Clinical trial NCT02141711: TAK-438 - Safety, Blood Levels & Effects of Repeated Doses
Official title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential-Panel, Multiple Repeat Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-438 in Healthy Non-Japanese Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Erosive Esophagitis(EE)
Gastroesophageal Reflux Disease (GERD)
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2014-05-19
Enrollment: 48
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: BASIC_SCIENCE

Brief summary: The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of TAK-438 in healthy, non-Japanese men male subjects following a randomized, double blind, placebo controlled, sequential panel, multiple-dose schedule.

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 pharmacokinetic (effect of the body on the drug) and pharmacodynamic properties (effect of the drug on the body) as well as look at lab results and side effects in people who took TAK-438. This study was designed as a randomized, sequential-panel, multiple repeat dose study.

The study population consisted of 4 Cohorts with 12 participants in each Cohort; with 9 participants randomized to receive a single dose of TAK-438, and 3 participants to receive placebo. Participants in each Cohort received a single dose of study drug once daily after a 10-hour fast. The starting dose was 10 mg followed by administrations of 20, 40, and 30 mg.

This single-centre trial was conducted in the United Kingdom. The overall time to participate in this study was up to 37 days. Participants made 2 visits to the clinic for screening, one 11-day period of confinement to the clinic, and 2 further visits after the confinement period. All participants were contacted by telephone 7 days after last dose of study drug for a follow-up assessment.

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, M-II, M-III and M-IV-Sul
timeFrame: Days 1 and 7
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, M-II, M-III and M-IV-Sul
timeFrame: Days 1 and 7
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, M-II, M-III and M-IV-Sul
timeFrame: Days 1 and 7
measure: Cmax: Maximum Observed Plasma Concentration for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul
timeFrame: Days 1 and 7
measure: Cmin,ss: Minimum Observed Plasma Concentration at Steady State for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul
timeFrame: Day 7
measure: Cmax,ss: Maximum Observed Plasma Concentration at Steady State for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul
timeFrame: Day 7
measure: (Cmax-Cmin)/Cavg: Fluctuation of Concentration at Steady State for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul
timeFrame: Day 7
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul
timeFrame: Days 1 and 7
measure: Terminal Elimination Rate Constant (λz) for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul
timeFrame: Days 1 and 7
measure: Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul
timeFrame: Days 1 and 7
measure: Apparent Clearance (CL/F) Pharmacokinetic Parameter for TAK-438
timeFrame: Days 1 and 7
measure: Apparent Volume of Distribution (Vz/F) for TAK-438
timeFrame: Days 1 and 7
measure: Ae(0-t): Total Amount of Drug Excreted in Urine from Time 0 to Time T for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul
timeFrame: Day 1 and Day 7
measure: Ae(0-tau): Total Amount of Drug Excreted in Urine from Time 0 to Time tau for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul
timeFrame: Day 1 and Day 7
measure: Renal Clearance (CLr) for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul
timeFrame: Day 1 and Day 7
measure: Fraction of TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul Excreted in Urine (Fe)
timeFrame: Day 1 and Day 7
measure: Physical Examination Findings
timeFrame: Baseline up to Day 9
measure: Number of Participants With Potentially Clinically Significant Vital Sign Findings
timeFrame: Baseline up to Day 9
measure: Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings
timeFrame: Baseline to Day 9
measure: Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings
timeFrame: Baseline up to Day 9
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs)
timeFrame: Baseline up to Day 9
measure: Safety of TAK-438
timeFrame: 3 months
measure: Tolerability of TAK-438
timeFrame: 3 months
measure: Pharmacokinetic analysis of plasma TAK-438 concentrations
timeFrame: 3 months
measure: Pharmacodynamic measurement for assay of gastric pH, measurement of gastrin, pepsinogen I, pepsinogen II and the pepsinogen I/II ratio in plasma samples
timeFrame: 3 months
Secondary outcomes:
measure: Percentage of Time the pH is Greater than pH 4 and 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 on Days 1, 4 and 7
measure: Percentage of Time the pH is Greater than pH 4 and pH 5 over a 48 Hour Period
timeFrame: Over a 48-hour period following the administration of study on Day 7
measure: Percentage of Time the PH is Greater than pH 4 and pH 5 from 8 PM to 8 AM
timeFrame: Over a 12-hour period from 8 PM to 8 AM on Days 1, 4 and 7
measure: Total Amount of Gastrin in Plasma
timeFrame: Predose Days 1 through 7 and Days 8 and 9
measure: Total Amount of Pepsinogen I in Plasma
timeFrame: Predose Days 1 through 7 and Days 8 and 9
measure: Total Amount of Pepsinogen II in Plasma
timeFrame: Predose Days 1 through 7 and Days 8 and 9
measure: Pepsinogen I/II Ratio in Plasma
timeFrame: Predose Days 1 through 7 and Days 8 and 9
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Hammersmith Medicines Research
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
affiliation: Hammersmith Medicines Research
name: Steve Warrington
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jenkins H, Sakurai Y, Nishimura A, Okamoto H, Hibberd M, Jenkins R, Yoneyama T, Ashida K, Ogama Y, Warrington S. Randomised clinical trial: safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a novel potassium-competitive acid blocker, in healthy male subjects. Aliment Pharmacol Ther. 2015 Apr;41(7):636-48. doi: 10.1111/apt.13121. Epub 2015 Feb 23.