NCT04020341CompletedPhase 3
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)
Conditions
Interventions
Drugs
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- GlaxoSmithKline
- Enrollment
- 1,531
- Locations
- 1
- Primary Endpoint
- 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)
Study Overview
Brief Summary
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 Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 12 Years to — (Child, Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
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:
- •Poorly controlled asthma or chronic obstructive pulmonary disease; acute severe pain; active peptic ulcer disease; Parkinson disease; myasthenia gravis; 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 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.
Arms & Interventions
Gepotidacin
Experimental
Participants will be administered oral doses of 1500 milligrams (mg) gepotidacin plus nitrofurantoin matching placebo twice daily (BID); approximately every 12 hours for 5 days
Intervention: Gepotidacin (Drug)
Gepotidacin
Experimental
Participants will be administered oral doses of 1500 milligrams (mg) gepotidacin plus nitrofurantoin matching placebo twice daily (BID); approximately every 12 hours for 5 days
Intervention: Placebo matching nitrofurantoin (Drug)
Nitrofurantoin
Active Comparator
Participants will be administered oral doses of 100 mg nitrofurantoin plus gepotidacin matching placebo BID; approximately every 12 hours for 5 days.
Intervention: Nitrofurantoin (Drug)
Nitrofurantoin
Active Comparator
Participants will be administered oral doses of 100 mg nitrofurantoin plus gepotidacin matching placebo BID; approximately every 12 hours for 5 days.
Intervention: Placebo matching gepotidacin (Drug)
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)
Time Frame: TOC visit (Days 9 to 16)
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.
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
Time Frame: 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 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.
Secondary Outcomes
- Number of Participants With Clinical Outcome at the TOC Visit - Micro-ITT NTF-S Population(TOC visit (Days 9 to 16))
- Number of Participants With Clinical Response at the TOC Visit - Micro-ITT NTF-S Population(TOC visit (Days 9 to 16))
- Number of Participants With Microbiological Outcome (MO) at the TOC Visit - Micro-ITT NTF-S Population(TOC Visit (Days 9 to 16))
- Number of Participants With Microbiological Response at the TOC Visit - Micro-ITT NTF-S Population(TOC visit (Days 9 to 16))
- Number of Participants With Clinical Response at the Follow up (FU) Visit - Micro-ITT NTF-S Population(FU visit (Days 21 to 31))
- Number of Participants With Microbiological Response at the Follow up (FU) Visit - Micro-ITT NTF-S Population(FU visit (Days 21 to 31))
- Number of Participants With Clinical Outcome at the Follow up (FU) Visit - Intent-to-Treat (ITT) Population(FU visit (Days 21 to 31))
- Number of Participants With Clinical Outcome at the TOC Visit - Intent-to-Treat (ITT) Population(TOC visit (Days 9 to 16))
- Number of Participants With Serious Adverse Events (SAEs)(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(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Change From Baseline in Hematology Parameter-hemoglobin Level at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (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(FU visit (Days 21 to 31))
- Number of Participants With Clinical Outcome at the Follow up (FU) Visit - Micro-ITT NTF-S Population(FU visit (Days 21 to 31))
- Plasma Concentration of Gepotidacin(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)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)(From the time of first dose (Day 1) through the final follow-up visit (Day 21-31))
- Change From Baseline in Hematology Parameter- Hematocrit Level at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Change From Baseline in Hematology Parameter- Erythrocytes Count at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Change From Baseline in Hematology Parameter - Mean Corpuscular Hemoglobin (MCH) at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Change From Baseline in Hematology Parameter - Mean Corpuscular Volume (MCV) at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Change From Baseline in Clinical Chemistry Parameters - Serum Urea Nitrogen, Glucose, Calcium, Chloride, Sodium, Magnesium, Phosphate, and Potassium Levels at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Change From Baseline in Clinical Chemistry Parameters - Total Bilirubin, Direct Bilirubin and Creatinine Levels at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Number of Participants With Microbiological Outcome (MO) at the Follow up (FU) Visit - Micro-ITT NTF-S Population(FU visit (Days 21 to 31))
- Number of Participants With Clinical Response at the TOC Visit - Intent-to-Treat (ITT) Population(TOC visit (Days 9 to 16))
- Number of Participants With Clinical Response at the Follow up (FU) Visit - Intent-to-Treat (ITT) Population(FU visit (Days 21 to 31))
- Urine Concentration of Gepotidacin(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)
- Change From Baseline in Clinical Chemistry Parameters - Albumin and Protein Levels at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Change From Baseline in Clinical Chemistry Parameters - Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline Phosphatase (ALP) Levels at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Number of Participants With Urinalysis Dipstick Results at Baseline, On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Absolute Mean Values of Urine Specific Gravity at Baseline, On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Absolute Mean Values of Urine Potential of Hydrogen (pH) at Baseline, On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at On-Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Change From Baseline in Pulse Rate at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
- Change From Baseline in Body Temperature at On Therapy and Test of Cure Visit(Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16))
Investigators
Study Sites (1)
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