A Study to Investigate the Efficacy and Safety With Gepotidacin in Japanese Female Participants With Uncomplicated Urinary Tract Infection (Acute Cystitis)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the consistency of therapeutic response of gepotidacin at the Test of cure (TOC) Visit (Days 10 to 13) in female participants with acute uncomplicated cystitis with qualifying bacterial uropathogen(s) at baseline that all are susceptible to nitrofurantoin in Japan, with that from global studies (Studies 204989 [NCT04020341] and 212390 [NCT04187144]).

Official Title
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A Phase III, Multicenter, Randomized, Active Reference, Double Blind, Double-dummy Study in Japanese Female Participants to Evaluate the Efficacy and Safety of Gepotidacin in the Treatment of Uncomplicated Urinary Tract Infection (Acute Cystitis)

Conditions
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Urinary Tract Infections

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has a body weight >=40 kilograms (kg). The participant has 2 or more of the following clinical signs and symptoms of acute cystitis with onset less than (<) 96 hours prior to study entry: dysuria, frequency, urgency, or lower abdominal pain. The participant has nitrite or pyuria (greater than [>]15 white blood cell [WBC]/high-power field [HPF] or the presence of 3 plus (+) /large leukocyte esterase) from a pretreatment clean-catch midstream urine sample based on local laboratory procedures. The participant is capable of giving signed informed consent/assent. Exclusion Criteria: The participant resides in a nursing home or dependent care type facility. The participant has a body mass index >=40.0 kilogram per meter square (kg/m^2) or a body mass index >=35.0 kg/m^2 and is experiencing obesity-related health conditions such as uncontrolled high blood pressure or uncontrolled diabetes. 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 any of the following: Poorly controlled asthma or chronic obstructive pulmonary disease; Acute severe pain; Active peptic ulcer disease; Parkinson disease; Myasthenia gravis; a history of seizure disorder requiring medications for control (this does not include a history of childhood febrile seizures); Or Known acute porphyria. Any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study intervention. The participant has a known glucose-6-phosphate dehydrogenase deficiency. The participant, in the judgment of the investigator, would not be able or willing to comply with the protocol or complete study follow-up. The participant has acute uncomplicated cystitis that is known or suspected to be due to fungal, parasitic, or viral pathogens; or known or suspected to be due to Pseudomonas aeruginosa or Enterobacterales (other than E. coli) as the contributing pathogen. 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, that may interfere with the clinical efficacy assessments or preclude complete resolution of acute cystitis symptoms. 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 or stricture of the urinary tract, primary renal disease (e.g., polycystic renal disease), or neurogenic bladder, or the participant has a history of anatomical or functional abnormalities of the urinary tract (e.g., chronic vesicoureteral reflux, detrusor insufficiency). The participant has an indwelling catheter, nephrostomy, ureter 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 symptom onset >=96 hours before study entry, or a temperature >=38 Degrees Celsius [°C], flank pain, chills, or any other manifestations suggestive of upper UTI. The participant has known anuria, oliguria, or significant impairment of renal function (creatinine clearance <60 milliliters per minute (mL/min) or clinically significant elevated serum creatinine as determined by the investigator). The participant presents with vaginal discharge at Baseline (e.g., suspected sexually transmitted disease). The participant has congenital long QT syndrome or known prolongation of the corrected QT (QTc) interval. The participant has uncompensated heart failure. The participant has severe left ventricular hypertrophy. The participant has a family history of QT prolongation or sudden death. The participant has a recent history of vasovagal syncope or episodes of symptomatic bradycardia or brady arrhythmia within the last 12 months. The participant is taking QT-prolonging drugs or drugs known to increase the risk of torsades de pointes (TdP) per the www.crediblemeds.org. Known Risk of TdP category at the time of her Baseline Visit, which cannot be safely discontinued from the Baseline Visit to the TOC Visit; or the participant is taking a strong cytochrome P450 enzyme 3A4 (CYP3A4) inhibitor. For any participant >=12 to <18 years of age, the participant has an abnormal ECG reading at Baseline. The participant has a QTc >450 msec or a QTc >480 msec for participants with bundle branch block. The participant has a documented or recent history of uncorrected hypokalemia within the past 3 months. The participant has a known alanine aminotransferase (ALT) value >2 times upper limit of normal (ULN). The participant has a known total bilirubin value >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent [%]). The participant has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice. The participant has a previous history of cholestatic jaundice/hepatic dysfunction associated with nitrofurantoin. The participant has received treatment with other systemic antimicrobials or systemic antifungals within 1 week before study entry.

