Comparison of Vonoprazan to Esomeprazole in Participants With Symptomatic GERD Who Responded Partially to a High Dose of Proton Pump Inhibitor (PPI)

A Randomized, Double-Blind, Proof-of-Concept, Phase 2 Study to Evaluate the Efficacy and Safety of Once Daily Oral Vonoprazan 20 mg or Vonoprazan 40 mg Compared to Esomeprazole 40 mg for the Treatment of Subjects With Symptomatic Gastro-Esophageal Reflux Disease Who Have a Partial Response Following Treatment With a High Dose of Proton Pump Inhibitor

The purpose of this study is to determine the effect of vonoprazan compared to esomeprazole for preventing heartburn symptoms over a 4-week treatment period in participants who have a partial response to treatment with esomeprazole.

Study Overview

• Status: Completed
• Conditions: Gastroesophageal Reflux
• Intervention / Treatment: Drug: Vonoprazan; Drug: Esomeprazole; Drug: Esomeprazole Placebo

Detailed Description

The drug being tested in this study is called vonoprazan. Vonoprazan is being tested to treat people who have symptomatic gastroesophageal reflux disease (GERD) with a partial response to treatment with a high dose of esomeprazole. This study will look at improvement in heartburn symptoms in participants who take vonoprazan compared to esomeprazole.

The study will enroll approximately 213 patients. All participants will receive esomeprazole or esomeprazole placebo-matching capsules (this is a capsule that looks like esomeprazole but has no active ingredient) during a 7-week run-in period. Participants will then be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

• Esomeprazole 40 mg
• Vonoprazan 20 mg
• Vonoprazan 40 mg

All participants will be asked to take one capsule at the same time each day throughout the study. All participants will be asked to record heartburn symptoms in a diary every morning upon waking and every evening before going to sleep.

This multi-center trial will be conducted in Europe. The overall time to participate in this study is 12 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone 1 week after the last dose of study drug for a follow-up assessment.

• Study Type: Interventional
• Enrollment (Actual): 256
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Gozee, Belgium, 6534
    • Medif
  • Grigomont, Belgium, 6887
    • SPRL Dr Yvan CALOZET
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Natoye, Belgium, 5360
    • SPRL MG Balthazar & Ballard
  • Oostham, Belgium, 3945
    • Mortelmans, Jaak
• Bulgaria
  • Pleven, Bulgaria, 5800
    • DCC 'Sv. Pantaleymon' OOD
  • Plovdiv, Bulgaria, 4002
    • UMHAT "Kaspela", EOOD
  • Ruse, Bulgaria, 7002
    • MHAT - Ruse, AD
  • Sliven, Bulgaria, 8800
    • MHAT "Hadzhi Dimitar", OOD
  • Sofia, Bulgaria, 1407
    • MHAT 'Tokuda Hospital Sofia', EAD
  • Sofia, Bulgaria, 1233
    • NMTH "Tsar Boris III"
  • Sofia, Bulgaria, 1407
    • "City Clinic UMHAC" EOOD
  • Sofia, Bulgaria, 1431
    • UMHAT "Sv. Ivan Rilski", EAD
  • Sofia, Bulgaria, 1527
    • UMHAT 'Tsaritsa Yoanna - ISUL', EAD
  • Sofia, Bulgaria, 1606
    • Fourth MHAT - Sofia EAD
  • Sofia, Bulgaria, 1797
    • UMHAT "SofiaMed", OOD
• Czechia
  • Strakonice, Czechia, 386 01
    • Okresni nemocniceStrakonice
• Estonia
  • Tallinn, Estonia, 10617
    • West Tallinn Central Hospital
  • Tallinn, Estonia, 13419
