A Study to Evaluate Efficacy and Safety of Gepotidacin in the Treatment of Uncomplicated Urinary Tract Infection (UTI)

Phase 3CompletedNCT04020341

GlaxoSmithKline1,531 enrolled

Overview

The study will be conducted to evaluate the therapeutic response (combined per participant microbiological and clinical response) of oral gepotidacin compared to oral nitrofurantoin for treatment of uncomplicated UTI (acute cystitis) in adolescent and adult female participants.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

1,531

Conditions

Urinary Tract Infections

Interventions

GepotidacinDRUG

Gepotidacin will be available as tablets containing 750 mg gepotidacin. Each dose should be taken with water after consumption of food.

Placebo matching nitrofurantoinDRUG

Placebo matching nitrofurantoin will be available as over-encapsulated unit-dose capsules. Each dose should be taken with water after consumption of food.

NitrofurantoinDRUG

Nitrofurantoin will be available as over-encapsulated capsules containing 25 mg nitrofurantoin macrocrystals and 75 mg nitrofurantoin. Each dose should be taken with water after consumption of food.

Eligibility

Sex: FEMALEMin age: 12 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participants having \>=12 years of age at the time of signing the informed consent/assent and have a body weight \>=40 kilograms (kg). * Participants having 2 or more of the following clinical signs and symptoms of acute cystitis with onset \<96 hours prior to study entry: dysuria, frequency, urgency, or lower abdominal pain. * Participants having nitrite or pyuria (greater than \[\>\]15 white blood cells \[WBC\]/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 female. * Participant is capable of giving signed informed consent/assent. Exclusion Criteria: * Participant resides in a nursing home or dependent care type-facility. * Participant has a body mass index \>=40.0 kilogram per square meter (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. * Participant has a history of sensitivity to the study treatments, or components thereof, or a history of a drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates her participation. * Participant is immunocompromised or has altered immune defenses that may predispose the participant to a higher risk of treatment failure and/or complications. * Participant has any of the following: 1. Poorly controlled asthma or chronic obstructive pulmonary disease; acute severe pain; active peptic ulcer disease; Parkinson disease; myasthenia gravis; Or 2. Known acute porphyria. 3. Any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study treatment. * Participant has a known glucose-6-phosphate dehydrogenase deficiency. * Participant has a serious underlying disease that could be imminently life-threatening, or the participant is unlikely to survive for the duration of the study period. * Participant has acute 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 Escherichia coli) as the contributing pathogen. * 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. * 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 (for example \[e.g.\], polycystic renal disease), or neurogenic bladder, or the participant has a history of anatomical or functional abnormalities of the urinary tract (e.g., chronic vesico-ureteral reflux, detrusor insufficiency). * Participant has an indwelling catheter, nephrostomy, ureter stent, or other foreign material in the urinary tract. * 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 \>=101.4 Degrees Fahrenheit (F) (\>=38 Degrees Celsius \[C\]), flank pain, chills, or any other manifestations suggestive of upper UTI. * Participant has known anuria, oliguria, or significant impairment of renal function (creatinine clearance \<60 milliliter per minute \[mL/min\] or clinically significant elevated serum creatinine as determined by the investigator). * Participant presents with vaginal discharge at Baseline (e.g., suspected sexually transmitted disease). * Participant has congenital long QT syndrome or known prolongation of the corrected QT (QTc) interval. * Participant has uncompensated heart failure. * Participant has severe left ventricular hypertrophy. * Participant has a family history of QT prolongation or sudden death. * Participant has a recent history of vasovagal syncope or episodes of symptomatic bradycardia or brady-arrhythmia within the last 12 months. * 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 electrocardiogram (ECG) reading. * Participant has a QTc \>450 millisecond (msec) or a QTc \>480 msec for participants with bundle-branch block. * Participant has a documented or recent history of uncorrected hypokalemia within the past 3 months. * Participant has a known alanine aminotransferase (ALT) value \>2 times upper limit of normal (ULN). * Participant has a known bilirubin value \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent \[%\]). * Participant has a current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), including symptomatic viral hepatitis or moderate-to-severe liver insufficiency (Child Pugh class B or C). * Participant has a previous history of cholestatic jaundice or hepatic dysfunction associated with nitrofurantoin. * Participant has received treatment with other systemic antimicrobials or systemic antifungals within 1 week before study entry.