Ages Eligible for Study
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Minimum Age: 12 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gepotidacin + Placebo<br> | Drug: Gepotidacin<br>* Gepotidacin will be administered.<br>Drug: Placebo<br>* Placebo will be administered.<br>|
| Active Comparator: Nitrofurantoin + Placebo<br> | Drug: Nitrofurantoin<br>* Nitrofurantoin will be administered.<br>Drug: Placebo<br>* Placebo will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with therapeutic response (combined per participant clinical and microbiological response) at the TOC Visit | A therapeutic success refers to participants who have been deemed both a microbiological success (reduction of all qualifying bacterial uropathogens [greater than or equal to {>=}10^5 colony-forming units per milliliter {CFU/mL}] recovered at Baseline to less than (<)10^3 CFU/mL as observed on quantitative urine culture without the participant receiving other systemic antimicrobials at the TOC Visit) and a clinical success (resolution of signs and symptoms of acute cystitis present at Baseline [and no new signs and symptoms] without the participant receiving other systemic antimicrobials at the TOC Visit). All other combinations (other than clinical success + microbiological success) are deemed failures for therapeutic response. | Days 10 to 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with therapeutic response to gepotidacin compared to nitrofurantoin at the TOC Visit |  | Days 10 to 13 | 
| Number of participants with clinical outcome and response at the TOC visit | Clinical success (response) is defined as clinical resolution. Clinical resolution (outcome) is defined as resolution of signs and symptoms of acute cystitis present at Baseline (and no new signs and symptoms) without the participant receiving other systemic antimicrobials. | Days 10 to 13 | 
| Number of participants with per participant microbiological outcome and response at the TOC visit | Participant-level microbiological success (response) is defined as microbiological eradication. Microbiological eradication (outcome) is defined as reduction of all qualifying bacterial uropathogens [>=10^5 CFU/mL] recovered at Baseline to <10^3 CFU/mL as observed on quantitative urine culture without the participant receiving other systemic antimicrobials. | Days 10 to 13 | 
| Number of participants with therapeutic response in female participants with acute uncomplicated cystitis who have qualifying uropathogen(s) resistant to two or more specific classes of antimicrobials |  | Days 10 to 13 | 
| Number of participants with clinical outcome and response in female participants with acute uncomplicated cystitis who have qualifying uropathogen(s) resistant to two or more specific classes of antimicrobials |  | Days 10 to 13 | 
| Number of participants with microbiological outcome and response in female participants with acute uncomplicated cystitis who have qualifying uropathogen(s) resistant to two or more specific classes of antimicrobials |  | Days 10 to 13 | 
| Number of participants with Investigator assessment of clinical response at the TOC Visit |  | Days 10 to 13 | 
| Number of participants with Treatment-Emergent Adverse Events (TEAEs) |  | Up to Day 31 | 
| Number of participants with Serious Adverse Events (SAEs) |  | Up to Day 31 | 
| Number of participants with Adverse Events of Special Interest (AESIs) |  | Up to Day 31 | 
| Change from baseline in hematology parameters: neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count and platelet count (Giga cells per liter) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in hematology parameter: Red Blood Cell (RBC) count (Trillion cells per liter) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in hematology parameter: Hemoglobin (Hb) (Grams per liter) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in hematology parameter: Hematocrit (Proportion of red blood cells in blood) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in hematology parameter: Mean Corpuscular Volume (MCV) (Femtoliters) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in hematology parameter: Mean Corpuscular Hemoglobin (MCH) (Picograms) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in clinical chemistry parameters: Blood urea nitrogen [BUN], glucose [non-fasting], calcium, chloride, sodium, magnesium, phosphate, and potassium levels (Millimoles per liter) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in clinical chemistry parameters: Total bilirubin, direct bilirubin and creatinine levels (Micromoles per liter) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in clinical chemistry parameters: albumin and total protein levels (Gram per liter) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in clinical chemistry parameters: Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase levels (International units per liter) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (Millimeters of mercury [mmHg]) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in pulse rate (Beats per minute) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in body temperature (Degrees Celsius) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in heart rate (Beats per minute) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Change from baseline in electrocardiogram parameters: PR Interval, QRS Duration, QT Interval, QT interval corrected for heart rate according Fridericia's formula (QTcF) and Bazett's formula (QTcB) (Milliseconds [msec]) |  | Baseline, On-Therapy (Days 2 to 4), and TOC (Days 10 to 13) | 
| Plasma concentration of gepotidacin |  | Up to Day 4 | 
| Urine concentration of gepotidacin |  | Up to Day 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute cystitis, Efficacy, Gepotidacin, Nitrofurantoin, Urinary Tract Infection, Japanese Female