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

Phase 3

Completed

Conditions: Urinary Tract Infections

Interventions: Drug: Gepotidacin
Drug: Nitrofurantoin
Drug: Placebo

Registration Number: NCT05630833

Lead Sponsor: GlaxoSmithKline

Brief Summary: The purpose of this study is to evaluate the consistency of therapeutic response of gepotidacin 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 \[NCT04187144\]).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 380

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Nitrofurantoin + Placebo	Placebo	-
Gepotidacin + Placebo	Placebo	-
Gepotidacin + Placebo	Gepotidacin	-
Nitrofurantoin + Placebo	Nitrofurantoin	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With Therapeutic Response (TR) (Combined Per-participant Microbiological and Clinical Success) for Gepotidacin at the Test of Cure (TOC) Visit	At TOC visit (Days 9 to 16)	TR at TOC (success/failure) is a measure of the overall efficacy response. A therapeutic success at TOC referred to participant who have been deemed both a microbiological success (reduction of all qualifying bacterial uropathogens recovered at BL to \<10\^3 colony forming units per milliliter \[CFU/mL\] without receiving other systemic antimicrobials \[AB\] before the TOC visit) and a clinical success (resolution of symptoms of acute cystitis present at BL and no new symptoms without receiving other AB before the TOC visit \[or AB for uUTI on day of TOC visit\]). Lack of clinical or microbiological success (including missing outcome assessments) was considered as therapeutic failure.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Therapeutic Response (TR) of Gepotidacin Compared to Nitrofurantoin at the Test of Cure (TOC) Visit - Micro-ITT NTF-S Population	At TOC visit (Days 9 to 16)	TR at TOC (success/failure) is a measure of the overall efficacy response. A therapeutic success at TOC referred to participant who have been deemed both a microbiological success (reduction of all qualifying bacterial uropathogens recovered at BL to \<10\^3 colony forming units per milliliter \[CFU/mL\] without receiving other systemic antimicrobials \[AB\] before the TOC visit) and a clinical success (resolution of symptoms of acute cystitis present at BL and no new symptoms without receiving other AB before the TOC visit \[or AB for uUTI on day of TOC visit\]). Lack of clinical or microbiological success (including missing outcome assessments) was considered as therapeutic failure.
Number of Participants With Clinical Outcome at the TOC Visit - Micro-ITT NTF-S Population	At TOC visit (Days 9 to 16)	Clinical outcome at TOC was categorized as clinical resolution, clinical improvement, clinical worsening and unable to determine. Clinical resolution at TOC was defined as resolution of signs and symptoms of acute cystitis present at BL (and no symptoms) without receiving any other AB before the TOC visit. Clinical improvement at TOC was defined as improvement (but not complete resolution) in total symptom score (CSS) from BL, without receiving any other AB before the TOC visit. Clinical worsening at TOC was defined as worsening or no change in CSS from BL or received other AB for the current infection (uUTI) before or on the date of the TOC visit. Unable to determine outcome criteria were: BL score is missing (and thus improvement/worsening cannot be determined), TOC assessment is missing, or receipt of other AB not for the current infection before the TOC visit (unless clinical worsening outcome criteria were met).
Number of Participants With Clinical Response at the TOC Visit - Micro-ITT NTF-S Population	At TOC visit (Days 9 to 16)	Clinical response at TOC was categorized as clinical success and clinical failure. Clinical success at TOC was defined as resolution of symptoms of acute cystitis present at BL (and no new symptoms), without receiving any other AB before the TOC visit. Lack of resolution, including receipt of an AB for uUTI at the TOC visit, or a missing outcome assessment was defined as Clinical Failure at TOC.
Number of Participants With Microbiological Outcome (MO) at the TOC Visit -Micro-ITT NTF-S Population	At TOC visit (Days 9 to 16)	Participant-level MO at TOC was categorized as microbiological eradication (ME), microbiological persistence (MP), microbiological recurrence (MR) and unable to determine (UTD). ME at TOC was defined as all baseline qualifying uropathogens (QUP) have an outcome of eradication at TOC (i.e., \<10\^3 CFU/mL without the participant receiving other systemic antimicrobials before the TOC Visit). MP at TOC was defined as at least 1 QUP has an outcome of persistence (≥10\^3 CFU/mL) at TOC. MR at TOC was defined as at least 1 QUP had an outcome of recurrence and none have an outcome of persistence at TOC. UTD at TOC was defined as all QUP outcomes are UTD at TOC.
Number of Participants With Microbiological Response at the TOC Visit -Micro-ITT NTF-S Population	At TOC visit (Days 9 to 16)	Participant-level microbiological response at TOC was categorized as microbiological success and microbiological failure. Microbiological success at TOC was defined as all baseline qualifying uropathogens (QUP) had a microbiological outcome of eradication at TOC visit. Microbiological failure was defined as lack of microbiological success, including those participants with UTD outcomes.
