The goal of this clinical trial is to learn if a short course of a potassium-competitive acid blocker (PCAB) test can guide treatment of adults with typical reflux symptoms as effectively as standard physiologic testing with endoscopy and 24-hour pH-impedance monitoring. It will also learn about the safety of PCAB-guided management.

The main questions it aims to answer are:

• Is PCAB test-guided treatment as effective as physiologic test-guided treatment in improving reflux symptoms after 4 weeks?
• How accurate is the PCAB test at detecting pathologic acid reflux compared with 24-hour pH-impedance monitoring?
• What medical problems do participants have when receiving PCAB-, proton-pump inhibitor-, or neuromodulator-based treatment?
• In this study, researchers will compare two strategies: one group will receive a 7-day course of vonoprazan (PCAB) as a diagnostic test and then treatment guided by the PCAB response, while the other group will undergo endoscopy and 24-hour pH-impedance monitoring with treatment guided by those results.

Participants will:

• Be randomly assigned to either the PCAB test-guided group or the physiologic test-guided group
• Take study medicines by mouth (such as vonoprazan, omeprazole, and/or nortriptyline or matching placebos) for about 4 weeks, depending on their test results and symptom type
• Attend scheduled clinic visits for checkups, questionnaires, and safety monitoring
• Keep a diary of their reflux symptoms, quality of life, and any use of rescue antacid medicine

This protocol describes a single-center, randomized, controlled, open-label, parallel-group, non-inferiority trial comparing a potassium-competitive acid blocker (PCAB) test-guided strategy with physiologic test-guided management in adults with typical reflux symptoms suggestive of gastroesophageal reflux disease (GERD).

The study will enroll approximately 120 participants aged 18-70 years with heartburn, regurgitation, or non-cardiac chest pain, and will exclude patients with Barrett's esophagus, peptic ulcer, prior upper GI surgery, significant comorbidities, or recent use of potent anti-secretory, neuromodulator, or prokinetic agents.

Participants are randomized in a 1:1 ratio to either a 7-day vonoprazan-based PCAB test or to a reference strategy using esophagogastroduodenoscopy (EGD) plus 24-hour pH-impedance monitoring and high-resolution manometry in accordance with Lyon Consensus 2.0 and Rome IV criteria.

The primary objective is to determine whether PCAB test-guided treatment is non-inferior to physiologic test-guided treatment with respect to clinical response, defined by improvement in reflux symptoms after 4 weeks of allocated therapy.

Secondary objectives include: (1) assessment of the diagnostic performance of the PCAB test for pathologic acid reflux using 24-hour pH-impedance monitoring as the reference standard; (2) comparison of changes in Reflux Disease Questionnaire (RDQ) scores, Likert symptom scales for heartburn, regurgitation and chest pain, EQ-5D quality-of-life scores, symptom-free days, rescue antaciduse, and patient satisfaction; and (3) evaluation of treatment-emergent adverse events andserious adverse events.

In the PCAB arm, vonoprazan 20 mg twice daily for 7 days constitutes the diagnostic test; PCAB responders and non-responders are then allocated to proton pump inhibitor (omeprazole-based) or neuromodulator (nortriptyline-based) regimens with matching placebos according to the underlying GERD phenotype (erosive esophagitis, non-erosive reflux disease,reflux hypersensitivity, or functional heartburn). In the physiologic-test arm, treatment selection (omeprazole versus nortriptyline, with placebos) is based directly on EGD and 24-hour pH-impedance findings and symptom association analysis. Outcomes are measured at multiple time points over 4 weeks using RDQ, symptom Likert scales, EQ-5D, symptom and antacid diaries, and standard safety assessments, and data will be analyzed primarily using non-inferiority methods for proportions and standard diagnostic accuracy metrics (sensitivity, specificity, predictive values, and likelihood ratios), with appropriate parametric ornon-parametric tests and longitudinal models.

Inclusion Criteria:

• Age between 18 and 70 years.
• Presence of specific gastroesophageal reflux disease (GERD) symptoms, including heartburn, regurgitation, and/or esophageal chest pain, occurring at least 4 times per week for more than 4 weeks prior to enrollment.

Exclusion Criteria:

• Presence of GERD complications, including esophageal stricture and/or Barrett's esophagus.
• Concomitant symptoms that may interfere with GERD treatment, such as frequent belching or rumination syndrome.
• History of gastric or duodenal ulcers.
• History of upper gastrointestinal surgery (involving the esophagus, stomach, or small intestine).
• Use of any of the following medications within 4 weeks prior to enrollment: aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), mucoprotective agents, prokinetics, or neuromodulators.
• Use of proton pump inhibitors (PPIs), histamine H2-receptor antagonists (H2RAs), or potassium-competitive acid blockers (PCABs) within 2 weeks prior to enrollment. (Note: Patients may become eligible if they complete a minimum 2-week washout period).
• Any contraindications for ambulatory esophageal reflux monitoring.
• Known history of hypersensitivity, allergy, or adverse reactions to the study medications: vonoprazan, omeprazole, or nortriptyline.
• Pregnant or breastfeeding women.

To protect participant confidentiality and comply with institutional and regulatory requirements, no IPD will be shared unless with reasonable request.