    • North Estonia Medical Centre Foundation
  • Tallinn, Estonia, 10617
    • Merekivi Perearstid OU
  • Tallinn, Estonia, 10117
    • OU Innomedica
  • Tallinn, Estonia, 10617
    • Merelahe Family Doctors Centre
  • Tartu, Estonia, 51014
    • Tartu University Hospital
• Poland
  • Bialystok, Poland, 15-275
    • SP ZOZ Wojewodzki Szpital Zespolony im. J. Sniadeckiego
  • Czestochowa, Poland, 42-217
    • NZOZ Inter-Med
  • Krakow, Poland, 31-009
    • Gabinet Endoskopii Przewodu Pokarmowego
  • Krakow, Poland, 30-349
    • Centrum Medyczne Plejady
  • Rzeszow, Poland, 35-055
    • Centrum Medyczne Medyk
  • Sopot, Poland, 81-756
    • Specjalistyczna Praktyka Lekarska dr med. Marek Horynski
  • Szczecin, Poland, 71-685
    • SONOMED Sp.z o.o
  • Torun, Poland, 87-100
    • Niepubliczny Zaklad Opieki Zdrowotnej Nasz Lekarz Praktyka Grupowa Lekarzy Rodzinnych z
  • Warszawa, Poland, 03-580
    • NZOZ Vivamed
  • Wroclaw, Poland, 53-114
    • LexMedica Osrodek Badan Klinicznych
  • Wroclaw, Poland, 54-144
    • EMC Instytut Medyczny S.A.
• United Kingdom
  • Devon
    • Plymouth, Devon, United Kingdom, PL7 1AD
      • Plympton Health Centre
  • Greater London
    • London, Greater London, United Kingdom, E11 1NR
      • Whipps Cross University Hospital
  • Hertfordshire
    • Watford, Hertfordshire, United Kingdom, WD25 0EA
      • Sheepcot Medical Centre
  • Staffordshire
    • Stoke on Trent, Staffordshire, United Kingdom, ST4 6QG
      • Royal Stoke University Hospital
  • Strathclyde
    • Glasgow, Strathclyde, United Kingdom, G20 0XA
      • CPS Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. Is a man or a woman and ≥18 years of age, at the time of the Screening visit.
4. Has a documented history of symptoms of both heartburn (burning pain) and acid regurgitation prior to entry into the study.
5. The subject has a medical history of ≥ 8 weeks of persistent heartburn symptoms in the presence of regurgitation symptoms (persistent heartburn symptoms defined as heartburn symptoms on ≥ 2 days a week) that are troublesome despite appropriate and correctly performed treatment with a PPI at standard doses.
6. Is ≥85% compliant at taking their Run-in medication and completing their e-Diary. Compliance for taking the Run-in medication is defined as the medication provided (esomeprazole and placebo) taken for 85% of the 6 weeks Run-in Period (or on 36 of 42 days of the Run-in Period).Compliance for the e-Diary is defined as the percentage of scheduled assessments that are completed based on 2 assessments per day (daytime and nighttime). For randomization, 85% compliance is required and is defined as 12 of 14 assessments completed over the 7-day period (Day -21 to Day-14) prior to the single blind Placebo Run-in Period.
7. Has a partial response to a PPI defined as having heartburn on 2 to 5 days and regurgitation on at least one day of the last week (Week 4) of a 4 week PPI Run-In Period with esomeprazole 40 mg and an increase of at least 2 symptom days of heartburn in the last week of a 2 week Placebo Run-In Period (4 to 7 symptom days) and at least one symptom day with regurgitation compared with the last week of the PPI Run-In Period.
8. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and for 4 weeks after last dose of the study medication.

