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INTRODUCTION: H. pylori causes considerable morbidity and mortality worldwide, and antimicrobial resistance has led to unacceptably low eradication rates for previously effective therapies. The WHO has categorized H. pylori as a pathogen for “High Priority” therapeutic development. A prior clinical study (NCT01980095) of RHB-105 showed an eradication rate of 89.4% in the mITT (received at least 1 dose of therapy and post treatment test of cure) population. METHODS: Phase 3, double-blind, active comparator study (NCT03198507) assessed HP eradication with 4 capsules RHB-105 (an ‘all-in-one’ fixed dose oral capsule providing rifabutin 50 mg, amoxicillin 1000 mg, omeprazole 40 mg) vs high dose PPI-amoxicillin dual therapy (amoxicillin 1000 mg, omeprazole 40 mg) Q8H for 14 days.Dyspeptic, treatment naïve subjects with confirmed HP infection, 13C UBT (urea breath test) and endoscopy (CLO test, pathology, or culture), had 13C UBT primary end point assessed at least 4 weeks post-therapy. Subjects who failed HP eradication were assessed for development of resistance and offered physician-directed standard of care. RESULTS: In 455 subjects randomized 1:1, the ITT eradication rate of RHB-105 (83.8%) was superior to that of active comparator (57.7%), P < 0.0001. A pre-specified PK population assessing efficacy in subjects with positive drug levels at day 13 similarly demonstrated superiority of RHB-105 over active comparator 90.3% vs. 64.7%, P < 0.0001. No rifabutin resistance was noted pre or post treatment. RHB-105 efficacy was unaffected by clarithromycin or metronidazole resistance. Drug compliance was similar in both groups (>95%). Comparable AEs were noted between arms with no drug related SAEs reported. AEs seen with RHB-105 (>1% over comparator) were diarrhea (10.1% vs 7.9%) and rash (1.3% vs 0.0%). Physician directed standard of care (primarily clarithromycin or metronidazole based) eradication rate was 53% in patients who failed double blinded therapy. CONCLUSION/DISCUSSION: RHB-105, an all-in-one rifabutin triple therapy, was safe, effective, well-tolerated in H. pylori eradication, and not affected by clarithromycin or metronidazole resistance. The efficacy for RHB-105 was substantially greater due to rifabutin and the difference was statistically significant and clinically meaningful. RHB-105 may be a new best in class, first line empiric treatment for H. pylori infection, with the potential to serve an unmet need in an environment of increasing antibiotic resistance.