TAK-438 - Safety, Blood Levels & Effects of Repeated Doses

NCT02141711 | Completed Phase 1

• 3 other identifiers: TAK-438_107U1111-1153-84432008-004975-22
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

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.

Conditions

Erosive Esophagitis(EE); Gastroesophageal Reflux Disease (GERD)

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (25)

• 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

  (AUC(0-tlqc) is a measure of total plasma exposure to the drug from time 0 to time of the last quantifiable concentration (AUC\[0-tlqc\]).

  Days 1 and 7

• 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

  AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.

  Days 1 and 7

• 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

  AUC(0-tau) is a measure of the area under the plasma concentration-time curve from time 0 to time tau over a dosing interval, where tau is the length of the dosing interval.

  Days 1 and 7

• Cmax: Maximum Observed Plasma Concentration for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul

  Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.

  Days 1 and 7

• 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

  Day 7

• 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

  Day 7

• (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

  (Cmax-Cmin)/Cavg, where Cmin is the minimum observed plasma concentration and Cavg is the average plasma concentration at steady state.

  Day 7

• 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

  Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.

  Days 1 and 7

• Terminal Elimination Rate Constant (λz) for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul

  Terminal elimination rate constant (λz) is the rate at which drugs are eliminated from the body.

  Days 1 and 7

• 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

  Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.

  Days 1 and 7

• Apparent Clearance (CL/F) Pharmacokinetic Parameter for TAK-438

  CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC(0-24), expressed in L/hr.

  Days 1 and 7

• Apparent Volume of Distribution (Vz/F) for TAK-438

  Vz/F is the distribution of a drug between plasma and the rest of the body following oral administration, calculated as CL/F divided by λz.

  Days 1 and 7

• 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

  Ae(0-t) is the total amount of drug excreted in urine from time 0 to t, where t is 24 hours on Day 1 and 48 hours on Day 7.

  Day 1 and Day 7

• 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

  Ae(0-tau) is the total amount of drug excreted in urine from time 0 to tau, where tau equals 24 hours.

  Day 1 and Day 7

• Renal Clearance (CLr) for TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul

  CLr is a measure of apparent clearance of the drug from the urine calculated as total amount excreted in the urine from time 0 to 24 hours postdose / plasma area under the curve from time 0 to 24 hours post-dose.

  Day 1 and Day 7

• Fraction of TAK-438 and TAK-438 metabolites M-I, M-II, M-III and M-IV-Sul Excreted in Urine (Fe)

  Fe is a measure of the fraction of drug excreted in urine and is calculated as Fe = (total amount excreted in the urine from time 0 to 24 hours post-dose / dose)×100.

  Day 1 and Day 7

• Physical Examination Findings

  A baseline physical examination (defined as the pretreatment assessment immediately prior to the start of study drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; (11) genitourinary system; and (12) other. All subsequent physical examinations should assess clinically significant changes from the baseline examination.

  Baseline up to Day 9

• 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 will include body temperature (oral temperature), sitting blood pressure (after sitting for 5 minutes), and pulse (bpm).

  Baseline up to Day 9

• Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings

  Full 12-lead ECGs will be recorded using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (using Bazett correction; QTcB) intervals. The investigator or other qualified physician will interpret each ECG using one of the following categories: within normal limits, abnormal but not clinically significant, or abnormal and clinically significant.

  Baseline to Day 9

• Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings

  Laboratory tests for hematology, serum chemistries, coagulation tests, and urinalysis will be performed.

  Baseline up to Day 9

• Number of Participants With Treatment-Emergent Adverse Events (AEs)

  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 7 days after the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug.

  Baseline up to Day 9

• Safety of TAK-438

  Assessed by physical examination, ECG, and safety tests of blood/urine

  3 months

• Tolerability of TAK-438

  Assessed by adverse events

  3 months

• Pharmacokinetic analysis of plasma TAK-438 concentrations

  Primary pharmacokinetic parameters (AUC (0-tlqc), AUC (0-inf), Cmax) for TAK-438 and its metabolites M-I, M-II, M-III and M-IV-Sul will be subject to statistical analysis

  3 months

• Pharmacodynamic measurement for assay of gastric pH, measurement of gastrin, pepsinogen I, pepsinogen II and the pepsinogen I/II ratio in plasma samples

  3 months

Secondary Outcomes (7)

• Percentage of Time the pH is Greater than pH 4 and pH 5 over a 24 Hour Period

  Over a 24-hour period at Baseline and over a 24-hour period following the administration of study on Days 1, 4 and 7

• Percentage of Time the pH is Greater than pH 4 and pH 5 over a 48 Hour Period

  Over a 48-hour period following the administration of study on Day 7

• Percentage of Time the PH is Greater than pH 4 and pH 5 from 8 PM to 8 AM

  Over a 12-hour period from 8 PM to 8 AM on Days 1, 4 and 7

• Total Amount of Gastrin in Plasma

  Predose Days 1 through 7 and Days 8 and 9

• Total Amount of Pepsinogen I in Plasma

  Predose Days 1 through 7 and Days 8 and 9

Study Arms (5)

Cohort 1: TAK-438 10 mg

EXPERIMENTAL

TAK-438 10 mg tablets, orally, once, daily, for 7 days.

Drug: TAK-438

Cohort 2: TAK-438 20 mg

EXPERIMENTAL

TAK-438 20 mg tablets, orally, once, daily, for 7 days.

Drug: TAK-438

Cohort 3: TAK-438 40 mg

EXPERIMENTAL

TAK-438 40 mg tablets, orally, once, daily, for 7 days.

Drug: TAK-438

Cohort 4: TAK-438 30 mg

EXPERIMENTAL

TAK-438 30 mg tablets, orally, once, daily, for 7 days.

Drug: TAK-438

Cohorts 1-4: Placebo

PLACEBO COMPARATOR

TAK-438 placebo-matching tablets, orally, once, daily, for 7 days.

Drug: TAK-438 Placebo

Interventions

TAK-438 DRUG

TAK-438 tablets

Cohort 1: TAK-438 10 mg; Cohort 2: TAK-438 20 mg; Cohort 3: TAK-438 40 mg; Cohort 4: TAK-438 30 mg

TAK-438 Placebo DRUG

TAK-438 placebo-matching tablets

Cohorts 1-4: Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Takeda: lead

Study Sites (1)

Hammersmith Medicines Research

London, NW10 7EW, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 25707624 DERIVED

MeSH Terms

Conditions

Gastroesophageal Reflux

Interventions

1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

Condition Hierarchy (Ancestors)

Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Gastrointestinal Diseases; Digestive System Diseases

Study Officials

• Medical Director Clinical Science

  Takeda

  STUDY DIRECTOR

• Steve Warrington

  Hammersmith Medicines Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2014
• First Posted: May 19, 2014
• Study Start: October 1, 2008
• Primary Completion: February 1, 2009
• Study Completion: February 1, 2009
• Last Updated: May 19, 2014

Record last verified: 2014-05

Locations

GB (1)