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

Overview

Urinary tract infections (UTIs; acute cystitis) are very common, with approximately 11 percentage of women (>18 years of age) reporting at least 1 episode of acute cystitis per year. The purpose of this study to evaluate the therapeutic response (combined microbiological and clinical efficacy per participant) of oral gepotidacin compared to oral nitrofurantoin for acute cystitis in adolescent and adult female participants. In this study, participants will be randomly assigned in a 1:1 ratio to receive either oral gepotidacin or oral nitrofurantoin. The study will enroll approximately 1200 participants with uncomplicated UTI. The duration of the study will be approximately 28 days with 4 planned study visits.

Full Title of Study: “A Phase III, Randomized, Multicenter, Parallel-Group, Double-Blind, Double-Dummy Study in Adolescent and Adult Female Participants Comparing the Efficacy and Safety of Gepotidacin to Nitrofurantoin in the Treatment of Uncomplicated Urinary Tract Infection (Acute Cystitis)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: December 20, 2021

Interventions

  • Drug: Gepotidacin
    • Gepotidacin will be available as tablets at a unit dose strength of 750mg. Participants will administer two 750 mg tablets, BID. Each dose will be taken with water after consumption of food.
  • Drug: Placebo matching nitrofurantoin
    • Placebo matching nitrofurantoin will be available as over-encapsulated unit-dose capsules. Participants will administer 1 capsule BID. Each dose should be taken with water after consumption of food.
  • Drug: Nitrofurantoin
    • Nitrofurantoin will be available as over-encapsulated 100 mg capsules containing 25 mg nitrofurantoin macrocrystals and 75 mg nitrofurantoin. Participants will administer one 100 mg capsule, BID. Each dose should be taken with water after consumption of food.
  • Drug: Placebo matching gepotidacin
    • Placebo matching gepotidacin will be available as unit-dose gepotidacin placebo-to-match tablet. Participants will administer two tablets, BID. Each dose should be taken with water after consumption of food.

Arms, Groups and Cohorts

  • Experimental: Gepotidacin
    • Participants will be administered oral doses of 1500 mg gepotidacin plus nitrofurantoin matching placebo BID; approximately every 12 hours for 5 days
  • Active Comparator: Nitrofurantoin
    • Participants will be administered oral doses of 100 mg nitrofurantoin plus gepotidacin matching placebo BID; approximately every 12 hours for 5 days.

Clinical Trial Outcome Measures

Primary Measures

  • Number of participants with therapeutic response at the Test-of-Cure (TOC) visit
    • Time Frame: Up to Day 13
    • A therapeutic success refers to participants who have been deemed both a “microbiological success” and a “clinical success”. All other combinations (other than clinical success + microbiological success) will be deemed failures for therapeutic response.

