The primary objectives of this study are to assess the efficacy of vonoprazan (10 mg and 20 mg once daily [QD]) compared to placebo (QD) in relief of heartburn over 4 weeks in participants with NERD.

Inclusion Criteria:

1. The participant is ≥18 years of age at the time of informed consent signing.
2. In the opinion of the investigator or subinvestigators, the participant is capable of understanding and complying with protocol requirements, including compliance with the electronic diary.
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 subject has a diagnosis of symptomatic gastroesophageal reflux disease (GERD) with heartburn as the subject's predominant symptom prior to the Screening Period, as documented in the subject's medical record.
5. History of onset of heartburn at least 6 months prior to the Screening Period.
6. Heartburn reported on 4 or more days during any consecutive 7-day period of 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.

Exclusion Criteria:

1. The participant has endoscopically confirmed erosive esophagitis (EE) during the Screening Period. Endoscopy conducted during the Screening Period should be performed after participants meet Inclusion Criterion 6 (i.e., heartburn reported on 4 or more days during any consecutive 7-day period of the Screening Period as recorded in the electronic diary).

2. The participant has active irritable bowel syndrome (IBS) or has 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 upper gastrointestinal disorders, such as:

   1. Functional heartburn, as described in the Rome IV Criteria.
   2. Functional dyspepsia, as described in the Rome IV Criteria.

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

5. 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.

6. The participant has scleroderma (systemic sclerosis) or systemic lupus erythematosus.

7. The participant has a history of surgery or endoscopic treatment affecting gastroesophageal reflux, including fundoplication and dilation for esophageal stricture (except dilation for a Schatzki's ring) or a history of gastric or duodenal surgery (except endoscopic removal of benign polyps).

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

9. The participant requires or is expected to require use of prescription or non-prescription proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) throughout the study.

10. The participant has received any investigational compound (including those in post-marketing studies) within 30 days prior to the start of the Screening Period or vonoprazan in a clinical trial at any time (including participation in Study NERD-201). 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.

11. 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.

12. The participant has had clinically significant upper or lower gastrointestinal bleeding within 4 weeks prior to the Screening Period.

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

14. 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, and titanium oxide, or red or yellow ferric oxide). Skin testing may be performed according to local standard practice to confirm hypersensitivity.

15. The participant 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 based on self-report. Participants must have a negative urine drug screen for cannabinoids/tetrahydrocannabinol (including prescription cannabinoids) and non-prescribed medications during the Screening Period.

16. The participant is taking any excluded medications or treatments listed in the protocol, including prescription cannabinoids/tetrahydrocannabinol.

17. 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.

18. 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.

19. The participant requires hospitalization or has surgery scheduled during the course of the study (from Visit 1 to end of Follow-up Period at Visit 10) or has undergone major surgical procedures within 30 days prior to the Screening Period.

20. The participant has a history of malignancy (including mucosa-associated lymphoid tissue lymphoma) 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 cured cutaneous basal cell carcinoma or cervical carcinoma in situ).

21. The participant has acquired immunodeficiency syndrome or human immunodeficiency virus infection, or tests positive for the hepatitis B surface antigen, hepatitis C virus (HCV) antibody, or HCV-ribonucleic acid (RNA). However, participants who test positive for HCV antibody but negative for HCV-RNA are permitted to participate.

22. 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 for participants with a diagnosis of Gilbert's syndrome).

23. The subject tests positive for active H pylori infection during the Screening Period, after ≥4 weeks free from antibiotics and bismuth and ≥2 weeks free from PPIs and histamine-2 receptor antagonists (H2RAs).