Dataset Information

Design of Two Phase III, Randomized, Multicenter Studies Comparing Gepotidacin with Nitrofurantoin for the Treatment of Uncomplicated Urinary Tract Infection in Female Participants.

ABSTRACT:

Background

Uncomplicated urinary tract infections (uUTIs) are among the most common community-acquired infections for women worldwide. Treatment options are increasingly limited by antibiotic resistance; novel oral antibiotics are urgently needed. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial deoxyribonucleic acid (DNA) replication by a distinct mechanism of action, which confers activity against most strains of target pathogens, such as Escherichia coli and Staphylococcus saprophyticus, including those resistant to current antibiotics. Here, we describe the designs of two near-identical phase III clinical trials (EAGLE-2 and EAGLE-3) evaluating gepotidacin for the treatment of uUTI.

Methods

These are phase III, randomized, multicenter, parallel-group, double-blind, double-dummy, comparator-controlled, noninferiority studies, comparing the efficacy and safety of gepotidacin to nitrofurantoin in the treatment of uUTI. Eligible participants are women aged ≥ 12 years with ≥ 2 uUTI symptoms, randomized (1:1) to receive oral gepotidacin (1500 mg) plus placebo or nitrofurantoin (100 mg) plus placebo, twice daily for 5 days. The primary therapeutic endpoint is composite clinical and microbiological efficacy, with noninferiority comparisons made in individuals with a qualifying (≥ 10⁵ colony-forming units/mL urine) nitrofurantoin-susceptible uropathogen.

Results

These trials were designed in accordance with US Food and Drug Administration (2019) and European Medicines Agency (2018) guidance, particularly the composite endpoint and microbiological evaluability requirements. Across the trials ~ 5000 participants are planned to be enrolled from > 200 centers globally.

Conclusions

Gepotidacin represents an important potential treatment option being evaluated to address the need for novel oral antibiotics to treat uUTI. These trials are registered at ClinicalTrials.gov ( https://clinicaltrials.gov/ ) where the full protocols can be accessed under trial IDs: NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3).

SUBMITTER: Perry C

PROVIDER: S-EPMC9589544 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Design of Two Phase III, Randomized, Multicenter Studies Comparing Gepotidacin with Nitrofurantoin for the Treatment of Uncomplicated Urinary Tract Infection in Female Participants.

Perry Caroline C Hossain Mohammad M Powell Marcy M Raychaudhuri Aparna A Scangarella-Oman Nicole N Tiffany Courtney C Xu Sherry S Dumont Etienne E Janmohamed Salim S

Infectious diseases and therapy 20221021 6

<h4>Background</h4>Uncomplicated urinary tract infections (uUTIs) are among the most common community-acquired infections for women worldwide. Treatment options are increasingly limited by antibiotic resistance; novel oral antibiotics are urgently needed. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial deoxyribonucleic acid (DNA) replication by a distinct mechanism of action, which confers activity against most strains of target pathog ...[more]

PMID: 36271314

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Project description:Importance:The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI). Objective:To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis. Design, Setting, and Participants:Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel. Interventions:Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection. Main Outcomes and Measures:The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events. Results:Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively). Conclusions and Relevance:Among women with uncomplicated UTI, 5-day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion. Trial Registration:ClinicalTrials.gov Identifier: NCT01966653.

