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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”.

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.

Derived Primary Endpoint: In studies not reporting the proportion of subjects with microbiological response of success in the micro-ITT population (studies reporting efficacy in the ME population only), the microbiological response of success for the micro-ITT population was derived from the ME population as follows:  The numerator for the derived microbiological response of success in the micro-ITT population, was the same as the numerator for microbiological response of success in the ME population.  The denominator for the derived microbiological response of success in the micro-ITT population, was the denominator of microbiological success in the ME population adjusted (increased to account for study drop outs) to include all women without outcome data at the TOC visit, as these were considered microbiological failures in the micro-ITT population. Data Analysis Methods: The female subjects from the studies meeting inclusion criteria for meta-analysis were included in the micro-ITT or ME populations. Micro-ITT population: Defined as a subset of the ITT population who had a baseline bacterial uropathogen on urine culture, in which the investigational and control drug would have antibacterial activity. Patients were not included in the micro-ITT population based upon events that occurred post randomization (e.g., loss to follow-up).

Microbiologically evaluable (ME) population: Defined as the population who met the definition of the micro-ITT population and who followed important components of the trial as specified in the study protocol (i.e. administration of a minimal amount of trial drug therapy) and for whom microbiological outcomes were assessed and reported at the TOC visit.

A frequentist approach was adopted to determine the treatment effect of nitrofurantoin or M1, which was defined as the difference of the microbiological response (proportion with microbiological success) between nitrofurantoin (active comparator) and placebo. The microbiological response rates for nitrofurantoin and placebo were estimated through cross trial comparison and illustrated with a forest plot. To account for inter-study variability, a weighted non-iterative, random effects model was fit, using R (Meta package) software and SAS to obtain estimates of the microbiological response rate and corresponding 95% CI for nitrofurantoin and placebo treatment. The overall microbiological response rate along with 95% confidence interval based on fixed effects model is also presented in the forest plots. The treatment effect for nitrofurantoin was calculated by taking the lower 95% confidence limit of the microbiological success rate for nitrofurantoin and subtracting the upper 95% confidence limit of the microbiological success rate for placebo. Inter-study heterogeneity was assessed with Cochran’s chi-square test for inter-study heterogeneity; I2 statistic and P values were computed and included in the forest plot of the meta-analysis. Once the treatment effect of nitrofurantoin (M1), was defined, the selection of non inferiority margin (M2), was determined based on clinical judgment which aimed to preserve substantial portion (at least 50%) of the M1 treatment effect. Also, to examine the sensitivity of the results of the primary meta-analysis, additional meta-analyses were conducted to estimate the microbiological success rate for nitrofurantoin and placebo in the micro-ITT population. These sensitivity analyses were performed to account for factors which could potentially lead to inflation or variability in the distribution of microbiological response derived from the historical data. This approach provided a conservative and robust estimate of the treatment effect of nitrofurantoin (active control) and a conservative method of determining the noninferiority margin, M2, or the largest clinically acceptable difference of the test drug compared to the active control. Limitations:  The publications identified in the literature review were contingent upon the search terms and language restrictions imposed. Non- English publications were excluded at second stage screening. With an attempt to make the search terms as general as possible in order to identify all relevant studies, the systematic screening of identified publications adhered to the recommendations set forth by the PRISMA statement.  The potential inclusion of open-label studies may have introduced bias related to the reported efficacy outcomes, yet these studies may provide informative data for both the active comparator and placebo treatment effects. Alternatively, the inclusion of open label studies increased the number of trials meeting inclusion criteria (sample size) and robustness of the treatment effect estimate for nitrofurantoin.  Publication bias was not assessed using funnel plot analysis and an Egger bias test due to the low number of studies included.  There was potential heterogeneity across the trials included in the meta-analysis; and due to the small number of studies included, it was not possible to explore heterogeneity by comparing the treatment effects between trials at high or unclear risk of bias vs. trials at low risk of bias. Modelling, which could have been helpful to understand heterogeneity was not in scope for this project. Heterogeneity or variation in true effect sizes and in factors that might influence those effect sizes is inherent in meta-analyses and not an issue which can necessarily be resolved. Heterogeneity could be due to clinical components and statistical

components. There are statistical approaches to quantify some elements of heterogeneity. Although heterogeneity was investigated and assessed for the study, it was not eliminated as an issue.  There was a potential for secular changes in the standard of medical care which may have influenced the treatment effect estimates from these historical studies spanning from 1982 to 2007. Study Results: Literature search for trials of treatment effect estimation in uncomplicated urinary tract infection (uUTI) Publication identification, screening, eligibility, and trial Nitrofurantoin Treatment Response Placebo Treatment Response Estimation inclusion according to PRISMA Embase Records PubMed Records Embase Records PubMed Records Number of records available (N) 562 160 660 666 Records excluded at first stage 529 144 648 651 screen Records eligible for full text review 33 16 12 15 Records excluded after full text 24 7 8 11 review Records Included 9 9 4 4 Duplicate records removed 9 4 Meta-analysis inclusion 9 4

