulcer, non-erosive gastroesophageal reflux disease, Barrett's esophagitis or Zollinger-Ellison syndrome. Is undergoing H. pylori eradication within 6 months before the initiation of the study drug administration. Has an inappropriate history of previous and current diseases for study participation including hepatic or renal disorders, and cardiovascular, hematological, endocrine, metabolic, pulmonary, gastrointestinal, neurological, urological, immunological, or psychological diseases. Has a history of drug and food allergy. Has a history of illegal drug abuse or alcoholism within 5 years before the initiation of the study drug administration. Has peripheral vessels being difficult. Has undergone whole blood drawing of at least 200 mL within 4 weeks or 400 mL within 12 weeks prior to initiation of the study drug administration. Has undergone whole blood drawing of at least 800 mL in total within 52 weeks prior to initiation of the study drug administration. Has undergone apheresis drawing [plasma (including platelet poor plasma or platelet rich plasma) and platelet component collection] within 2 weeks prior to initiation of the study drug administration. Is taking any prescriptions or over the counter (OTC) drugs within 4 weeks prior to the study drug administration. Has taken any vitamins, herbal medicines, and supplements including St. John's wort, Ginseng, kava kava, ginkgo biloba, melatonin within 4 weeks prior to initiation of the study drug administration. Has had grapefruit (juice and pulp), or caffeine- or alcohol-containing foods or drinks within 72 hr prior to initiation of the study drug administration. Has received other study drugs within 16 weeks prior to initiation of the study drug administration. Participants whom the investigator or subinvestigator judged to be ineligible for study participation.

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: Step 1: TAK-438 1 mg<br>TAK-438 1 mg, tablets, orally, once on Day 1. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Experimental: Step 2: TAK-438 5 mg<br>TAK-438 5 mg, tablets, orally, once on Day 1. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Experimental: Step 3: TAK-438 10 mg<br>TAK-438 10 mg, tablets, orally, once on Day 1. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Experimental: Step 4: TAK-438 20 mg<br>TAK-438 20 mg, tablets, orally, once on Day 1. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Experimental: Step 5: TAK-438 40 mg<br>TAK-438 40 mg, tablets, orally, once on Day 1. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Experimental: Step 6: TAK-438 80 mg<br>TAK-438 80 mg, tablets, orally, once on Day 1. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Experimental: Step 7: TAK-438 120 mg<br>TAK-438 120 mg, tablets, orally, once on Day 1. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Placebo Comparator: Steps 1-7: Placebo<br>TAK-438 placebo-matching tablets, orally, once on Day 1. | Drug: Placebo<br>* TAK-438 placebo-matching tablets<br>|
| Experimental: Step 8A: TAK-438 10 mg<br>TAK-438 10 mg, tablets, orally, under fasted conditions, once on Day 1, Period 1, followed by a 13 day washout period, followed by TAK-438 10 mg, tablets, orally, under fed conditions, once on Day 1, Period 2. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Experimental: Step 8 B: TAK-438 10 mg<br>TAK-438 10 mg, tablets, orally, under fed conditions, once on Day 1, Period 1, followed by a 13 day washout period, followed by TAK-438 10 mg, tablets, orally, under fasted conditions, once on Day 1, Period 2. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Experimental: Step 9A: TAK-438 40 mg<br>TAK-438 40 mg, tablets, orally, under fasted conditions, once on Day 1, Period 1, followed by a 13 day washout period, followed by TAK-438 40 mg, tablets, orally, under fed conditions, once on Day 1, Period 2. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Experimental: Step 9B: TAK-438 40 mg<br>TAK-438 40 mg, tablets, orally, under fed conditions, once on Day 1, Period 1, followed by a 13 day washout period, followed by TAK-438 40 mg, tablets, orally, under fasted conditions, once on Day 1, Period 2. | Drug: TAK-438<br>* TAK-438 tablets<br>|
| Placebo Comparator: Steps 8 (A & B) and 9 (A & B): Placebo<br>TAK-438 placebo-matching tablets, orally, once on Day 1, Period 1, followed by a 13 day washout period, followed by TAK-438 placebo-matching tablets, orally, once on Day 1, Period 2. | Drug: Placebo<br>* TAK-438 placebo-matching tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AE) | Treatment-emergent adverse events are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug. | Day 1 to Day 15 | 
| Number of Participants With Potentially Clinically Significant Vital Sign Findings | Participants with at least one potentially clinically significant post-baseline vital sign finding. Vital signs included blood pressure, pulse, respiratory rate, and body temperature (armpit), body weight, and body mass index (BMI). | Day 1 to Day 15 | 