Locations (103)

Outcomes

Primary Outcomes

Number of Participants With Therapeutic Response (TR) (Combined Per Participant Clinical and Microbiological Response) at the Test-of-Cure (TOC) Visit - Micro-ITT NTF-S (IA Set)

Therapeutic response (success/failure) is a measure of the overall efficacy response. A therapeutic success referred to participants who had 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 before 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 before the TOC Visit). Lack of clinical or microbiological success (including missing outcome assessments) was considered as therapeutic failure.

Time frame: TOC visit (Days 9 to 16)

Number of Participants With Therapeutic Response (TR) (Combined Per Participant Clinical and Microbiological Response) at the Test-of-Cure (TOC) Visit - Micro-ITT NTF-S Population

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 Baseline \[BL\] 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.

Time frame: TOC visit (Days 9 to 16)

Secondary Outcomes

Number of Participants With Clinical Outcome at the TOC Visit - Micro-ITT NTF-S Population

Clinical outcomes at TOC were 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 baseline (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).

Data from ClinicalTrials.gov

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Placebo matching gepotidacin will be available as unit-dose gepotidacin placebo-to-match tablet. Each dose should be taken with water after consumption of food.

GSK Investigational Site

Birmingham, Alabama, United States

GSK Investigational Site

Phoenix, Arizona, United States

GSK Investigational Site

Tucson, Arizona, United States

GSK Investigational Site

Beverly Hills, California, United States

GSK Investigational Site

Chula Vista, California, United States

GSK Investigational Site

La Mesa, California, United States

GSK Investigational Site

Lomita, California, United States

GSK Investigational Site

Long Beach, California, United States

GSK Investigational Site

Northridge, California, United States

GSK Investigational Site

Northridge, California, United States

...and 93 more locations

Time frame: TOC visit (Days 9 to 16)

Number of Participants With Clinical Response at the TOC Visit - Micro-ITT NTF-S Population

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.

Time frame: TOC visit (Days 9 to 16)

Number of Participants With Microbiological Outcome (MO) at the TOC Visit - Micro-ITT NTF-S Population

Participant-level MOs at TOC were 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.

Time frame: TOC Visit (Days 9 to 16)

Number of Participants With Microbiological Response at the TOC Visit - Micro-ITT NTF-S Population

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)s had a microbiological outcome of eradication at TOC visit. Microbiological failure was defined as lack of microbiological success, including those participants with UTD outcomes.

Time frame: TOC visit (Days 9 to 16)

Number of Participants With Therapeutic Response (TR) (Combined Per Participant Clinical and Microbiological Response) at the Follow up (FU) Visit-Micro-ITT NTF-S Population

TR at FU was categorized as therapeutic success and therapeutic failure. A therapeutic success at FU referred to participants who have been deemed both a microbiological success (reduction of all QUPs recovered at BL to \<10\^3 CFU/mL, following microbiological eradication at the TOC visit, without receiving other AB before the FU visit) and a clinical success (resolution of signs and symptoms of acute cystitis demonstrated at the TOC visit persist at the FU visit and no new signs and symptoms, without receiving other AB before the FU visit \[or AB for uUTI on day of FU visit\]). Lack of clinical or microbiological success (including missing outcome assessments) was considered as therapeutic failure.

Time frame: FU visit (Days 21 to 31)

Number of Participants With Clinical Outcome at the Follow up (FU) Visit - Micro-ITT NTF-S Population

Clinical outcomes at FU were categorized as SCR, DCR, CI, CW, CR and UTD. SCR at FU was resolution of symptoms of acute cystitis demonstrated at the TOC persist at the FU (and no symptoms), without receiving other AB before the FU. DCR at FU was resolution of symptoms of acute cystitis present at BL after clinical failure at TOC without receiving AB before FU. CI at FU was improvement in CSS from BL, but not complete resolution without receiving AB before FU. CW at FU was worsening or no change in CSS at FU compared to BL after clinical failure at TOC or receiving other AB for the current infection (uUTI) before or on the date of the FU. CR at FU was symptoms of acute cystitis reoccur at FU after clinical success at TOC. Unable to determine outcome criteria at FU were BL score missing, FU assessment missing or received other AB not for the current infection (uUTI) prior to the assessment (unless CS or CR outcome criteria were met).

Time frame: FU visit (Days 21 to 31)

Number of Participants With Clinical Response at the Follow up (FU) Visit - Micro-ITT NTF-S Population

Clinical response at FU was categorized as clinical success and clinical failure. Clinical success at FU was defined as resolution of symptoms of acute cystitis demonstrated at TOC persist at the FU visit (and no new symptoms), without receiving other AB before the FU visit. Lack of sustained clinical resolution or a missing outcome assessment was defined as clinical failure.

