Safety, Tolerability, and Pharmacokinetics of TAK-438 in Healthy Western Male Subjects, Preliminary Food Effect Analysis, and an Ethnic Comparison With Japanese Subjects

NCT02141698 | Completed Phase 1

• 3 other identifiers: TAK-438_1012007-003616-66U1111-1153-8406
• Study Type: interventional
• Target: 73
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Dose Finding Study

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (27)

• 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

• 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

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

  Day 1

• 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

  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.

  Day 1

• Cmax: Maximum Observed Plasma Concentration for TAK-438 and TAK-438 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

• Cmin,ss: Minimum Observed Plasma Concentration at Steady State for TAK-438 and TAK-438 metabolites M-I and M-II

  Day 7

• Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-438 and TAK-438 metabolites M-I and M-II

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

  Day 1

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

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

  Day 1

• Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for TAK-438 and TAK-438 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

• Apparent Clearance (CL/F) Pharmacokinetic Parameter for TAK-438 and TAK-438 metabolites M-I and M-II

  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

• Apparent Volume of Distribution (Vz/F) for TAK-438 and TAK-438 metabolites M-I and M-II

  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.

  Day 1

• Total Amount of Drug Excreted in Urine for TAK-438 and TAK-438 metabolites M-I and M-II

  Day 1

• Renal Clearance (CLr) for TAK-438 and TAK-438 metabolites M-I and M-II

  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

• Fraction of TAK-438 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

• Percentage of the Total Time the pH is Greater than pH 5

  Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 24-hour period at Baseline and over a 96-hour period following the administration of study drug.

  Over a 24-hour period at Baseline and over a 96-hour period following the administration of study drug

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

  Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 24-hour period at Baseline and over a 24-hour period following the administration of study drug.

  Over a 24-hour period at Baseline and over a 24-hour period following the administration of study drug

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

  Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 24-hour period at Baseline and over a 24-hour period following the administration of study drug.

  Over a 24-hour period at Baseline and over a 24-hour period following the administration of study drug

• Total Amount of Gastrin in Plasma

  Baseline and Day 1

• Total Amount of Pepsinogen I/II in Plasma

  Baseline and Day 1

• 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 30

• 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 (tympanic measurement), sitting blood pressure (BP) (after resting for 5 minutes), and pulse (beats per minute (bpm)).

  Baseline up to Day 30

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

  Baseline to Day 30

• Number of Participants With Potentially Clinically Significant Telemetry Findings

  Baseline up to Day 30

• Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings

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

  Baseline up to Day 30

• 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 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.

  Baseline up to Day 30

• Percentage of Time the pH is Greater than pH 4 from 8PM to 8AM.

  Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 12-hour period at Baseline and over a 12-hour period following the administration of study drug.

  Over a 12-hour period at Baseline and over a 12-hour period between 8PM and 8AM following the administration of study drug

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

  Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 12-hour period at Baseline and over a 12-hour period following the administration of study drug.

  Over a 12-hour period at Baseline and over a 12-hour period between 8pm and 8 am following the administration of study drug

• • Percentage of the Total Time the pH is Greater than pH 4

  Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 24-hour period at Baseline and over a 96-hour period following the administration of study drug.

  Over a 24-hour period at Baseline and over a 96-hour period following the administration of study drug

Study Arms (15)

Cohort 1: TAK-438 1 mg

EXPERIMENTAL

TAK-438 1 mg, tablets, orally, once on Day 1.

Drug: TAK-438

Cohort 2: TAK-438 5 mg

EXPERIMENTAL

TAK-438 5 mg, tablets, orally, once on Day 1.

Drug: TAK-438

Cohort 3: TAK-438 10 mg

EXPERIMENTAL

TAK-438 10 mg, tablets, orally, once on Day 1.

Drug: TAK-438

Cohort 4: TAK-438 20 mg

EXPERIMENTAL

TAK-438 20 mg, tablets, orally, once on Day 1.

Drug: TAK-438

Cohort 5: TAK-438 15 mg

EXPERIMENTAL

TAK-438 15 mg, tablets, orally, once on Day 1.

Drug: TAK-438

Cohort 6: TAK-438 40 mg

EXPERIMENTAL

TAK-438 40 mg, tablets, orally, once on Day 1.

Drug: TAK-438

Cohort 7: TAK-438 30 mg

EXPERIMENTAL

TAK-438 30 mg, tablets, orally, once on Day 1.

Drug: TAK-438

Cohort 8A: Food-effect

EXPERIMENTAL

TAK-438 20 mg, tablets, orally, under fasted conditions, once on Day 1, Period 1, followed by a 13 day washout period, followed by TAK-438 20 mg, tablets, orally, under fed conditions, once on Day 1, Period 2.

Drug: TAK-438

Cohort 8B: Food-effect

EXPERIMENTAL

TAK-438 20 mg, tablets, orally, under fed conditions, once on Day 1, Period 1.

Drug: TAK-438

Cohort 9: TAK-438 Multiple Dose 1

EXPERIMENTAL

TAK-438 tablet, orally, fixed dose, on Day 1 and Days 8-14. Dose to be determined from data collected in Cohorts 1-7.

Drug: TAK-438

Cohort 10: TAK-438 Multiple Dose 2

EXPERIMENTAL

TAK-438 tablet, orally, fixed dose, on Day 1 and Days 8-14. Dose to be determined from data collected in Cohorts 1-7.

Drug: TAK-438

Cohort 11: TAK-438 Multiple Dose 3

EXPERIMENTAL

TAK-438 tablet, orally, fixed dose, on Day 1 and Days 8-14. Dose to be determined from data collected in Cohorts 1-7.

Drug: TAK-438

Cohort 12: Ethnic Bridging

EXPERIMENTAL

TAK-438 tablets, dose 1, orally, on Days 1-7 of Period 1, followed by a 4-week washout period followed by TAK-438 tablets, dose 2, orally, Days 1-7 of Period 2, followed by a 4-week washout period, followed by esomeprazole tablets, 40 mg, orally, on Days 1-7 of Period 3. TAK-438 doses to be determined from data collected in Cohorts 9-11.

Drug: TAK-438; Drug: Esomeprazole

Cohorts 1-7: Placebo

PLACEBO COMPARATOR

TAK-438 placebo-matching tablets, orally, once on Day 1

Drug: TAK-438 Placebo

Cohorts 9-11: Placebo

PLACEBO COMPARATOR

TAK-438 placebo-matching tablets, orally, once on Day 1, where available, if required.

Drug: TAK-438 Placebo

Interventions

TAK-438 DRUG

TAK-438 tablets

Cohort 10: TAK-438 Multiple Dose 2; Cohort 11: TAK-438 Multiple Dose 3; Cohort 12: Ethnic Bridging; Cohort 1: TAK-438 1 mg; Cohort 2: TAK-438 5 mg; Cohort 3: TAK-438 10 mg; Cohort 4: TAK-438 20 mg; Cohort 5: TAK-438 15 mg; Cohort 6: TAK-438 40 mg; Cohort 7: TAK-438 30 mg; Cohort 8A: Food-effect; Cohort 8B: Food-effect; Cohort 9: TAK-438 Multiple Dose 1

TAK-438 Placebo DRUG

TAK-438 placebo-matching tablets

Cohorts 1-7: Placebo; Cohorts 9-11: Placebo

Esomeprazole DRUG

Esomeprazole tablets

Cohort 12: Ethnic Bridging

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
• Richmond Pharmacology Limited: collaborator

MeSH Terms

Interventions

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

Intervention Hierarchy (Ancestors)

Omeprazole; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Medical Director Clinical Science

  Takeda

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• 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, 2007
• Primary Completion: February 1, 2008
• Study Completion: February 1, 2008
• Last Updated: May 19, 2014

Record last verified: 2014-05