Secondary Measures

  • Number of participants with clinical outcome at the TOC visit
    • Time Frame: Up to Day 13
    • The clinical signs and symptoms score for acute cystitis will be determined by the investigator and used to programmatically determine the clinical outcome.
  • Number of participants with clinical outcome at the follow up visit
    • Time Frame: Up to Day 31
    • The clinical signs and symptoms score for acute cystitis will be determined by the investigator and used to programmatically determine the clinical outcome.
  • Number of participants with clinical response at the TOC visit
    • Time Frame: Up to Day 13
    • The clinical signs and symptoms score for acute cystitis will be determined by the investigator and used to programmatically determine the clinical response.
  • Number of participants with clinical response at the follow up visit
    • Time Frame: Up to Day 31
    • The clinical signs and symptoms score for acute cystitis will be determined by the investigator and used to programmatically determine the clinical response.
  • Number of participants with microbiological outcome at the TOC visit
    • Time Frame: Up to Day 13
    • The microbiological outcome to study intervention will be determined by pre-specified programmed algorithm for each participant or uropathogen. The microbiological outcome by Baseline qualifying uropathogen will be determined by comparing the baseline culture results to the culture results at each subsequent visit.
  • Number of participants with microbiological outcome at the follow up visit
    • Time Frame: Up to Day 31
    • The microbiological outcome to study intervention will be determined by pre-specified programmed algorithm for each participant or uropathogen. The microbiological outcome by baseline qualifying uropathogen will be determined by comparing the baseline culture results to the culture results at each subsequent visit.
  • Number of participants with microbiological response at the TOC visit
    • Time Frame: Up to Day 13
    • The microbiological response to study intervention will be determined by pre-specified programmed algorithm for each participant or uropathogen.
  • Number of participants with microbiological response at the follow up visit
    • Time Frame: Up to Day 31
    • The microbiological response to study intervention will be determined by pre-specified programmed algorithm for each participant or uropathogen
  • Number of participants with therapeutic response at the follow up visit
    • Time Frame: Up to Day 31
    • A therapeutic success refers to participants who have been deemed both a “microbiological success” and a “clinical success”. All other combinations (other than clinical success + microbiological success) will be deemed failures for therapeutic response.
  • Number of participants with treatment-emergent adverse events (AEs) and serious adverse events (SAEs)
    • Time Frame: Up to Day 31
    • An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, any other situation that require medical or scientific judgment.
  • Change from Baseline in neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count and platelet count (Giga cells per Liter)
    • Time Frame: Baseline and up to Day 13
    • Blood samples will be collected for the assessment of neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count and platelet count.
  • Change from Baseline in hemoglobin level (grams per deciliter)
    • Time Frame: Baseline and up to Day 13
    • Blood samples will be collected for the assessment of hemoglobin level.
  • Change from Baseline in hematocrit level (Proportion of red blood cells in blood)
    • Time Frame: Baseline and up to Day 13
    • Blood samples will be collected for the assessment of hematocrit level
  • Change from Baseline in red blood cell (RBC) count (Trillion cells per liter)
    • Time Frame: Baseline and up to Day 13
    • Blood samples will be collected for the assessment of RBC count.
  • Change from Baseline in mean corpuscular hemoglobin (MCH) (Picograms)
    • Time Frame: Baseline and up to Day 13
    • Blood samples will be collected for the assessment of MCH
  • Change from Baseline in mean corpuscular volume (MCV) (Femtoliters)
    • Time Frame: Baseline and up to Day 13
    • Blood samples will be collected for the assessment of MCV.
  • Change from Baseline in blood urea nitrogen (BUN), glucose non-fasting, calcium, chloride, sodium, magnesium, phosphorus, and potassium levels (millimoles per liter)
    • Time Frame: Baseline and up to Day 13
    • Blood samples will be collected for the assessment of BUN, glucose non-fasting, calcium, chloride, magnesium, phosphorus, sodium and potassium levels.
  • Change from Baseline in total bilirubin, direct bilirubin and creatinine levels (micromoles per Liter)
    • Time Frame: Baseline and up to Day 13
    • Blood samples will be collected for the assessment of total bilirubin, direct bilirubin and creatinine levels.
  • Change from Baseline in albumin and total protein levels (gram per Liter)
    • Time Frame: Baseline and up to Day 13
    • Blood samples will be collected for the assessment of albumin and total protein levels.
  • Change from Baseline in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase levels (International units per Liter)
    • Time Frame: Baseline and up to Day 13
    • Blood samples will be collected for the assessment of AST, ALT and alkaline phosphatase levels.
  • Number of participants with abnormal urinalysis Dipstick results
    • Time Frame: Up to Day 13
    • Urine samples will be collected to assess pH, glucose, protein, nitrite, leukocyte esterase, blood and ketones by Dipstick method. Microscopic examination will be performed if blood or protein will be abnormal.
  • Change from Baseline in specific gravity of urine
    • Time Frame: Baseline and up to Day 13
    • Urine samples will be collected for the measurement of specific gravity.
  • Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)
    • Time Frame: Baseline and up to Day 13
    • SBP and DBP will be assessed in a semi-supine position after 5 minutes rest.
  • Change from Baseline in pulse rate
    • Time Frame: Baseline and up to Day 13
    • Pulse rate will be assessed in a semi-supine position after 5 minutes rest.
  • Change from Baseline in body temperature
    • Time Frame: Baseline and up to Day 13
    • Changes in body temperature from Baseline will be assessed.
  • Change from Baseline in PR, QRS, QT, and corrected QT interval (QTc) intervals (milliseconds [msec])
    • Time Frame: Baseline and up to Day 4
    • Twelve lead electrocardiograms (ECG) will be obtained using an ECG machine that will automatically measure the PR, QRS, QT and QTc intervals.

