Clinical trial NCT02141698: Safety, Tolerability, and Pharmacokinetics of TAK-438 in Healthy Western Male Subjects, Preliminary Food Effect Analysis, and an Ethnic Comparison With Japanese Subjects
Official title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential-Panel, Ascending Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-438 in Healthy Western Male Subjects, Preliminary Food Effect Analysis, and an Ethnic Comparison With Japanese Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Dose Finding Study
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Richmond Pharmacology Limited
First posted: 2014-05-19
Enrollment: 73
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of TAK-438 following single or multiple doses of TAK-438 in healthy Western men, to investigate the effect of food on the pharmacokinetics of TAK-438, and to compare the TAK-438 pharmacokinetics of Western with Japanese men.

Detailed description: The drug being tested in this study is called TAK-438. TAK-438 is being tested to find a safe and well-tolerated dose. This study looked at the pharmacodynamic and pharmacokinetic properties (how the drug moves throughout the body) of the drug and safety (lab results and side effects) in people who took TAK-438.

This study was designed to consist of 4 sequential substudies: a single rising dose study (Cohorts 1 to 7), a food-effect study (Cohort 8), a multiple rising dose study (Cohorts 9 to 11), and a Japanese bridging study (Cohort 12). However, the protocol was halted during the food effect study (Cohort 8) following the discovery of previously unidentified metabolites and as a result, the multiple rising dose (Cohorts 9-11) and ethnicity (Cohort 12) studies were not carried out.

The study population for each of Cohorts 1 to 7 consisted of 9 subjects; with 6 subjects randomized to receive a single dose of TAK-438, and 3 subjects to receive placebo. Subjects in Cohorts 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, 15, 40, and 30 mg.

In Cohort 8 the plan was to assign 12 participants in a 2-sequence, 2-period crossover design. Six participants were to receive a single dose of TAK-438 on Day 1, in the fasted state, followed by a second single dose of TAK-438 on Day 15 in the alternative fed state. The other 6 participants were to receive the study drug like-wise but in the fed then fasted state.

To investigate the effect of multiple dosing, a further 3 cohorts (Cohorts 9-11), each comprising 12 participants were to be introduced to the protocol following completion of the single rising dose study. A final cohort, Cohort 12, consisting of 24 Western participants and 24 Japanese participants was to be used to assess the effect of TAK-438 and esomeprazole on the safety, tolerability, pharmacokinetics and pH of the stomach between these 2 ethnic groups.

This single-centre trial was conducted in the United Kingdom.

Eligibility criteria: Inclusion Criteria:

* Male subjects aged 18 to 45, inclusive, who are in good health, as determined by medical history, physical examination, clinical laboratory evaluations and urine drug screen
* The subject has the ability to tolerate the pH probe for 24 hours prior to Randomization (Day 1).

Exclusion Criteria:

* Clinically significant history of hypersensitivity to any drug or food or any excipients of TAK-438.
* History of gastroesophageal reflux disease (GERD), symptomatic GERD, erosive esophagitis, duodenal ulcer,gastric ulcer, dyspepsia, Barrett's esophagus, or Zollinger-Ellison syndrome
* The subject has a positive test result for Helicobacter pylori at the Initial Screening Visit.
* Any clinically significant results from physical examinations or clinical laboratory results as deemed by the investigator.

Primary outcomes:
measure: 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
timeFrame: Day 1
measure: AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 1
measure: AUC(0-tau): Area Under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 1
measure: Cmax: Maximum Observed Plasma Concentration for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 1
measure: Cmin,ss: Minimum Observed Plasma Concentration at Steady State for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 7
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 1
measure: Terminal Elimination Rate Constant (λz) for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 1
measure: Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 1
measure: Apparent Clearance (CL/F) Pharmacokinetic Parameter for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 1
measure: Apparent Volume of Distribution (Vz/F) for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 1
measure: Total Amount of Drug Excreted in Urine for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 1
measure: Renal Clearance (CLr) for TAK-438 and TAK-438 metabolites M-I and M-II
timeFrame: Day 1
measure: Fraction of TAK-438 Excreted in Urine (Fe)
timeFrame: Day 1
measure: Percentage of the Total Time the pH is Greater than pH 5
timeFrame: Over a 24-hour period at Baseline and over a 96-hour period following the administration of study drug
measure: Percentage of Time the pH is Greater than pH 4 over a 24 Hour Period
timeFrame: Over a 24-hour period at Baseline and over a 24-hour period following the administration of study drug
measure: Percentage of Time the pH is Greater than pH 5 over a 24 Hour Period.
timeFrame: Over a 24-hour period at Baseline and over a 24-hour period following the administration of study drug
measure: Total Amount of Gastrin in Plasma
timeFrame: Baseline and Day 1
measure: Total Amount of Pepsinogen I/II in Plasma
timeFrame: Baseline and Day 1
measure: Physical Examination Findings
timeFrame: Baseline up to Day 30
measure: Number of Participants With Potentially Clinically Significant Vital Sign Findings
timeFrame: Baseline up to Day 30
measure: Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings
timeFrame: Baseline to Day 30
measure: Number of Participants With Potentially Clinically Significant Telemetry Findings
timeFrame: Baseline up to Day 30
measure: Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings
timeFrame: Baseline up to Day 30
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs)
timeFrame: Baseline up to Day 30
measure: Percentage of Time the pH is Greater than pH 4 from 8PM to 8AM.
timeFrame: Over a 12-hour period at Baseline and over a 12-hour period between 8PM and 8AM following the administration of study drug
measure: • Percentage of Time the pH is Greater than pH 5 from 8 PM to 8 AM
timeFrame: Over a 12-hour period at Baseline and over a 12-hour period between 8pm and 8 am following the administration of study drug
measure: • Percentage of the Total Time the pH is Greater than pH 4
timeFrame: Over a 24-hour period at Baseline and over a 96-hour period following the administration of study drug
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References: