Phase 3 Study to Evaluate the Acid-Inhibitory Effect of Multiple Oral Doses of Vonoprazan (TAK-438)

Phase 3

Completed

• Conditions: Healthy Volunteers
• Interventions: Drug: Vonoprazan; Drug: Esomeprazole; Drug: Rabeprazole sodium

• Registration Number: NCT02037477
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study is to investigate the acid-inhibitory effect of multiple oral doses of Vonoprazan (TAK-438) and the relative effect of vonoprazan versus two controls (esomeprazole and rabeprazole sodium) in healthy Japanese adult male participants with the CYP2C19 extensive metabolizer (EM) genotype.

Detailed Description

This is a Phase 3 open-label crossover study to evaluate the acid-inhibitory effect following 7 days multiple doses of vonoprazan (20 mg per dose) and esomeprazole (20 mg per dose) (Cohort 1) or vonoprazan (20 mg per dose) and rabeprazole sodium (10 mg per dose) (Cohort 2) in healthy Japanese adult male participants (CYP2C19 genotype: EM). There will be a total of 20 participants, 5 per group for both Cohorts 1 and 2. At least 2 participants each with the homo EM (\*1/\*1) or hetero EM (\*1/\*2, \*1/\*3) CYP2C19 genotype will be enrolled among the 5 participants per group.

The drug being tested in this study is called vonoprazan. This study will look at the acid inhibitory effect following 7 days multiple doses of vonoprazan and esomeprazole (Cohort 1) or vonoprazan and rabeprazole sodium (Cohort 2) in healthy Japanese adult male participants with the CYP2C19 EM genotype.

The study will enroll a total of 20 participants, 5 per group for both Cohorts. At least 2 participants each with the homo EM (\*1/\*1) or hetero EM (\*1/\*2, \*1/\*3) CYP2C19 genotype will be enrolled among the 5 participants per group.

* Group A, Cohort 1: vonoprazan (20 mg per dose for 7 days) followed by esomeprazole (20 mg per dose for 7 days)

* Group B, Cohort 1: esomeprazole (20 mg per dose for 7 days) followed by TAK-438 (20 mg per dose for 7 days)

* Group C, Cohort 2: vonoprazan (20 mg per dose for 7 days) followed by rabeprazole sodium (10 mg per dose for 7 days)

* Group D, Cohort 2: rabeprazole sodium (10 mg per dose for 7 days) followed by vonoprazan (20 mg per dose for 7 days).

All participants will be asked to take Study Medication at the same time each day throughout the study. This single center trial will be conducted in Japan. The overall time to participate in this study is 31 days.

Study Timeline

• Study Start: 2014-01
• Study First Submitted: 2014-01-14
• Study First Submitted QC: 2014-01-14
• Study First Posted: 2014-01-16
• Primary Completion: 2014-03
• Study Completion: 2014-03
• Results First Submitted: 2015-03-27
• Status Verified: 2016-08
• Results First Submitted QC: 2016-08-22
• Last Update Submitted: 2016-08-22
• Results First Posted: 2016-10-17
• Last Update Posted: 2016-10-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 20

Inclusion Criteria

1. Is a healthy Japanese adult male volunteer.
2. Is aged 20 to 45 years, inclusive, at the time of informed consent.
3. Has been confirmed at CYP2C19 genotyping as an Extensive Metabolizer [EM (*1/*1,*1/*2,*1/*3)].
4. Capable of understanding and complying with the protocol requirements.
5. The participant signs and dates a written informed consent form prior to the initiation of any study procedures.
6. Weighs 50 kg or more and has body mass index (BMI) of 18.5 or more and less than 25.0 kg/m^2 at Screening or admission (Day -3).
7. H. pylori-negative at Screening.

