Safety, Tolerability, Pharmacokinetic and Microbiological Investigation of GSK3882347 in Female Participants With Urinary Tract Infections

Study Overview
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Brief Summary
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This phase 1b study is a double-blind, double-dummy, nitrofurantoin-controlled study designed to evaluate microbiological response at the test of cure (ToC) visit along with safety, tolerability and pharmacokinetic (PK) response following daily oral dosing for 5 days of GSK3882347 in an adult female with uncomplicated urinary tract infections (uUTI). Comparator nitrofurantoin will be included in the study to ensure unbiased reporting of safety events. The study will be separated into 2 cohorts. Cohort 1 consists of an inpatient treatment period and PK analysis at frequent timepoints. Cohort 2 includes an outpatient treatment period and PK analysis conducted less frequently, at key trough timepoints.

Official Title
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A Double-Blind, Double Dummy, Randomized, Phase 1b, Nitrofurantoin Controlled, Repeat Oral Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics and Microbiological Response of GSK3882347 in Female Participants With Acute Uncomplicated Urinary Tract Infection

Conditions
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Uncomplicated Urinary Tract Infections

Intervention / Treatment
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* Drug: GSK3882347
* Drug: Nitrofurantoin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be greater than or equal to (>=)18 years of age and less than or equal to (<=)70 years The participant has 2 or more of the following clinical signs and symptoms of uncomplicated urinary tract infections (uUTI) with onset less than (<) 96 hours of the screening assessment: dysuria, frequency, urgency, or lower abdominal pain Participant has nitrite OR pyuria (≥ 10 white blood cells/ cubic millimeter [WBC/mm^3], OR > 5 WBC/high power field [HPF]) OR the presence of 2+ leukocyte esterase from a pre-treatment clean-catch midstream urine sample Participants with body mass index (BMI) >= 19.0 kilograms per square meter (kg/m^2) A female participant is eligible to participate who is not pregnant (as confirmed by a highly sensitive pregnancy test before the first dose of study intervention) or breastfeeding and one of the following conditions apply: 1) Woman participant of non-childbearing potential (WONCBP) Or 2) Woman participant of childbearing potential (WOCBP) using a contraceptive method that is highly effective, with a failure rate of < 1 percentage (%), during the study intervention period and up to 5 days post intervention Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol. Exclusion Criteria: The participant has a BMI >= 40.0 kg/ m^2 or a BMI >=35.0 kg/ m^2 with obesity related health conditions such as high blood pressure or uncontrolled diabetes (non-fasting glucose value >300 milligram/deciliter [mg/dL]) The participant is immunocompromised or has altered immune defenses that may predispose the participant to a higher risk of treatment failure and/or complications The participant has symptoms known or suspected to be caused by another disease process, such as asymptomatic bacteriuria, overactive bladder, chronic incontinence, or chronic interstitial cystitis The participant has an anatomical or physiological anomaly that predisposes the participant to UTIs or may be a source of persistent bacterial colonization, including calculi, obstruction of the urinary tract, primary renal disease, or neurogenic bladder, or the participant has a history of anatomical or functional abnormalities of the urinary tract The participant has an indwelling catheter, nephrostomy, ureteral stent, or other foreign material in the urinary tract The participant who, in the opinion of the investigator, has an otherwise complicated UTI, an active upper UTI (e.g., pyelonephritis, urosepsis), signs and symptoms onset >=96 hours before the screening assessment, or a temperature >=101-degree Fahrenheit (°F) (>=38 degree Celsius [°C]), flank pain, chills, or any other manifestations suggestive of upper UTI The participant has anuria, oliguria, or significant impairment of renal function The participant presents at enrollment with a suspected sexually transmitted infection A positive confirmation of Coronavirus Disease 2019 (COVID-19) infection, or high clinical index of suspicion for COVID-19 The participant has received treatment with other systemic antimicrobials or systemic antifungals within 1 week or 10 weeks for dalbavancin or oritavancin before study entry. Regular alcohol consumption within 6 months prior to the study with an average weekly intake of >14 units for females and one unit is equivalent to approximately 8 g of alcohol: a half-pint (250 mL) of beer, one glass (125 mL) of wine or one (35 mL) measure of spirits Unable to take nitrofurantoin. E.g. hypersensitivity to the active substance

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This will be a randomized double-blind study and participants will be randomized to receive either GSK3882347 or nitrofurantoin in a 3:1 allocation ratio using an interactive response technology (IRT).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK3882347 + Placebo<br>Participants will be administered GSK3882347 plus placebo. | Drug: GSK3882347<br>* GSK3882347 will be administered on each dosing day.<br>Drug: Placebo<br>* Placebo matching study drug (GSK3882347) or Nitrofurantoin will be administered on each dosing day.<br>|
| Active Comparator: Nitrofurantoin+ Placebo<br>Participants will be administered nitrofurantoin plus placebo. | Drug: Nitrofurantoin<br>* Nitrofurantoin will be administered on each dosing day.<br>Drug: Placebo<br>* Placebo matching study drug (GSK3882347) or Nitrofurantoin will be administered on each dosing day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numbers of participants with microbiological response (responder/non-responder of GSK3882347) at the test of cure (TOC) visit | Microbiological response is defined as the response of less than (<)10^3 colony forming unit (CFU)/milliliter (mL) for all qualifying Escherichia coli (identified at baseline urine microbiology visit) at TOC visit, without receiving other systemic antimicrobials (rescue medications) prior to TOC | Day 10 to Day 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) and serious adverse events (SAEs) | AEs and SAEs will be collected. | Up to Day 31 | 
| Number of participants with clinically significant change from baseline in hematology parameters | Blood samples will be collected for the assessment of hematology parameters. | Baseline (Day 1) and up to Day 31 | 
| Number of participants with clinically significant change from baseline in clinical chemistry | Blood samples will be collected for the assessment of chemistry parameters. | Baseline (Day 1) and up to Day 31 | 
| Number of participants with clinically significant change from baseline in urinalysis | Blood samples will be collected for the assessment of urinalysis parameters. | Baseline (Day 1) and up to Day 31 | 
| Number of participants with clinically significant change from baseline in vital signs |  | Baseline (Day 1) and up to Day 31 | 
| Number of participants with clinically significant change from baseline in 12- lead Electrocardiogram (ECG) findings |  | Baseline (Day 1) and up to Day 31 | 
| Plasma concentration of GSK3882347 single dose | Blood samples will be collected for the concentrations of GSK3882347. | Up to Day 5 | 
| Urine concentration of GSK3882347 at 22-24-hour (h) interval collection post-dose | Urine samples will be collected for the concentrations of GSK3882347. | Up to Day 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microbiological response, Urinary tract infections (UTI), GSK3882347, Nitrofurantoin, Pharmacokinetics, Escherichia coli (E. coli)