Project description:Abstract Background Gepotidacin (GSK2140944) is a first in class novel oral triazaacenaphthylene bacterial topoisomerase inhibitor. In this study, we evaluated the potential impact of orally administered gepotidacin on the human microbiome, across three body-sites and at three specific time-points, as an exploratory endpoint in a Phase 2a clinical trial for the treatment of uncomplicated Urinary Tract Infection (uUTI) (ClinicalTrials.gov: NCT03568942). Methods Through DNA sequencing of the 16S rRNA variable region 4, we analyzed samples collected with consent from study subjects from the gastrointestinal tract or GIT (stool), pharyngeal cavity (saliva swabs) and vagina (vaginal swabs). Samples were taken at three time points which were pre-dosing (Day 1), end of dosing (Day 5) and follow-up visit (Day 28 ±3 days). A total of 156 samples were collected and 141 samples passed quality control criteria for DNA sequence analyses. Using a rigorous computational work-flow, changes in microbiome diversity and relative abundances of microbial species were quantified. Results Time series analyses showed that microbiota alpha diversity dropped, relative to pre-dose, by the end of gepotidacin dosing but trended a return trajectory to original pre-dose levels by the follow-up visit, for all body sites (Figure). However, the character and extent of the microbiota changes varied by location. The relative ordering from least to greatest changes in microbiota diversity of body sites is vaginal, pharyngeal and GIT. We found no statistically significant occurrences of pathogen related taxa, such as Clostridioides or Enterobacterales spp., at the final timepoints. Conclusion Since gepotidacin is both orally dosed and elimination includes the biliary route, it was predicted to affect the GIT microbiome, however changes in the distal pharyngeal and vaginal microbiota were also observed. Gepotidacin alteration of the endogenous microbial community appears to be temporary and reversible as microbiota diversity rebounded to near pre-dosing status within a period of several weeks. Our study illustrates how microbiome analyses in antibiotic clinical studies can quantify patterns of microbiota disruption and recovery. Disclosures Andrea Nuzzo, PHD, GlaxoSmithKline (Employee) Stephanie Van Horn, B.Sc., GlaxoSmithKline (Employee) Christopher Traini, PHD, GlaxoSmithKline (Employee) Caroline R. Perry, PhD, GlaxoSmithKline (Employee) Etienne Dumont, MD, GlaxoSmithKline (Employee) Nicole Scangarella-Oman, MS, GlaxoSmithKline plc. (Employee, Shareholder) David Gardiner, MD, GlaxoSmithKline (Employee) James R. Brown, PhD, GlaxoSmithKline (Employee)

Project description:BackgroundTreatment failure (TF) in uncomplicated urinary tract infection (uUTI) increases disease burden and risk of antimicrobial resistance. Identification of risk factors for TF could inform empiric treatment decisions and reduce suboptimal outcomes.ObjectiveTo evaluate the incidence of TF to empirically prescribed oral antibiotics and identify risk factors for TF in females with uUTI in the United States (US).DesignThis retrospective cohort study used Optum's de-identified Electronic Health Record dataset (January 2017-September 2022).PatientsEligible female patients aged ≥ 12 years had ≥ 1 diagnosis of urinary tract infection (UTI) in an outpatient ambulatory/emergency department (ED) setting, ≥ 1 empiric oral antibiotic prescription, and no evidence of complicated UTI (cUTI).Main measuresTF was defined as having a new/repeat oral antibiotic prescription, IV antibiotic administration or acute UTI diagnosis ≤ 28 days following initial empiric oral antibiotic prescription. Risk factors of TF were selected using LASSO and reported using adjusted risk ratios (aRR) and 95% CIs.Key resultsOf 376,004 patients with uUTI, 62,873 (16.7%) experienced TF. Incidence of TF was highest in patients with history of antibiotic TF (33.9%) or fosfomycin prescription (30.1%). Significant risk factors of TF included ≥ 3 prior antibiotic prescriptions (aRR [95% CI]: 1.60 [1.56-1.64]); fosfomycin prescription (1.60 [1.38-1.86]); uUTI diagnosis in ED (1.49 [1.46-1.52]), Southern US residence (1.37 [1.35-1.40]), age ≥ 75 years (1.35 [1.29-1.41]), recurrent UTI (1.12 [1.10-1.14]) and obesity (1.06 [1.04-1.08]).ConclusionsIncidence of TF to empirically prescribed oral antibiotics for uUTI is considerable. Prior infections requiring antibiotic prescription and location of care are key risk factors for TF in female outpatients with uUTI. Knowledge of these TF risk factors can inform shared-decision making and supplement existing guidance on uUTI treatment.

