Non-Antibiotic Herbal Therapy (BNO 1045) versus Antibiotic Therapy (Fosfomycin Trometamol) for the Treatment of Acute Lower Uncomplicated Urinary Tract Infections in Women: A Double-Blind, Parallel-Group, Randomized, Multicentre, Non-Inferiority Phase III Trial

Abstract

Introduction: This randomized, controlled, Phase III non-inferiority clinical trial aimed to determine whether herbal therapy with Canephron® N (BNO 1045) is non-inferior to fosfomycin trometamol (FT) in treating acute lower uncomplicated urinary tract infections (uUTIs).

Materials and methods: Women aged 18-70 years with typical symptoms of newly diagnosed acute lower uUTIs were randomized to BNO 1045 (n = 325) or FT (n = 334), with corresponding matched placebo. The primary endpoint was the proportion of patients who received additional antibiotics (ABs) to treat uUTIs between Days 1 and 38 ±3.

Results: Between Days 1 and 38, 238 (83.5%) patients in the BNO 1045 group and 272 (89.8%) patients in the FT group received no additional ABs. At a 15% non-inferiority margin, BNO 1045 was non-inferior to FT in treating uUTIs (non-AB rate difference: -6.26%; 95% CI -11.99 to -0.53%; 2-sided p = 0.0014). Adverse event rates were similar between groups, with higher rates of gastrointestinal disorders in the FT group and pyelonephritis in the BNO 1045 group. During the trial, no patient died or discontinued due to a treatment-related adverse event.

Conclusions: BNO 1045 has the potential to reduce outpatient use of ABs for uUTIs and thus may have a significant impact on antimicrobial stewardship strategies.

Trial registration: NCT02639520, EudraCT number 2013-004529-99.

Keywords: Antibiotics; Herbal treatment; Symptomatic treatment; Urinary tract infection.

The Author(s). Published by S. Karger AG, Basel.

Figures

Fig. 1

Disposition of patients. * Additional AB intake with possible influence on uUTIs; † Forbidden medicine intake; ‡ Microbiology results requested (possible unblinding); § Premature discontinuation and no documentation of uUTIs relevant AB intake; ¶ Violation of inclusion/exclusion criteria; †† Violation of time window for V4. AB, antibiotic; FAS, full analysis set; FT, fosfomycin trometamol; PPS, per protocol set; SAF, safety analysis set.

Fig. 2

Non-inferiority of BNO 1045 vs FT (non-AB rate) in the PPS. Percentages are the proportion of patients within each respective treatment group who did not take AB between Day 1 and 38 ± 3. Error bars represent the 95% CIs. Comparison of the non-AB rates between treatments was performed by means of Farrington and Manning test statistics, with 2-sided 95% confidence limits and 2-sided p values for the difference in non-AB rates between the groups. FT, fosfomycin trometamol.

Fig. 3

Comparison of mean sum-scores of the ACSS-typical domain between Days 1 and 38 ± 3 (FAS). Datapoints are mean ­ACSS-typical domain sum-scores for each respective treatment group at each timepoint. Error bars represent Hodges-Lehman confidence intervals. Numbers in parenthesis are the standard deviations (σ) for BNO 1045 and FT sum-scores respectively. ACSS, Acute Cystitis Symptom Score; FAS, full analysis set; FT, fosfomycin trometamol.

Fig. 4

ACSS-QoL, discomfort because of symptoms in past 24 h (FAS). ACSS-QoL, Acute Cystitis Symptom Score-Quality of Life; FAS, full analysis set; FT, fosfomycin trometamol.