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The Study Listed May Include Approved and Non-Approved Uses, Formulations Or Treatment Regimens The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Gepotidacin Study Number: 207625 Title: Meta-analysis to estimate the microbiological treatment effect of nitrofurantoin for determination of the non-inferiority margin in a phase 3 clinical trial of uncomplicated urinary tract infection (uUTI). Rationale: Active-comparator, non-inferiority study designs are generally used in uUTI trials, given the ethical implications of placebo treatment. In order to design, execute, and analyze a non-inferiority trial, an estimate of the treatment effect (M1) of the planned active comparator (nitrofurantoin), must be obtained from historical randomized or open label studies. Once an estimate of M1 (nitrofurantoin treatment effect) is obtained, a non-inferiority margin (M2) or the largest clinically acceptable difference of the test drug compared to the active comparator must be determined. Determination of M1 and M2 is critical to the design, analysis and interpretation of a non-inferiority trial. The rationale for this study was to estimate the treatment effect of an active comparator (nitrofurantoin) in order to determine the non-inferiority margin for a Phase III study, which will demonstrate the efficacy of a new antibacterial gepotidacin (GSK2140944) for the treatment of subjects ( females ≥18 years of age) with uncomplicated UTI (or acute cystitis). Study Period: 20 January 2017 to 22 March 2017 Objectives: The primary objective of this systematic literature review was to identify clinical trials which assessed the microbiological response of nitrofurantoin and placebo in adult female subjects with uUTI, and subsequently to conduct a meta-analysis in order to estimate the treatment effect of nitrofurantoin and inform on an acceptable non-inferiority margin for a Phase III randomized control trial (RCT). The specific study objectives were: To estimate the microbiological response (success) of nitrofurantoin among adult female subjects with uUTI at test of cure (TOC), in the microbiological intent-to-treat (micro-ITT) and microbiologically evaluable (ME) populations. To estimate the microbiological response (success) of placebo among adult female subjects with uUTI at TOC, in the micro-ITT and ME populations. To estimate the treatment effect (M1) of nitrofurantoin by calculating the difference in pooled microbiological response rates between nitrofurantoin and placebo (as per Food and Drug Administration [FDA] guidance on non-inferiority [NI] trials). To determine the non-inferiority margin (M2) for a Phase III registrational trial of gepotidacin compared to nitrofurantoin via a meta-analysis. Indication: Uncomplicated Urinary Tract Infection Study Investigators/Centres: GlaxoSmithKline (GSK) conducted study. Research Methods: A systematic literature review was conducted using the Medline (PubMed) and Embase search engines, in order to identify all historical nitrofurantoin and placebo trials, which evaluated a microbiological response at the TOC (~ 5-9 days after treatment) in female subjects with uUTI. The systematic review and meta-analysis was designed and executed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) which incorporated recommendations for standardized data quality assessment and reporting of results. Data Source: Systematic literature review was conducted in both PubMed and Embase, by two independent reviewers, using the search terms and search strings listed below, with no limits applied for publication date, language or country. Non-English publications were excluded at first stage screen (with the exception of one publication for which GSK had a certified translation conducted previously). For each search the publications were restricted to dates before 10 December 2016 (the search date) and the search terms included abbreviation, plural and full phrase versions of the selected search terms. Different search strings (as follows) were used in combination, with Boolean operations such as “AND,” to find relevant articles for each of the study objectives. “uncomplicated urinary tract infection” OR “uUTI” OR “urinary tract infection” OR “acute cystitis” OR “uncomplicated UTI” “Clinical trial” OR “randomized clinical trial” OR “open label study”. “Nitrofurantoin” OR “Macrodantin” OR “Furadantin”. “Placebo” OR “placebo control” OR “placebo controlled”. 1 Study Design: The literature search and systematic review was conducted independently by two reviewers in PubMed and Embase to select representative trials of nitrofurantoin and placebo treatment in uUTI, for inclusion in the meta- analysis. All identified publications underwent an abstract review (first stage screen). Studies meeting eligibility criteria at first stage screen, were then taken to full text review (second stage screen), and categorized for inclusion or exclusion into the meta-analysis based on apriori criteria (uUTI target population, baseline microbiological entry criteria, microbiological response endpoint) and general study quality. After full text review, studies included in the meta- analysis were partitioned from excluded studies with a categorical explanation for exclusion of every study taken to full text review. The reviewers independently abstracted efficacy data from each study and summarized the potential sources of clinical heterogeneity across studies as well as risk of bias using the Cochrane Risk of Bias Tool; this was incorporated into the meta-analysis as a sensitivity analyses. Study Population/Study Selection Procedure: From the publication hits retrieved in the PubMed and Embase searches, studies meeting the final meta-analysis inclusion were selected by a two-step selection process. First Stage Screen of Title and Abstract: Randomized, open label and blinded clinical trials of nitrofurantoin or placebo treatment among symptomatic females with uUTI or acute cystitis were selected by reviewing the title and abstract. Clinical Trials published in non-English language/Observational studies/Narrative review/Case reports or case series/ Animal studies/Paediatric clinical trials inclusive of UTI/UTI prevention or prophylactic studies/Clinical trial of asymptomatic bacteriuria (ASB) or studies with a primary objective of describing the pharmacokinetic or pharmacodynamic properties of nitrofurantoin, without nitrofurantoin efficacy data were excluded from the study. Second Stage Screening of Full Text Publications: The full text of all publications selected for first stage screen were read and assessed against second stage exclusion criteria, which are stated in detail below. If the study did not meet the following second stage exclusion criteria, then it was included in the final uUTI meta-analysis. Exclusion Criteria: Clinical trial which included subjects with complicated UTI (cUTI) and uUTI, with efficacy data reported in aggregate and not stratified by UTI indication Clinical trial which did not assess for the microbiological response (success) of nitrofurantoin or placebo Clinical trial which reported efficacy data which was captured in another primary publication of the same study population (duplicate) Clinical trial which included subjects with concomitant use of systemic antibiotics Clinical trial which included subjects with uUTI receiving intravenous (IV) antibacterial therapy, or subjects with clinical signs and symptoms of complicated UTI or acute pyelonephritis (fever >38°C within the last 24 hours, flank pain or costavertebral angle tenderness (CVA) Clinical trial conducted in patient subgroups with comorbidities which would currently be classified as cUTI, such as studies in: diabetics, pregnant women, subjects with urological procedures or urological abnormalities, or in males Clinical trial in uUTI which did not specify a baseline colony count requirement for meeting the study entry criteria (i.e. entry criteria based on the presence of clinical symptoms only) Study Exposures, Outcomes: As part of the systematic review, the following variables were abstracted for each clinical trial meeting the final meta-analysis inclusion: General study information (title, author, country, year[s], publication year, number of centres, number enrolled, inclusion/exclusion criteria, study population, demographics and baseline population characteristics). Antimicrobial treatment details (dose, route, timing, and duration of treatment). Study biases and limitations (bias in randomization procedure, allocation concealment, blinding, incomplete outcome data for each of trials included in the meta-analysis) The meta-analysis variables included: Primary Endpoint: Microbiological response endpoint had a binary outcome, measured as success or failure. Outcome definitions of microbiological response were study dependent however, typically measured as microbiological success and defined as subjects who demonstrated that a qualifying bacterial uropathogen recovered at study entry was reduced to <104 colony forming units per millilitre (CFU/mL) (no growth) or by at least 1-log (CFU/mL) on quantitative urine culture at the TOC visit. 2 Derived Primary Endpoint: In studies not reporting the proportion of subjects with microbiological response of success
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