Number of Participants With Therapeutic Response (TR) at the TOC Visit	At TOC visit (Days 9 to 16)	TR at TOC (success/failure) is a measure of the overall efficacy response. A therapeutic success at TOC referred to participant who have been deemed both a microbiological success (reduction of all qualifying bacterial uropathogens recovered at BL to \<10\^3 colony forming units per milliliter \[CFU/mL\] without receiving other systemic antimicrobials \[AB\] before the TOC visit) and a clinical success (resolution of symptoms of acute cystitis present at BL and no new symptoms without receiving other AB before the TOC visit \[or AB for uUTI on day of TOC visit\]). Lack of clinical or microbiological success (including missing outcome assessments) was considered as therapeutic failure.
Number of Participants With Clinical Outcome at the TOC Visit	At TOC visit (Days 9 to 16)	Clinical outcome at TOC was categorized as clinical resolution, clinical improvement, clinical worsening and unable to determine. Clinical resolution at TOC was defined as resolution of signs and symptoms of acute cystitis present at BL (and no symptoms) without receiving any other AB before the TOC visit. Clinical improvement at TOC was defined as improvement (but not complete resolution) in CSS from BL, without receiving any other AB before the TOC visit. Clinical worsening at TOC was defined as worsening or no change in CSS from BL or received other AB for the current infection (uUTI) before or on the date of the TOC visit. Unable to determine outcome criteria were: BL score is missing (and thus improvement/worsening cannot be determined), TOC assessment is missing, or receipt of other AB not for the current infection before the TOC visit (unless clinical worsening outcome criteria were met).
Number of Participants With Clinical Response at the TOC Visit	At TOC visit (Days 9 to 16)	Clinical response at TOC was categorized as clinical success and clinical failure. Clinical success at TOC was defined as resolution of symptoms of acute cystitis present at BL (and no new symptoms), without receiving any other AB before the TOC visit. Lack of resolution, including receipt of an AB for uUTI at the TOC visit, or a missing outcome assessment was defined as Clinical Failure at TOC.
Number of Participants With Microbiological Outcome at the TOC Visit	At TOC visit (Days 9 to 16)	Participant-level MO at TOC was categorized as microbiological eradication (ME), microbiological persistence (MP), microbiological recurrence (MR) and unable to determine (UTD). ME at TOC was defined as all baseline qualifying uropathogens (QUP) have an outcome of eradication at TOC (i.e., \<10\^3 CFU/mL without the participant receiving other systemic antimicrobials before the TOC Visit). MP at TOC was defined as at least 1 QUP has an outcome of persistence (≥10\^3 CFU/mL) at TOC. MR at TOC was defined as at least 1 QUP had an outcome of recurrence and none have an outcome of persistence at TOC. UTD at TOC was defined as all QUP outcomes are UTD at TOC.
Number of Participants With Microbiological Response at the TOC Visit	At TOC visit (Days 9 to 16)	Participant-level microbiological response at TOC was categorized as microbiological success and microbiological failure. Microbiological success at TOC was defined as all baseline qualifying uropathogens (QUP) had a microbiological outcome of eradication at TOC visit. Microbiological failure was defined as lack of microbiological success, including those participants with UTD outcomes.
Number of Participants With Investigator Assessed Clinical Response	At TOC visit (Days 9 to 16)	Clinical response as assessed by investigator at TOC was categorized as clinical success and clinical failure. Clinical success at TOC was defined as sufficient resolution of acute cystitis signs and symptoms such that no additional systemic AB was required for the current infection. No apparent response to treatment, use of additional systemic AB for the current infection and death related to acute cystitis prior to the visit was considered as Clinical failure. Indeterminate/Missing was defined as participant lost to follow-up and/or the clinical assessment was not undertaken, use of confounding systemic AB for another infection, and death prior to the visit where acute cystitis was clearly noncontributory.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	From first dose (Day 1) to Follow-up visit (Days 21 to 31)	An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. TEAE is defined as any AE with an onset date on or after treatment start date/time. AEs were coded using Medical Dictionary for Regulatory Activities (MedDRA).
Number of Participants With Serious AEs (SAEs) and Adverse Events of Special Interest (AESIs)	From first dose (Day 1) to Follow-up visit (Days 21 to 31)	An SAE is defined as any untoward medical occurrence that, at any dose may result in death or is life-threatening or requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity or is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment or is associated with liver injury and impaired liver function. Adverse events of special interest (AESI) for gepotidacin included clostridium difficile, cardiovascular \& gastrointestinal events and potential acetylcholinesterase-inhibition AESIs. SAEs were coded using MedDRA.
