A Study to Evaluate the Efficacy and Safety of Vonoprazan Compared to Placebo in Participants With Symptomatic Non-Erosive Gastroesophageal Reflux Disease

Study Overview
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Brief Summary
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The primary objectives of this study are to assess the efficacy of vonoprazan (10 mg, 20 mg, and 40 mg On-Demand) compared to placebo (On-Demand) in relief of episodic heartburn over 6 weeks in participants with symptomatic non-erosive gastroesophageal reflux disease (NERD), and to assess the safety of vonoprazan (10 mg, 20 mg, and 40 mg On-Demand) compared to placebo (On-Demand) in participants with symptomatic NERD.

Official Title
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A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Vonoprazan 10 mg, 20 mg, and 40 mg Compared to Placebo for Relief of Episodic Heartburn in Subjects With Symptomatic Non-Erosive Gastroesophageal Reflux Disease

Conditions
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Non-Erosive Gastro-Esophageal Reflux Disease, Heartburn

Intervention / Treatment
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* Drug: Vonoprazan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Run-In Period The participant is ≥18 years of age at the time of informed consent signing. In the opinion of the investigator or sub investigators, the participant is capable of understanding and complying with protocol requirements. The participant signs and dates a written informed consent form (ICF) and any required privacy authorization prior to the initiation of any study procedures. The participant is informed of the full nature and purpose of the study, including possible risks and side effects. The participant has the ability to cooperate with the investigator. Ample time and opportunity should be given to read and understand verbal and/or written instructions. The participant identified their main symptom as heartburn, a burning sensation in the retrosternal area (behind the breastbone). History of episodes of heartburn for 6 months or longer prior to screening. Heartburn reported on 4 or more days during any 7 consecutive days in the Screening Period as recorded in the electronic diary. A female participant of childbearing potential who is or may be sexually active with a non sterilized male partner agrees to routinely use adequate contraception from the signing of informed consent until 4 weeks after the last dose of study drug. Inclusion Criteria for On-Demand Treatment Period The participant completes the Run-In Period, during which the participant was at least 80% compliant with open-label study drug. The participant has stable disease, ie, no heartburn the last 7 days of the Run-In Period. The participant continues to fulfill all eligibility criteria for the Run-In Period (except Inclusion Criteria 4). Participant completes at least 80% of diary entries during Run-In Period, including 80% of diary entries over the last 7 days. Exclusion Criteria for Run-In Period Endoscopically confirmed erosive esophagitis (EE) during the Screening Period assessed by the investigator. Endoscopy should be performed after participants meet Inclusion Criteria 6. Any endoscopic confirmation performed in a routine clinical setting within 7 days before signing the informed consent is acceptable to use for the purpose of fulfilling the screening requirement. The participant has active irritable bowel syndrome (IBS) or had a flare of IBS requiring therapy within the prior 6 months. The participant has a history of or is suspected of having functional heartburn diagnosed by the Rome IV criteria. The participant has a history of or is suspected of having functional dyspepsia diagnosed by the Rome IV criteria. The participant has endoscopic Barrett's esophagus (>1 cm of columnar-lined esophagus) and/or definite dysplastic changes in the esophagus. The participant has any other clinically significant condition affecting the esophagus, including eosinophilic esophagitis; esophageal varices; viral or fungal infection; esophageal stricture; a history of radiation therapy, radiofrequency ablation, endoscopic mucosal resection, or cryotherapy to the esophagus; or any history of caustic or physiochemical trauma (including sclerotherapy or esophageal variceal band ligation). However, participants diagnosed with Schatzki's ring (mucosal tissue ring around lower esophageal sphincter) or hiatal hernia are eligible to participate. The participant has scleroderma (systemic sclerosis). The participant has a history of surgery or endoscopic treatment affecting gastroesophageal reflux, including fundoplication and dilation for esophageal stricture (except Schatzki's ring) or a history of gastric or duodenal surgery (except endoscopic removal of benign polyps). The participant has an active gastric or duodenal ulcer within 4 weeks before the first dose of study drug. Use of prescription or non-prescription proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) throughout the study. The participant has received vonoprazan in a clinical trial at any time or any other investigational compound (including those in post-marketing studies) within 30 days prior to the start of the Screening Period. A participant who has been screen failed from another clinical study and who has not been dosed may be considered for enrollment in this study. The participant is a study site employee, an immediate family member, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or who may have consented under duress. The participant has cutaneous lupus erythematosus or systemic lupus erythematosus. The participant has had clinically significant upper or lower gastrointestinal bleeding within 4 weeks prior to screening. The participant has Zollinger-Ellison syndrome or other gastric acid hypersecretory conditions. The participant has a history of hypersensitivity or allergies to vonoprazan (including the formulation excipients: D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, fumaric acid, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 8000, titanium oxide, or red or yellow ferric oxide). Skin testing may be performed according to local standard practice to confirm hypersensitivity. The participant has a history of alcohol abuse, illegal drug use, drug addiction, 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 based on self-report within the 12 months prior to screening. Participants must have a negative urine drug screen for cannabinoids/ tetrahydrocannabinol and nonprescribed medications at screening. Participants taking prescription drugs (except prescription cannabinoids/tetrahydrocannabinol) will be