Primary and Secondary Outcomes: Study characteristics of 9 published nitrofurantoin trials identified in a systematic review which assess for the microbiological response of success, in adult females with uncomplicated urinary tract infection (uUTI) Quantitative Urine Microbiological Culture Criteria Response by Assess (CFU/mL) population at TOC Study Dose ment Author, Year Comparator TOC Design (duration) Micro- Windo (definition ME Entry ITT w of N (%) N (%) response) Gupta, 2007 <102 or one 100 mg 141/162 141/154 5-9 TMP/SXT OL RCT ≥102 log (5 days) (87.0)* (91.2) days PT difference Christiaens, 2002 100 mg Negative 17/29 17/23 7 days Placebo RCT ≥105 (3 days) culture (58.6)* (73.9) PE Stein, 1999 100 mg 127/252 127/157 Fosfomycin DB RCT ≥105 ≤104 Day 7 (7 days) (50.4)* (80.9) Iravani , 1999 Ciprofloxacin 100 mg 153/179 153/177 ~ 4-10 DB RCT ≥103 ˂103 TMP/SXT (7 days) (85.5) (86.4) days PT Hooten, 1995 TMP/SXT 100 mg Bacteriuria 32/42 32/38 4-6 Cefadroxil DB RCT ≥102 (3 days) eradication (76.2) (84.2) days PE Amoxicillin Spencer, 1994 100 mg 79/101 79/96 9-15 TMP/SXT OL RCT ≥104 NS (7 days) (78.2)* (82.3) days PE Van Pienbroek, 1993 50 mg 104/115 99/110 Fosfomycin DB RCT ≥105 <105 Day 9 (7 days) (90.4) * (90) Lightstone, 1988 100 mg Negative 22/28 Day 14 Nalidixic acid OL RCT >105 NR (7 days) culture (78.6) PT Meyer, 1987 Pipemidic 50 mg 21/26 21/26 OL RCT >105 NS Day 10 acid (10 days) (80.7) (80.7) *Microbiological response (success) in the micro-ITT population was not reported in the study report, therefore, the micro-ITT rates were derived from the microbiological response (success) in the ME population with adjustment for subjects lost to follow-up; considered failures in the micro-ITT population and added to denominator of the ME population to obtain derived microbiological response in the micro-ITT population. OL= open label trial; DB= double blind; NS= not specified; NR= not reported; PE= post enrollment; PT= post start of therapy; TOC = test of cure; TMP/SXT= cotrimoxazole

Study characteristics of 4 published placebo trials identified in a systematic review which assess for the microbiological response of success, in adult females with uncomplicated urinary tract infection (uUTI) Quantitative Urine Microbiological Response Culture CFU/mL by population Study TOC Assessment Author, Year Comparator Design (definition Window Micro-ITT ME duration Entry of N (%) N (%) response) Ferry, 2007 DB RCT 72/212 Pivmecillinam ≥103 <103 Days 8-10 78/227 (34.4)* 7 days (34.0) Christiaens, 2002 DB RCT Nitrofurantoin ≥105 <103 Day 7 9/27 (33.3) 9/22 (40.9) 3 days Asbach, 1991 positive Cefixime DB RCT urine Ofloxacin NA Days14-17 5/19 (26.3) NR 1 dose between TMP/SXT ≥103 to 107 Dubi, 1982 RCT Amoxicillin ≥105 <105 Week 1 8/18 (44.4) NR 1 dose *Microbiological response (success) in the micro-ITT population was not reported in the study report, therefore, the micro-ITT rates were derived from the microbiological response (success) in the ME population with adjustment for subjects lost to follow-up; considered failures in the micro-ITT population and added to denominator of the ME population to obtain derived microbiological response in the micro-ITT population. Micro-ITT = microbiological intent to treat population; DB= double blind; RCT= randomized clinical trial; NS= colony count not specified; NR=not reported

Summary of primary meta-analysis and sensitivity analyses to estimate the nitrofurantoin treatment effect in uUTI Primary meta-analysis and sensitivity analyses 95% Upper CI 95% Lower CI Population M1* endpoints used in estimation Placebo Nitrofurantoin Primary meta-analysis: all studies included micro-ITT 39.7% 66.5% 26.8%

Sensitivity: Removed Stein micro-ITT 39.7% 77.5% 37.8%

Sensitivity: Removed Stein & Christiaens micro-ITT 39.7% 80.8% 41.1%

Sensitivity: Stein visit 3 replaced with visit 2 micro-ITT 39.7% 75.9% 36.2%

Sensitivity: Stein micro-ITT replaced with ME ME 39.7% 78.1% 38.4% Sensitivity: Placebo micro-ITT replaced with placebo ME 40.7% 66.5% 25.8% ME efficacy *M1 =difference between 95% lower CI of Nitrofurantoin and 95% Upper CI of placebo. CI=confidence interval Conclusion:  The entire effect of the active control or nitrofurantoin (M1) was reasonably estimated at 26.8%.  For the selection of a noninferiority margin, at least 50% of M1 should be preserved to maintain the important treatment effects of antibacterial drugs in the treatment of uUTI. Thus, a noninferiority margin (M2) of 12.5% can be supported for clinical trials of uUTI with nitrofurantoin as active comparator using a microbiological response as the primary endpoint in the micro-ITT population at TOC.