VONOPRAZAN FOR THE TREATMENT OF HEARTBURN IN NON-EROSIVE REFLUX DISEASE: A RANDOMIZED TRIAL

Background: Proton pump inhibitors (PPIs) are the mainstay of therapy for non-erosive reflux disease (NERD). Potassium-competitive acid blockers (PCABs) have more potent and rapid inhibition of gastric acid secretion than PPIs. However, randomized trials in subjects with NERD from Japan failed to document efficacy of vonoprazan in their primary endpoints. We performed a randomized trial in U.S. subjects diagnosed with NERD of vonoprazan vs. placebo over a period of 4 weeks followed by a 20-week active-treatment extension to assess longer term treatment effect.
Methods: Adult subjects with heartburn ≥4 days/week during screening without erosive esophagitis on endoscopy were randomized to placebo, vonoprazan 10mg, or vonoprazan 20mg. Electronic diaries were completed twice daily for heartburn and use of rescue antacids. After 4 weeks, subjects on placebo were re-randomized to vonoprazan 10 or 20mg and those already on vonoprazan continued at the same dose for 20 weeks. The primary endpoint was percentage of days without daytime or nighttime heartburn (24-hour heartburn-free days); the secondary endpoint was percentage of days without rescue antacid use.
Results: Among 772 subjects in the placebo-controlled trial, the mean age was 51 years, 68% were female, 16% were Black, 32% were Latino, and mean BMI was 30.3 kg/m². The least squares mean percentage of 24-hour heartburn-free days over the placebo-controlled period was 27.7% for placebo vs. 44.8% for vonoprazan 10mg (difference=17.1%, p<0.0001) and 44.4% for vonoprazan 20mg (difference from placebo=16.7%, p<0.0001). Similar results were seen for other endpoints (Table 1). The percentage of subjects with 24-hour heartburn-free days is shown on each day from the last week of the screening period through the placebo and extension periods in Figures 1a and 1b. In the placebo-controlled period, the differences in the percentage of subjects with a 24-hour heartburn-free day for vonoprazan 10mg vs. placebo and vonoprazan 20mg vs. placebo were 8.3% and 11.6% on day 1 and 18.1% and 23.2% on day 2, respectively. The mean/median percentages of 24-hour heartburn-free days over the extension period were 61.9%/78.3% for subjects initially on placebo and re-randomized to vonoprazan 10mg at 4 weeks (N=119), 62.9%/76.2% for subjects initially on placebo and re-randomized to vonoprazan 20mg at 4 weeks (N=122), 62.6%/77.7% for those on vonoprazan 10mg throughout (N=247), and 60.7%/79.4% for those on vonoprazan 20mg throughout (N=235).
Conclusions: Vonoprazan reduced heartburn symptoms in subjects diagnosed with NERD, with the benefit appearing to begin as early as the first day of therapy. Treatment effect persisted after the initial 4-week placebo-controlled period throughout the 20-week extension period. The two vonoprazan doses (10 and 20mg) were similar in efficacy.