Clinical trial NCT04020341: A Study to Evaluate Efficacy and Safety of Gepotidacin in the Treatment of Uncomplicated Urinary Tract Infection (UTI)
Official title: 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: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Urinary Tract Infections
Keywords: Acute cystitis
Efficacy
Gepotidacin
Nitrofurantoin
Urinary Tract Infection
Simple cystitis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2019-07-16
Enrollment: 1531
Sex: FEMALE
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: TOC visit (Days 9 to 16)
measure: 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
timeFrame: TOC visit (Days 9 to 16)
Secondary outcomes:
measure: Number of Participants With Clinical Outcome at the TOC Visit - Micro-ITT NTF-S Population
timeFrame: TOC visit (Days 9 to 16)
measure: Number of Participants With Clinical Response at the TOC Visit - Micro-ITT NTF-S Population
timeFrame: TOC visit (Days 9 to 16)
measure: Number of Participants With Microbiological Outcome (MO) at the TOC Visit - Micro-ITT NTF-S Population
timeFrame: TOC Visit (Days 9 to 16)
measure: Number of Participants With Microbiological Response at the TOC Visit - Micro-ITT NTF-S Population
timeFrame: TOC visit (Days 9 to 16)
measure: 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
timeFrame: FU visit (Days 21 to 31)
measure: Number of Participants With Clinical Outcome at the Follow up (FU) Visit - Micro-ITT NTF-S Population
timeFrame: FU visit (Days 21 to 31)
measure: Number of Participants With Clinical Response at the Follow up (FU) Visit - Micro-ITT NTF-S Population
timeFrame: FU visit (Days 21 to 31)
measure: Number of Participants With Microbiological Outcome (MO) at the Follow up (FU) Visit - Micro-ITT NTF-S Population
timeFrame: FU visit (Days 21 to 31)
measure: Number of Participants With Microbiological Response at the Follow up (FU) Visit - Micro-ITT NTF-S Population
timeFrame: FU visit (Days 21 to 31)
measure: Number of Participants With Clinical Outcome at the TOC Visit - Intent-to-Treat (ITT) Population
timeFrame: TOC visit (Days 9 to 16)
measure: Number of Participants With Clinical Response at the TOC Visit - Intent-to-Treat (ITT) Population
timeFrame: TOC visit (Days 9 to 16)
measure: Number of Participants With Clinical Outcome at the Follow up (FU) Visit - Intent-to-Treat (ITT) Population
timeFrame: FU visit (Days 21 to 31)
measure: Number of Participants With Clinical Response at the Follow up (FU) Visit - Intent-to-Treat (ITT) Population
timeFrame: FU visit (Days 21 to 31)
measure: Plasma Concentration of Gepotidacin
timeFrame: 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
measure: Urine Concentration of Gepotidacin
timeFrame: 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
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: From the time of first dose (Day 1) through the final follow-up visit (Day 21-31)
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: From the time of first dose (Day 1) through the final follow-up visit (Day 21-31)
measure: 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
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Change From Baseline in Hematology Parameter-hemoglobin Level at On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Change From Baseline in Hematology Parameter- Hematocrit Level at On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Change From Baseline in Hematology Parameter- Erythrocytes Count at On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Change From Baseline in Hematology Parameter - Mean Corpuscular Hemoglobin (MCH) at On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Change From Baseline in Hematology Parameter - Mean Corpuscular Volume (MCV) at On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: 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
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Change From Baseline in Clinical Chemistry Parameters - Total Bilirubin, Direct Bilirubin and Creatinine Levels at On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Change From Baseline in Clinical Chemistry Parameters - Albumin and Protein Levels at On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: 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
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Number of Participants With Urinalysis Dipstick Results at Baseline, On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Absolute Mean Values of Urine Specific Gravity at Baseline, On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Absolute Mean Values of Urine Potential of Hydrogen (pH) at Baseline, On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at On-Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Change From Baseline in Pulse Rate at On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
measure: Change From Baseline in Body Temperature at On Therapy and Test of Cure Visit
timeFrame: Baseline (on or before Day 1), On-Therapy (Days 2 to 5), and Test of cure (Days 9 to 16)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: Beverly Hills
country: United States
facility: GSK Investigational Site
state: California
city: Chula Vista
country: United States
facility: GSK Investigational Site
state: California
city: La Mesa
country: United States
facility: GSK Investigational Site
state: California
city: Lomita
country: United States
facility: GSK Investigational Site
state: California
city: Long Beach
country: United States
facility: GSK Investigational Site
state: California
city: Northridge
country: United States
facility: GSK Investigational Site
state: California
city: Northridge
country: United States
facility: GSK Investigational Site
state: California
city: Palm Springs
country: United States
facility: GSK Investigational Site
state: California
city: San Diego
country: United States
facility: GSK Investigational Site