Time frame: FU visit (Days 21 to 31)

Number of Participants With Microbiological Outcome (MO) at the Follow up (FU) Visit - Micro-ITT NTF-S Population

Participant-level MOs at FU were categorized as sustained microbiological eradication (SME), microbiological recurrence (MR), microbiological persistence (MP), delayed microbiological eradication (DME) and unable to determine (UTD). SME at FU was defined as all baseline QUPs had an outcome of sustained eradication at FU (i.e., \<10\^3 CFU/mL without the participant receiving other systemic antimicrobials before the FU Visit). MR at FU was defined as at least one QUP had an outcome of recurrence (≥10\^3 CFU/mL) and none had an outcome of persistence at FU. MP at FU was defined as at least one QUP had an outcome of persistence at FU. DME at FU was defined as at least one QUP had an outcome of delayed eradication and none had an outcome of persistence or recurrence at FU. UTD at FU was defined as all QUP outcomes were unable to determine at FU.

Time frame: FU visit (Days 21 to 31)

Number of Participants With Microbiological Response at the Follow up (FU) Visit - Micro-ITT NTF-S Population

Participant- level microbiological response at FU was categorized as microbiological success and microbiological failure. Microbiological success at FU was defined as all baseline QUPs had a microbiological outcome of sustained eradication at FU visit. Microbiological failure at FU was defined as not meeting criteria of microbiological success including those participants with UTD outcome.

Time frame: FU visit (Days 21 to 31)

Number of Participants With Clinical Outcome at the TOC Visit - Intent-to-Treat (ITT) Population

Clinical outcomes at TOC were categorized as clinical resolution, clinical improvement, clinical worsening and unable to determine. Clinical resolution at TOC was defined as resolution symptoms of acute cystitis present at baseline (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).

Time frame: TOC visit (Days 9 to 16)

Number of Participants With Clinical Response at the TOC Visit - Intent-to-Treat (ITT) Population

Clinical response at TOC was categorized as clinical success and clinical failure. Clinical success at TOC was defined as resolution of signs and 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.

Time frame: TOC visit (Days 9 to 16)

Number of Participants With Clinical Outcome at the Follow up (FU) Visit - Intent-to-Treat (ITT) Population

Clinical outcomes at FU were categorized as Sustained Clinical Response (SCR), Delayed Clinical Response (DCR), CI, CW, Clinical Recurrence (CR) and UTD. SCR at FU was resolution of symptoms of acute cystitis demonstrated at TOC persist at the FU (and no symptoms), without receiving other AB before the FU. DCR at FU was resolution of symptoms of acute cystitis present at BL after clinical failure at TOC without receiving AB before FU. CI at FU was improvement in CSS from BL, but not complete resolution without receiving AB before FU. CW at FU was worsening or no change in CSS at FU compared to BL after clinical failure at TOC or receiving other AB for the current infection (uUTI) before or on the date of the FU. CR at FU was symptoms of acute cystitis reoccur at FU after clinical success at TOC. UTD outcome criteria at FU were BL score missing, FU assessment missing or received other AB not for current infection (uUTI) prior to assessment (unless CS or CR outcome criteria were met).

Time frame: FU visit (Days 21 to 31)

Number of Participants With Clinical Response at the Follow up (FU) Visit - Intent-to-Treat (ITT) Population

Time frame: FU visit (Days 21 to 31)

Plasma Concentration of Gepotidacin

Blood samples were collected for plasma concentration of gepotidacin.

Time frame: Baseline (Day 1) 0-2 hour (h) and >2h post-dose; On-therapy (Day 2), morning (am) pre-dose, 0-6h, 6-8h, 8-10h, 10-12h post-dose, 0-2h, >2h evening (pm) post-dose; On-therapy (Day 3 to 5), 0-6h, 6-8h, 8-10h, 10-12h post-dose

Urine Concentration of Gepotidacin

Urine samples were collected from participants.

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

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.

Time frame: From the time of first dose (Day 1) through the final follow-up visit (Day 21-31)

Number of Participants With Serious Adverse Events (SAEs)

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.

Time frame: From the time of first dose (Day 1) through the final follow-up visit (Day 21-31)

Change From Baseline in Hematology Parameters - Neutrophil Count, Lymphocyte Count, Monocyte Count, Eosinophil Count, Basophil Count and Platelet Count at On Therapy and Test of Cure Visit

Blood samples were collected for the analysis of hematology parameters: neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count and platelet count. Baseline is defined as the latest pre-dose assessment with a non-missing value.