Project description:BackgroundGepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is active against most strains of Neisseria gonorrhoeae (N. gonorrhoeae). Phase II data suggested higher exposures were needed for efficacy and to suppress resistance development. A translational approach using in vitro pharmacokinetic/pharmacodynamic (PK/PD) and clinical data was used to select a gepotidacin dose for a phase III study. In this narrative review of previously shown data, we summarise how a translational approach based on in vitro PK/PD and population PK modelling and simulation data was undertaken to select a dosing regimen for the ongoing phase III gepotidacin study in participants with uncomplicated urogenital gonorrhoea.MethodsFor dose selection, prior in vitro minimum inhibitory concentrations (MICs) and PK/PD data were available. PK modelling was conducted to determine a dose that would limit plasma concentrations to less than 14 µg/mL (as concentrations above this are associated with QT prolongation and effects associated with acetylcholinesterase inhibition) while maintaining ≥90% probability of target attainment (PTA) for efficacy and resistance suppression against N. gonorrhoeae isolates with gepotidacin MICs ≤1 µg/mL.ResultsTwo 3000 mg gepotidacin doses, administered 10-12 hours apart, resulted in PTA of ≥97.5% and ≥91.7% for gepotidacin MICs ≤1 µg/mL for the ratio of the area under the free drug plasma concentration-time curve over 24 hours to the MIC (fAUC0-24/MIC) efficacy, and resistance suppression targets of 40 and 46, respectively, but limited the occurrence of maximum plasma concentrations ≥14 µg/mL.ConclusionsTwo gepotidacin 3000 mg oral doses 10-12 hours apart provide ~2-fold higher systemic exposures, increase efficacy for higher gepotidacin MIC N. gonorrhoeae isolates, reduce resistance potential and limit plasma concentrations of potential safety concern, compared with higher doses.

Project description:BackgroundWe evaluated associations between antibiotic prescription and healthcare resource use and costs (Part A), and between antibiotic switching and healthcare resource use, costs, and uncomplicated urinary tract infection recurrence (Part B) in female patients with uncomplicated urinary tract infection in the United States.MethodsThis retrospective cohort study of linked Optum and Premier Healthcare Database data included female patients ≥12 years old with an uncomplicated urinary tract infection diagnosis (index date), who were prescribed antibiotics during an outpatient/emergency department visit between January 1, 2013 and December 31, 2018. In Part A, patients were stratified by antibiotic prescription appropriateness: appropriate and optimal (compliant with Infectious Diseases Society of America 2011 guidelines for drug class/treatment duration) versus inappropriate/suboptimal (inappropriate drug class/treatment duration per Infectious Diseases Society of America 2011 guidelines, and/or treatment failure). In Part B, patients were stratified by treatment pattern (antibiotic switch vs no antibiotic switch). Healthcare resource use and costs during index episode (within 28 days of index date) and 12-month follow-up were compared.ResultsOf 5870 patients (mean age 44.5 years), 2762 (47.1%) had inappropriate/suboptimal prescriptions and 567 (9.7%) switched antibiotic. Inappropriate/suboptimal prescriptions were associated with higher healthcare resource use (mean number of ambulatory care and pharmacy claims [both p < 0.001]), and higher total mean cost (inpatient, outpatient/emergency department, ambulatory visits, and pharmacy costs) per patient ($2616) than appropriate and optimal prescriptions ($649; p < 0.001) (Part A). Antibiotic switching was associated with more pharmacy claims and higher total mean costs (p ≤ 0.01), and a higher incidence of recurrent uncomplicated urinary tract infection (18.9%) than no antibiotic switching (14.2%; p < 0.001) (Part B).ConclusionsInappropriate/suboptimal prescriptions and antibiotic switching were associated with high costs, ambulatory care, and pharmacy claims, suggesting a need for improved uncomplicated urinary tract infection prescribing practices in the United States.

Dataset Information

Design of Two Phase III, Randomized, Multicenter Studies Comparing Gepotidacin with Nitrofurantoin for the Treatment of Uncomplicated Urinary Tract Infection in Female Participants.

Background

Methods

Results

Conclusions

Publications

Design of Two Phase III, Randomized, Multicenter Studies Comparing Gepotidacin with Nitrofurantoin for the Treatment of Uncomplicated Urinary Tract Infection in Female Participants.

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