Exclusion Criteria:

1. Has received any investigational compound within 30 days prior to the Screening Visit.
2. Has received vonoprazan in a previous clinical study.
3. Is an immediate family member, study site employee, is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling), or may have consented under duress.
4. Has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening.
5. Has a history of erosive esophagitis of Los Angeles (LA) Classification Grade B severity or worse prior to screening or at Screening endoscopy.
6. Has a history of or any coexisting diseases affecting the esophagus (eg, Barrett's esophagus, eosinophilic esophagitis, esophageal varices, scleroderma, viral or fungal infection, or esophageal stricture), history of radiation therapy or cryotherapy to the esophagus, caustic trauma, or physiochemical trauma such as sclerotherapy to the esophagus.
7. Has "alarm features" in symptomatology, including odynophagia, severe dysphagia, bleeding, weight loss, anemia, and blood in stool, pointing to a possible malignant disease of the gastrointestinal (GI) tract. Participants displaying "alarm symptoms" in addition to the "typical" gastroesophageal reflux disease (GERD) symptoms may be included based on endoscopic exclusion of malignancy.
8. Has current or historical chest pain due to cardiac diseases (eg, within one year).
9. Has had surgical treatment for GERD (eg, cardiaplasty), dilation of an esophageal stricture (other than Schatzki ring) or gastric or duodenal surgery, except simple oversew of an ulcer or endoscopic polypectomy of benign polyps.
10. Has active gastric or duodenal ulcers which have been confirmed by endoscopy within 30 days prior to Screening. Gastric or duodenal erosions are not exclusionary, unless considered severe and symptomatic by the investigator.
11. Has had an acute upper gastrointestinal hemorrhage within 30 days prior to Screening.
12. Has current or historical evidence of Zollinger-Ellison syndrome or other hypersecretory condition.
13. Has current or historical evidence of eosinophilic esophagitis (evidence may be based on the following: missing response to acid suppressive therapy, the presence of eosinophilia in histological probes of the esophageal mucosa, a normal pH profile of the distal esophagus, symptoms of dysphagia and food impaction). The exclusion of participants based on a predominance of the "typical" eosinophilic esophagitis symptoms only (as above) is considered acceptable. However, in participants with a predominance of "typical" symptoms and co-existing significant dysphagia and food impaction, the syndrome should be excluded by endoscopy with biopsy.
14. Has a documented history (within 6 months prior to screening) of functional dyspepsia (suggested by the presence of one or more of the following symptoms: epigastric pain, postprandial fullness or early satiety), or irritable bowel syndrome or other gastrointestinal diseases which are not acid-related, and therefore, are nonresponsive to gastric acid-blocking treatment.
15. Has a documented history of familial adenomatous polyposis.
16. Has known intolerance, hypersensitivity or allergies to any PPI or their components (including lansoprazole, dexlansoprazole, omeprazole, rabeprazole, pantoprazole, or esomeprazole), any component of vonoprazan, or antacid(s) selected as rescue medication for this study.
17. Has a history of alcohol abuse, illegal drug use, or drug addiction within the 12 months prior to Screening, or regularly consumes >21 units of alcohol (1 unit = 12 oz/300 mL beer, 1.5 oz/25 mL hard liquor/spirits, or 5 oz/100 mL wine) per week. Participants must have a negative drug screen at Screening.
18. Has evidence of a serious uncontrolled concomitant disease including: clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, systemic, or endocrine disease or other abnormality (other than the disease being studied), which may impact the ability of the participant to participate or potentially confound the study results.
19. Has planned, or is likely to require, in-patient surgery during the course of the study.
20. Has a history of cancer (except basal cell carcinoma of the skin) within 3 years prior to Screening.
21. Is known to have acquired immunodeficiency syndrome or chronic hepatitis due to any etiology.
22. Has abnormal laboratory values at Screening that suggest a clinically significant underlying disease or condition that may prevent the participant from completing the study.
23. Has an alanine aminotransferase (ALT), aspartate aminotransferase (AST) or T-bilirubin level which exceeds upper limit of normal (ULN) set by the testing laboratory at the Screening.
24. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.
25. Is required to take excluded medications or it is anticipated that the participant will require treatment with at least 1 of the disallowed concomitant medications during the study.
26. In the opinion of the investigator, is unable to comply with the requirements of the study or is unsuitable for any reason.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Esomeprazole 40 mg; Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by esomeprazole 40 mg, over encapsulated tablets, orally, once daily for 4 weeks during the active treatment period.	Drug: Vonoprazan; Vonoprazan over-encapsulated capsules; Other Names: TAK-438; Drug: Esomeprazole; Esomeprazole over-encapsulated tablets; Drug: Esomeprazole Placebo; Esomeprazole placebo-matching capsules
Experimental: Vonoprazan 20 mg; Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 20 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the treatment period.	Drug: Vonoprazan; Vonoprazan over-encapsulated capsules; Other Names: TAK-438; Drug: Esomeprazole; Esomeprazole over-encapsulated tablets; Drug: Esomeprazole Placebo; Esomeprazole placebo-matching capsules
Experimental: Vonoprazan 40 mg; Esomeprazole 40 mg over-encapsulated tablets, orally, once daily for 4 weeks then esomeprazole placebo-matching capsules, orally, once daily for 2 weeks during the run-in period, followed by vonoprazan 40 mg, over-encapsulated capsules, orally, once daily for 4 weeks during the active treatment period.	Drug: Esomeprazole; Esomeprazole over-encapsulated tablets; Drug: Esomeprazole Placebo; Esomeprazole placebo-matching capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Heartburn-Free 24-Hour Periods (Day and Night) During 4 Weeks of Treatment	Participants used the Reflux Symptom Questionnaire Electronic Diary (RESQ-eD) every morning upon waking and every evening before going to sleep to document the presence of daytime and nighttime heartburn and regurgitation. The percentage of heartburn-free (HBF) 24-hour periods was calculated for each participant using the following formula: (total 24-hour periods that are heartburn free / total 24-hour periods for which both a daytime and nighttime result is marked) x 100%.	4 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With ≥1 Sustained Resolution of Heartburn During the 4-Week Treatment Period	≥1 sustained resolution of heartburn is defined as ≥7 consecutive days without both daytime and nighttime heartburn anytime during the 4-week treatment period. Daytime and nighttime heartburn were documented by all participants using the Reflux Symptom Questionnaire Electronic Diary (RESQ-eD).	4 Weeks

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2016
• Primary Completion (Actual): October 5, 2018
• Study Completion (Actual): October 12, 2018

Study Registration Dates

• First Submitted: April 14, 2016
• First Submitted That Met QC Criteria: April 14, 2016
• First Posted (Estimate): April 19, 2016

Study Record Updates

• Last Update Posted (Actual): February 18, 2020
• Last Update Submitted That Met QC Criteria: February 5, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Drug therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Gastroesophageal Reflux; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Esomeprazole
• Other Study ID Numbers: Vonoprazan-2001; U1111-1172-2373 (Registry Identifier: WHO); 2015-001154-14 (EudraCT Number); 16/LO/0285 (Registry Identifier: NRES)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.