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

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.