Number of Participants With Urinalysis Dipstick Results	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Urine samples were collected for urinalysis: Urine Glucose (GLU), Urine Ketones (KET), Urine Nitrite (NIT) and Urine Protein (PRO). Baseline is defined as the latest pre-dose assessment with a non-missing value. The dipstick test gives results in a semi-quantitative manner, and results can be read as Negative, Positive, 2777.55 micromole per liter (µmol/l), \>=27775.5 µmol/l, 8332.65 µmol/l, 5 milligram/dl (mg/dL), 20 mg/dL, \>=80 mg/dL, 300 mg/dL, 1000 mg/dL, \>=5000 mg/dL indicating concentrations in the urine sample. In the row title (GLU, Baseline, 2777.55 micromole per liter), GLU indicates parameter, Baseline is the visit and 2777.55 micromole per liter indicates the concentration/presence in the urine sample. Data is presented in similar way for other parameters.
Change From Baseline (CFB) in Electrocardiograms (ECGs): Heart Rate	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Triplicate 12-lead ECGs (over an approximate 5 to 10 minute period) were performed using an ECG machine that automatically calculated the heart rate, measured PR, QRS, QT, and QT interval corrected for heart rate according to Fridericia's formula (QTcF). Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Electrocardiograms (ECGs): PR, QRS, QT and QTcF	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Triplicate 12-lead ECGs (over an approximate 5 to 10 minute period) were performed using an ECG machine that automatically calculated the heart rate, measured PR, QRS, QT, and QTcF. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Vital Sign: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	SBP and DBP were measured in a semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Vital Sign: Temperature	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Temperature was measured in a semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Vital Sign: Pulse Rate	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Pulse rate was measured in a semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Plasma Concentrations of Gepotidacin	Baseline (Day 1 at 0-2h & >2h Post dose), Day 2 to 5 at Pre-dose, 0-2h & >2h Post Dose	Blood samples were collected for plasma concentration of Gepotidacin.
Urine Concentrations of Gepotidacin	Baseline (Day 1 at 0-2h & >2h Post dose), Day 2 to 5 at Pre-dose, 0-2h & >2h Post Dose	Urine samples were collected for urine concentration of Gepotidacin.
Change From Baseline (CFB) in Hematology Parameters - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, and Platelets at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of hematology parameters: basophils, eosinophils, lymphocytes, monocytes, neutrophils, and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Hematology Parameter-Hemoglobin Level at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of hemoglobin level. Baseline is defined as the latest pre-dose assessment with a non-missing value
Change From Baseline (CFB) in Hematology Parameter- Hematocrit Level at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of hematocrit level. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Hematology Parameter- Erythrocytes Count at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of erythrocytes count. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Hematology Parameter - Mean Corpuscular Hemoglobin (MCH) at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of MCH. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Hematology Parameter - Mean Corpuscular Volume (MCV) at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of MCV. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Clinical Chemistry Parameters - Calcium, Glucose, Potassium, Magnesium, Phosphate, Sodium, and Urea Nitrogen Levels at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Clinical Chemistry Parameters - Serum Chloride at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value
Change From Baseline (CFB) in Clinical Chemistry Parameters - Direct Bilirubin, Total Bilirubin and Creatinine Levels at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Clinical Chemistry Parameters - Creatinine Clearance at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Clinical Chemistry Parameters - Albumin and Protein Levels at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Clinical Chemistry Parameters - Alkaline Phosphatase (ALP) and Alanine Aminotransferase (ALT) Levels at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value.
Change From Baseline (CFB) in Clinical Chemistry Parameter - Aspartate Aminotransferase (AST) Levels at On Therapy and Test of Cure Visit	Baseline (Day 1), On-Therapy (Days 2 to 5), and at TOC visit (Days 9 to 16)	Blood samples were collected for the analysis of clinical chemistry parameters. Baseline is defined as the latest pre-dose assessment with a non-missing value.