Proof-of-Concept of Non-Inferiority in the First Randomized Controlled Trial Comparing D-Mannose to Fosfomycin in Acute Uncomplicated Lower Urinary Tract Infections

Background/Objectives: Antibiotics are the recommended first-line therapy for acute uncomplicated lower urinary tract infections (cystitis), but antibiotic resistance and tolerability concerns require antibiotic-sparing strategies. This study evaluated D-mannose as a stand-alone alternative. Methods: This multicenter, randomized, controlled, double-blind study, compared D-mannose to fosfomycin in women aged 18–70 with cystitis. Clinical cure (CC) was assessed using the Acute Cystitis Symptom Score (ACSS) up to day 8, with non-inferiority tested at the 15% margin. Post hoc analytical approaches accounted for potential bias due to low sample sizes and missing values. Results: The study randomized 118 patients. At baseline, severe symptoms (ACSS ≥12) were more frequent in the D-mannose group compared to fosfomycin (32.8% vs. 22.8%). Efficacy analyses were performed on the per-protocol set (D-mannose: N = 57; fosfomycin: N = 54). Median time to CC was 5.0 days (D-mannose) and 3.0 days (fosfomycin) overall, and 4.0 days vs. 3.0 days in the subgroup of moderate disease severity. The point estimate for the CC rate difference on day 8 (−10.1%) favored fosfomycin but was within the non-inferiority margin. Due to wide confidence intervals, non-inferiority was not statistically demonstrated. The post hoc analysis yielded smaller confidence intervals with estimated CC rates of 84.2% (D-mannose) vs. 83.5% (fosfomycin) on day 8 and statistically confirmed non-inferiority. Recurrence rates were similar (13.2% vs. 13.3%) and there was no statistically significant difference for additional antibiotic use (19.3% vs. 11.1%). Investigators and patients favored D-mannose over fosfomycin for tolerability, and gastrointestinal adverse events were less frequent (9.8% vs. 24.6%). Conclusions: D-mannose treatment was non-inferior to fosfomycin in uncomplicated cystitis according to post hoc analyses and may be an alternative to antibiotic first-line therapy, not least because of the favorable risk-benefit ratio.