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.

Inclusion Criteria for Run-In Period

1. The participant is ≥18 years of age at the time of informed consent signing.
2. In the opinion of the investigator or sub investigators, the participant is capable of understanding and complying with protocol requirements.
3. 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.
4. The participant identified their main symptom as heartburn, a burning sensation in the retrosternal area (behind the breastbone).
5. History of episodes of heartburn for 6 months or longer prior to screening.
6. Heartburn reported on 4 or more days during any 7 consecutive days in the Screening Period as recorded in the electronic diary.
7. 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

1. The participant completes the Run-In Period, during which the participant was at least 80% compliant with open-label study drug.
2. The participant has stable disease, ie, no heartburn the last 7 days of the Run-In Period.
3. The participant continues to fulfill all eligibility criteria for the Run-In Period (except Inclusion Criteria 4).
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

1. 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.

2. The participant has active irritable bowel syndrome (IBS) or had a flare of IBS requiring therapy within the prior 6 months.

3. The participant has a history of or is suspected of having functional heartburn diagnosed by the Rome IV criteria.

4. The participant has a history of or is suspected of having functional dyspepsia diagnosed by the Rome IV criteria.

5. The participant has endoscopic Barrett's esophagus (>1 cm of columnar-lined esophagus) and/or definite dysplastic changes in the esophagus.

6. 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.

7. The participant has scleroderma (systemic sclerosis).

8. 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).

9. The participant has an active gastric or duodenal ulcer within 4 weeks before the first dose of study drug.

10. Use of prescription or non-prescription proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) throughout the study.

11. 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.

12. 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.

13. The participant has cutaneous lupus erythematosus or systemic lupus erythematosus.

14. The participant has had clinically significant upper or lower gastrointestinal bleeding within 4 weeks prior to screening.

15. The participant has Zollinger-Ellison syndrome or other gastric acid hypersecretory conditions.

16. 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.

17. 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.

18. The participant is taking any excluded medications or treatments listed in the protocol.

19. 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.

20. 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.

21. 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.

22. 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).

23. 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.

24. The participant has any of the following abnormal laboratory test values at the start of the Screening Period:

    1. Creatinine levels: >2 mg/dL (>177 μmol/L)
    2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the upper limit of normal (ULN) or total bilirubin >2 × ULN (except participants with Gilbert Syndrome)

Data from this study will be published; however, it is undecided if patient level data will be made available at this time.

During the Run-In Period, participants will receive open-label vonoprazan.