| Change from Baseline in Body Weight |  | Day 1 to Day 15 | 
| Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings |  | Day 1 to Day 15 | 
| Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings | Laboratory tests for hematology, biochemistry, coagulation and urinalysis were be performed. | Day 1 to Day 15 | 
| AUC(0-48): Area Under the Plasma Concentration-Time Curve From Time 0 to hour 48 for TAK-438 and TAK-438 metabolites M-I and M-II | AUC(0-48) is a measure of the area under the plasma concentration-time curve from time 0 to 48 hours, calculated using the linear trapezoidal rule. | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-438 and TAK-438 metabolites M-I and M-II | (AUC(0-tlqc) is a measure of total plasma exposure to the drug from time 0 to time of the last quantifiable concentration (AUC[0-tlqc]). | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| AUMC(0-tlqc): Area Under the First Moment Plasma Concentration-time Curve from Time 0 (t1) to Time of the Last Quantifiable Concentration (tlqc) for TAK-438F and TAK-438F metabolites M-I and M-II | AUMC(0-tlqc) is a measure of the area under the first moment plasma concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc), calculated using the linear trapezoidal rule. | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| MRT(0-tlqc): Mean Residence Time from Time 0 (t1) to Time of the Last Quantifiable Concentration (tlqc) for TAK-438F and TAK-438F metabolites M-I and M-II | MRT(0-tlqc) is a measure of the mean residence time from time 0 to time of the last quantifiable concentration (tlqc) calculated as MRT(0-tlqc)=AUMC(0-tlqc)/AUC(0-tlqc). | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| Cmax: Maximum Observed Plasma Concentration TAK-438F and TAK-438F metabolites M-I and M-II | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-438F and TAK-438F metabolites M-I and M-II | Time to reach the maximum plasma concentration (Tmax), equal to time (hours) to Cmax. | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-438F and TAK-438F metabolites M-I and M-II | AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity. | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| Terminal Elimination Rate Constant (λz) for TAK-438F and TAK-438F metabolites M-I and M-II | Terminal elimination rate constant (λz) is the rate at which drugs are eliminated from the body. | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| Terminal Elimination Half-life (T1/2) for TAK-438F and TAK-438F metabolites M-I and M-II | Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| Apparent Clearance (CL/F) Pharmacokinetic Parameter for TAK-438F | CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC(0-24), expressed in L/hr. | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| AUMC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-438F and TAK-438F metabolites M-I and M-II | AUMC(0-inf) is a measure of the area under the first moment plasma concentration-time curve from time 0 to infinity, calculated as AUMC(0-tlqc) + lqc x tlqc/λz + lqc/λz^2. | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| MRT: Mean Residence Time for TAK-438F and TAK-438F metabolites M-I and M-II | Mean residence time, calculated as MRT=AUMC(0-inf)/AUC(0-inf). | Day 1 predose (0 hours) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, and 48 hours postdose | 
| Cumulative Urinary Excretion Ratio for TAK-438F and TAK-438F metabolites M-I and M-II | The cumulative urinary excretion ratio is defined as the percentage of the dose excreted in the urine. | Day 1 predose and 0-6, 6-12, 12-24, 24-36 and 36-48 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-Hour Intragastric pH Profile | To obtain intragastric pH a portable pH measuring device with a miniature glass electrode that was calibrated using standard pH 4 and pH 7 solutions was placed in the stomach transnasally and its positioned confirmed by X-ray guidance. pH data was recorded electronically 8:30 AM to 9:10 AM of the following day every 10 seconds. | Baseline and Day 1 | 
| Total Amount of Serum Gastrin |  | Baseline at prospective time of dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post prospective dose and Day 1 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose | 
| Total Amount of Serum Pepsinogen I |  | Baseline at prospective time of dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post prospective dose and Day 1 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose | 
| Total Amount of Serum Pepsinogen Ii |  | Baseline at prospective time of dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours post prospective dose and Day 1 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36 and 48 hours postdose | 

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