Exclusion Criteria

1. Has undergone resection of the upper gastrointestinal tract or vagotomy.
2. Was determined to have hypoacidity or anacidity.
3. Has a present or past history of acid-related disease (reflux esophagitis, gastric ulcer, duodenal ulcer, non-erosive gastroesophageal reflux, Barrett's esophagus, Zollinger-Ellison syndrome, etc.).
4. Has undergone eradication of H. pylori within 6 months prior to the start of the study drug administration.
5. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormalities which may impact the ability of the subject to participate or potentially confound the study results.
6. Has a known hypersensitivities or allergies to drugs or food.
7. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 5 years prior to the start of the study drug administration.
8. Has poor peripheral venous access.
9. Had 200 mL or more of whole blood drawn within 4 weeks (28 days) prior to the start of the study drug administration or 400 mL or more of whole blood drawn within 12 weeks (84 days) prior to the start of the study drug administration.
10. Had a total volume of 800 mL or more of whole blood drawn within 52 weeks (364 days) prior to the start of the study drug administration.
11. Has undergone blood component draw within 2 weeks (14 days) prior to the start of the study drug administration.
12. Requires treatment with any of the excluded medications specified in the study or requires nutrition with any vitamin supplements or foods prohibited in the study.
13. Has received study medication within 16 weeks (112 days) prior to the start of the study drug administration.
14. Has received vonoprazan (TAK-438) in the past.
15. Has a history of cancer.
16. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen or serological reaction for syphilis at Screening.
17. Has a Screening or admission (Day -3) abnormal clinically significant electrocardiogram (ECG).
18. Has abnormal Screening or admission (Day -3) laboratory values that suggest a clinically significant underlying disease or subject with the following lab abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > twice the upper limit of the normal range.
19. Is an immediate family member, study site employee, or in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress.
20. Participant who, in the opinion of the investigator or sub-investigator, is unlikely to comply with the protocol or is unsuitable for any other reasons.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sequence D (Cohort 2): Rabeprazole Sodium + Vonoprazan	Vonoprazan	Rabeprazole sodium 10 mg, orally, once daily for 7 days, followed by a washout period of at least 7 days; then vonoprazan 20 mg, orally, once daily for 7 days.
Sequence A (Cohort 1): Vonoprazan + Esomeprazole	Vonoprazan	Vonoprazan (TAK-438) 20 mg, orally, once daily for 7 days, followed by a washout period of at least 7 days; then esomeprazole 20 mg, orally, once daily for 7 days.
Sequence A (Cohort 1): Vonoprazan + Esomeprazole	Esomeprazole	Vonoprazan (TAK-438) 20 mg, orally, once daily for 7 days, followed by a washout period of at least 7 days; then esomeprazole 20 mg, orally, once daily for 7 days.
Sequence C (Cohort 2): Vonoprazan + Rabeprazole Sodium	Vonoprazan	Vonoprazan 20 mg, orally, once daily for 7 days, followed by a washout period of at least 7 days; then Rabeprazole sodium 10 mg, orally, once daily for 7 days.
Sequence B (Cohort 1): Esomeprazole + Vonoprazan	Vonoprazan	Esomeprazole 20 mg, orally, once daily for 7 days, followed by a washout period of at least 7 days; then vonoprazan 20 mg, orally, once daily for 7 days.
Sequence B (Cohort 1): Esomeprazole + Vonoprazan	Esomeprazole	Esomeprazole 20 mg, orally, once daily for 7 days, followed by a washout period of at least 7 days; then vonoprazan 20 mg, orally, once daily for 7 days.
Sequence C (Cohort 2): Vonoprazan + Rabeprazole Sodium	Rabeprazole sodium	Vonoprazan 20 mg, orally, once daily for 7 days, followed by a washout period of at least 7 days; then Rabeprazole sodium 10 mg, orally, once daily for 7 days.
Sequence D (Cohort 2): Rabeprazole Sodium + Vonoprazan	Rabeprazole sodium	Rabeprazole sodium 10 mg, orally, once daily for 7 days, followed by a washout period of at least 7 days; then vonoprazan 20 mg, orally, once daily for 7 days.

Primary Outcome Measures

Name	Time	Method
Intragastric pH Time Course Over 24 Hours	At baseline (Day -2 to Day -1), administration period (Days 1 to Day 2 and Days 7 to Day 8)	Intragastric pH was measured continuously for 24 hours (hr) by pH monitor. pH holding time ratio (HTR) is the percentage of time a pH is maintained at a particular level. For example, pH 4 HTR is the percentage of time the pH = 4.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Abnormal 12-lead Electrocardiogram (at Rest) Findings	At Screening, baseline (Day -3), administration period (Day 8), and post-test (Day 28)
Frequency of Adverse Events	31 days	The frequency of adverse events by type, seriousness, time to onset. 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 to the last dose of study drug.
Number of Participants With Abnormal Changes From Baseline in Vital Signs	At screening, baseline (Day -3, Day -2, Day -1), administration period (Days 1, Day 2, Day 7, Day 8), and post-test (Day 28)	Vital signs included body temperature (oral or tympanic measurement), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm).
Number of Participants With Markedly Abnormal Laboratory Values	At Screening, baseline (Day -3), administration period (Day 1, Day 8), and post-test (Day 28)	The number of participants with markedly abnormal laboratory values for Chemistry, Hematology and Urinalysis during the study is reported.