state: California
city: DeLand
country: United States
facility: GSK Investigational Site
state: Florida
city: Hialeah
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami Springs
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Pompano Beach
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Columbus
country: United States
facility: GSK Investigational Site
state: Georgia
city: Fayetteville
country: United States
facility: GSK Investigational Site
state: Georgia
city: Wichita
country: United States
facility: GSK Investigational Site
state: Kansas
city: New Orleans
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Shreveport
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Watertown
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Dearborn Heights
country: United States
facility: GSK Investigational Site
state: Michigan
city: Norfolk
country: United States
facility: GSK Investigational Site
state: Nebraska
city: East Brunswick
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Albuquerque
country: United States
facility: GSK Investigational Site
state: New Mexico
city: Endwell
country: United States
facility: GSK Investigational Site
state: New York
city: Fayetteville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Scottdale
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Smithfield
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Clarksville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Arlington
country: United States
facility: GSK Investigational Site
state: Texas
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Corpus Christi
country: United States
facility: GSK Investigational Site
state: Texas
city: Forney
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Blagoevgrad
country: Bulgaria
facility: GSK Investigational Site
city: Dupnitsa
country: Bulgaria
facility: GSK Investigational Site
city: Pernik
country: Bulgaria
facility: GSK Investigational Site
city: Pleven
country: Bulgaria
facility: GSK Investigational Site
city: Plovdiv
country: Bulgaria
facility: GSK Investigational Site
city: Sliven
country: Bulgaria
facility: GSK Investigational Site
city: Smolyan
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Yambol
country: Bulgaria
facility: GSK Investigational Site
city: Bory
country: Czechia
facility: GSK Investigational Site
city: Kromeríž
country: Czechia
facility: GSK Investigational Site
city: Praha
country: Czechia
facility: GSK Investigational Site
city: Giessen
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Muelheim an der Ruhr
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Heraklion
country: Greece
facility: GSK Investigational Site
city: Larisa
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Ballószög
country: Hungary
facility: GSK Investigational Site
city: Csongrad
country: Hungary
facility: GSK Investigational Site
city: Nyíregyháza
country: Hungary
facility: GSK Investigational Site
city: Orosháza-Szentetornya
country: Hungary
facility: GSK Investigational Site
city: Ahmedabad
country: India
facility: GSK Investigational Site
city: Surat
country: India
facility: GSK Investigational Site
city: Varanasi
country: India
facility: GSK Investigational Site
city: Ciudad de Mexico
country: Mexico
facility: GSK Investigational Site
state: Campeche
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Monterrey
country: Mexico
facility: GSK Investigational Site
state: Nuevo León
city: Monterrey
country: Mexico
facility: GSK Investigational Site
state: Nuevo León
city: San Juan del Río
country: Mexico
facility: GSK Investigational Site
state: Querétaro
city: Jalisco
country: Mexico
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucuresti
country: Romania
facility: GSK Investigational Site
city: Iasi
country: Romania
facility: GSK Investigational Site
city: Oradea
country: Romania
facility: GSK Investigational Site
city: Timisoara
country: Romania
facility: GSK Investigational Site
city: Bratislava
country: Slovakia
facility: GSK Investigational Site
city: Kosice
country: Slovakia
facility: GSK Investigational Site
city: Nitra
country: Slovakia
facility: GSK Investigational Site
city: Pruske
country: Slovakia
facility: GSK Investigational Site
city: Sala
country: Slovakia
facility: GSK Investigational Site
city: Trencin
country: Slovakia
facility: GSK Investigational Site
city: Trencin
country: Slovakia
facility: GSK Investigational Site
city: Alicante
country: Spain
facility: GSK Investigational Site
city: Cordoba
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Vic
country: Spain
facility: GSK Investigational Site
city: Crownhill, Plymouth
country: United Kingdom
facility: GSK Investigational Site
city: Liskeard
country: United Kingdom
facility: GSK Investigational Site
city: Peterborough
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Perry C, Hossain M, Powell M, Raychaudhuri A, Scangarella-Oman N, Tiffany C, Xu S, Dumont E, Janmohamed S. Design of Two Phase III, Randomized, Multicenter Studies Comparing Gepotidacin with Nitrofurantoin for the Treatment of Uncomplicated Urinary Tract Infection in Female Participants. Infect Dis Ther. 2022 Dec;11(6):2297-2310. doi: 10.1007/s40121-022-00706-9. Epub 2022 Oct 21.
citation: Fishman C, Caverly Rae JM, Posobiec LM, Laffan SB, Lerman SA, Pearson N, Janmohamed S, Dumont E, Nunn-Floyd D, Stanislaus DJ. Novel Bacterial Topoisomerase Inhibitor Gepotidacin Demonstrates Absence of Fluoroquinolone-Like Arthropathy in Juvenile Rats. Antimicrob Agents Chemother. 2022 Nov 15;66(11):e0048322. doi: 10.1128/aac.00483-22. Epub 2022 Oct 18.
citation: Scangarella-Oman NE, Hossain M, Hoover JL, Perry CR, Tiffany C, Barth A, Dumont EF. Dose Selection for Phase III Clinical Evaluation of Gepotidacin (GSK2140944) in the Treatment of Uncomplicated Urinary Tract Infections. Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0149221. doi: 10.1128/AAC.01492-21. Epub 2022 Jan 3.