Herbal Treatment with Uva Ursi Extract versus Fosfomycin for Women with Uncomplicated Urinary Tract Infection: A Double-Blind, Randomised, Controlled Comparative Effectiveness Phase 4 Trial (REGATTA)

Abstract

Background: Antimicrobial resistance threatens the treatment success in patients with uncomplicated urinary tract infection (UTI). Uva Ursi (UU) is a widely used herbal remedy, which is approved in Germany as Arbutin to treat symptoms of UTIs. We aimed to explore whether initial treatment with UU reduces antibiotic use in women with uncomplicated UTI without increasing symptom burden and rate of complications. Methods: We did a pragmatic double-blind, randomised, placebo-controlled non-inferiority trial in 42 German general practices. Women aged 18–75 years with suspected uncomplicated UTI and at least two of the symptoms dysuria, urgency, frequency or low abdominal pain were randomly assigned (1:1) to either UU (dry extract) 105 mg 3 × 2 tablets for 5 days (intervention) or fosfomycin 3g single dose (control) and respective placebo dummies. Both participants and investigators were blinded. The two co-primary outcomes were 1) number of all antibiotic courses regardless of indication from day 0–28, and 2) symptom burden, defined as weighted sum of daily total symptom scores from day 0–7, both assessed by intention to treat. The predefined non-inferiority margin for symptom burden was 125%. Findings: Between May 3, 2017, and May 23, 2019, 917 women were screened, of whom 398 were randomly allocated to either UU (207) or fosfomycin (191). For the co-primary outcome 1) 385 women were analysed (UU 196, fosfomycin 189) and for 2) 398 (UU 207 and fosfomycin 191). Five women did not receive the intervention (UU 3, fosfomycin 2), and for 13 patients no information on antibiotic intake was available (UU 11, fosfomycin 2). The number of antibiotic courses from day 0–28 was 63∙6% lower (95% confidence interval (CI) 53∙6%–71.4%, p<0.0001) in the UU group, with 92 courses as compared to 233 in the fosfomycin group. The ratio of the total symptom burden in the UU group compared to control was 136.5% (95% CI 122∙7–151∙9). In the UU group, eight women developed pyelonephritis and three fever as compared to two women with pyelonephritis and none with fever in the fosfomycin group. Otherwise there was no difference in the occurrence of adverse events. Interpretation: Initial treatment with UU reduced antibiotic use but lead to higher symptom burden in women with uncomplicated UTI. Higher occurrence of pyelonephritis and fever argue against UU as initial treatment in general. Our findings suggest that UU might provide a further non-antibiotic treatment approach for women who wish to avoid immediate antibiotics and as long as fast switch to antibiotic treatment is warranted. Trial Registration: The trial is registered with Clinical trials.gov, NCT03151603. Funding Statement: The study was funded by the German Federal Ministry of Education and Research (BMBF) No. 01KG1601. Declaration of Interests: All authors declare that they have no competing interest and no financial relationships with any organisations that might have an interest in the submitted work. All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf. Ethics Approval Statement: The trial was done in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki and in cooperation with the Clinical Trials Unit of the University Medical Centre Gottingen. The trial protocol was developed following SPIRIT guidelines (standard protocol items: recommendations for interventional trials)19 and was approved by the Ethics Committee of the University Medical Center Gottingen in November 2016 (Ref. Nr. 16/11/16).