Participating in This Clinical Trial

Inclusion Criteria

  • The participant is >=12 years of age at the time of signing the informed consent/assent and has a body weight >=40 kilogram (kg).
  • The participant has 2 or more of the following clinical signs and symptoms of acute cystitis with onset <=72 hours prior to study entry: dysuria, frequency, urgency, or lower abdominal pain
  • The participant has nitrite or pyuria (>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 female.
  • Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • A female participant is eligible to participate if she is a woman of childbearing potential (WOCBP) who is not pregnant as confirmed by a high sensitivity urine pregnancy test at Baseline (Day 1) regardless of current or prior contraception use or abstinence, is not breastfeeding, or is not a WOCBP.
  • Additional requirements for pregnancy testing during and after study intervention are specified.
  • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
  • The participant is capable of giving signed informed consent/assent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF)/assent form and protocol.

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 high blood pressure or uncontrolled diabetes.
  • The participant has a history of sensitivity to the study interventions, 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.
  • The participant is immunocompromised or has altered immune defenses that may predispose the participant to a higher risk of treatment failure and/or complications (e.g., uncontrolled diabetes, renal transplant recipients, participants with clinically significant persistent granulocytopenia [absolute neutrophil count <1000/microliter (μL)], and participants receiving immunosuppressive therapy, including corticosteroid therapy [>40 milligrams (mg)/day prednisolone or equivalent for >1 week, >=20 mg/day prednisolone or equivalent for >2 weeks, or prednisolone or equivalent >=10 mg/day for >6 weeks]). Participants with a known cluster of differentiation 4 (CD4) count of <200 cells per cubic millimeter (cells/mm^3) should not be enrolled.
  • The participant has any of the following: Medical condition that requires medication that may be impacted by inhibition of acetylcholinesterase, such as;
  • Medical condition that requires medication that may be impacted by inhibition of acetylcholinesterase, such as:
  • Poorly controlled asthma or chronic obstructive pulmonary disease at Baseline and, in the opinion of the investigator, not stable on current therapy
  • Acute severe pain, uncontrolled with conventional medical management
  • 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
  • Any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study intervention (e.g., ileostomy or malabsorption syndrome)
  • The participant has a known glucose-6 phosphate dehydrogenase deficiency.
  • The 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.
  • The 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 Enterobacteriaceae (other than Escherichia 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.
  • 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 vesico-ureteral 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 >=101 degree Fahrenheit, 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 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 or a strong P-glycoprotein (P-gp) inhibitor.
  • For any participant >=12 to <18 years of age, the participant has an abnormal ECG reading at Baseline or during the study intervention.
  • 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 ALT value >2 × upper limit of normal (ULN).
  • The participant has a known bilirubin value >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • 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.
  • The participant must agree not to use the medications or nondrug therapies from the Baseline Visit through the TOC Visit
  • The participant has been previously enrolled in this study or has previously been treated with gepotidacin.
  • The participant has participated in a clinical trial and has received an investigational product within 30 days or 5 half-lives, whichever is longer.

Gender Eligibility: Female

Minimum Age: 12 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • GlaxoSmithKline
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Contact(s)
    • US GSK Clinical Trials Call Center, 877-379-3718, GSKClinicalSupportHD@gsk.com

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