allowed. The participant is taking any excluded medications or treatments listed in the protocol. If female, the participant is pregnant, lactating, or intending to become pregnant before, during, or within 4 weeks after participating in this study, or intending to donate ova during such time period. The participant has a history or clinical manifestations of significant central nervous system, cardiovascular, pulmonary, hepatic, renal, metabolic, other gastrointestinal, urological, endocrine, or hematological disease that, in the opinion of the investigator, would confound the study results or compromise participant safety. The participant requires hospitalization or has surgery scheduled during the course of the study or has undergone major surgical procedures within 30 days prior to the Screening Visit. The participant has a history of malignancy or has been treated for malignancy within 5 years prior to the start of the Screening Period (Visit 1). (The participant may be included in the study if he/she has recovered from cutaneous basal cell carcinoma or cervical carcinoma in situ). The participant has acquired immune deficiency syndrome (AIDS) or human immunodeficiency virus (HIV) infection, or tests positive for the hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or HCV ribonucleic acid (HCV-RNA). However, participants who test positive for HCV antibody but negative for HCV-RNA are permitted to participate. The participant has any of the following abnormal laboratory test values at the start of the Screening Period: Creatinine levels: >2 mg/dL (>177 μmol/L) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the upper limit of normal (ULN) or total bilirubin >2 × ULN (except participants with Gilbert Syndrome)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Run-In Period<br>Participants will receive vonoprazan 20 mg once daily for up to 4 weeks. | Drug: Vonoprazan<br>* Orally via capsules<br>|
| Experimental: Vonoprazan 10 mg: On-Demand Treatment Period<br>Participants who have stable disease (no heartburn on the last 7 days of the Run-In Period) will take vonoprazan 10 mg when heartburn occurs during the 6 week On-Demand Treatment Period. Participants can take no more than one dose in a 24 hour period. | Drug: Vonoprazan<br>* Orally via capsules<br>|
| Experimental: Vonoprazan 20 mg: On-Demand Treatment Period<br>Participants who have stable disease (no heartburn on the last 7 days of the Run-In Period) will take vonoprazan 20 mg when heartburn occurs during the 6 week On-Demand Treatment Period. Participants can take no more than one dose in a 24 hour period. | Drug: Vonoprazan<br>* Orally via capsules<br>|
| Experimental: Vonoprazan 40 mg: On-Demand Treatment Period<br>Participants who have stable disease (no heartburn on the last 7 days of the Run-In Period) will take vonoprazan 40 mg when heartburn occurs during the 6 week On-Demand Treatment Period. Participants can take no more than one dose in a 24 hour period. | Drug: Vonoprazan<br>* Orally via capsules<br>|
| Placebo Comparator: Placebo: On-Demand Treatment Period<br>Participants who have stable disease (no heartburn on the last 7 days of the Run-In Period) will take a placebo when heartburn occurs during the 6 week On-Demand Treatment Period. Participants can take no more than one dose in a 24 hour period. | Drug: Placebo<br>* Orally via capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Evaluable Heartburn Episodes Completely Relieved Within 3 Hours and With No Further Heartburn Reported for 24 Hours After Taking Study Drug | An evaluable heartburn episode was an episode for which study drug was taken and for which the participant completed at least one entry in the heartburn episode diary. For a heartburn episode to be considered completely relieved, a participant must not have taken rescue antacid within 3 hours of taking study drug. For sustained relief, complete relief must have been accompanied by 24 hours without another heartburn episode after taking study drug. | On-Demand Treatment Period: Day 1 to Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Evaluable Heartburn Episodes Completely Relieved Within 3 Hours After Taking Study Drug | An evaluable heartburn episode was an episode for which study drug was taken and for which the participant completed at least one entry in the heartburn episode diary. For a heartburn episode to be considered completely relieved, a participant must not have taken rescue antacid within 3 hours of taking study drug. | On-Demand Treatment Period: Day 1 to Day 42 | 
| Percentage of Evaluable Heartburn Episodes for Each Participant That Are Completely Relieved Within 3 Hours and With No Further Heartburn Reported for 24 Hours After Taking Study Drug | An evaluable heartburn episode was an episode for which study drug was taken and for which the participant completed at least one entry in the heartburn episode diary. For a heartburn episode to be considered completely relieved, a participant must not have taken rescue antacid within 3 hours of taking study drug. For sustained relief, complete relief must have been accompanied by 24 hours without another heartburn episode after taking study drug. | On-Demand Treatment Period: Day 1 to Day 42 | 
| Mean Number of Tablets of Rescue Antacid Taken Per Day Over the On-Demand Treatment Period |  | On-Demand Treatment Period: Day 1 to Day 42 | 
| Percentage of Participants With Complete Relief of Heartburn Within 3 Hours After the First Episode and With No Further Heartburn Reported for 24 Hours After Taking Study Drug | An evaluable heartburn episode was an episode for which study drug was taken and for which the participant completed at least one entry in the heartburn episode diary. For a heartburn episode to be considered completely relieved, a participant must not have taken rescue antacid within 3 hours of taking study drug. For sustained relief, complete relief must have been accompanied by 24 hours without another heartburn episode after taking study drug. | On-Demand Treatment Period: Day 1 to Day 42 | 
| Percentage of Days Study Drug Was Taken Over the On-Demand Treatment Period |  | On-Demand Treatment Period: Day 1 to Day 42 | 
| Percentage of 24-Hour Heartburn-Free Days Over the On-Demand Treatment Period | A 24-hour heartburn-free day was defined as a day having no heartburn among all diary entries for that day. The percentage of 24-hour heartburn-free days was calculated using all days with at least 1 evening or morning diary entry during the treatment period of this phase. | On-Demand Treatment Period: Day 1 to Day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Symptomatic Non-Erosive Gastroesophageal Reflux Disease, NERD, Vonoprazan, Heartburn