Clinical trial NCT04187144: Comparative Study to Evaluate Efficacy and Safety of Gepotidacin to Nitrofurantoin in 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: 2019-12-05
Enrollment: 1606
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:

* 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 \<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 female.
* 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 has a history of sensitivity to the study treatment, 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.
* The 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 intervention .
* 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 Enterobacterales (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 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 (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).
* 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 \>=101.4 degree Fahrenheit (\>=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 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.
* 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 times upper limit of normal (ULN).
* The 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 \[%\]).
* 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.

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: 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
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
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 (RBC) Count
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)
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)
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 Blood Urea Nitrogen (BUN), Glucose Non-fasting, Calcium, Chloride, Sodium, Magnesium, Phosphate, and Potassium Levels
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
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
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
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
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
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)
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
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 Maximum Change From Baseline in Electrocardiograms (ECG) Parameter: QT Interval Corrected for Heart Rate According to Bazett's Formula (QTcB) at Worst-case Post-baseline
timeFrame: Up to Day 31
measure: Number of Participants With Maximum Change From Baseline in Electrocardiograms (ECG) Parameter- QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) at Worst-case Post-baseline
timeFrame: Up to Day 31
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Homewood
country: United States
facility: GSK Investigational Site
state: Alabama
city: Huntsville
country: United States
facility: GSK Investigational Site
state: Alabama
city: Gilbert
country: United States
facility: GSK Investigational Site
state: Arizona
city: Peoria
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facility: GSK Investigational Site
state: Arizona
city: Phoenix
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facility: GSK Investigational Site
state: Arizona
city: La Mesa
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facility: GSK Investigational Site
state: California
city: Modesto
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facility: GSK Investigational Site
state: California
city: Northridge
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facility: GSK Investigational Site
state: California
city: Sacramento
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facility: GSK Investigational Site
state: California
city: Valencia
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facility: GSK Investigational Site
state: California
city: Washington
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facility: GSK Investigational Site
state: District of Columbia
city: Apollo Beach
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facility: GSK Investigational Site
state: Florida
city: Boynton Beach
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facility: GSK Investigational Site
state: Florida
city: Clearwater
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state: Florida
city: Coconut Creek
country: United States
facility: GSK Investigational Site
state: Florida
city: Gainesville
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facility: GSK Investigational Site
state: Florida
city: Hialeah
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facility: GSK Investigational Site
state: Florida
city: Lake Worth
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state: Florida
city: Leesburg
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state: Florida
city: Miami
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facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
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: Ormond Beach
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facility: GSK Investigational Site
state: Florida
city: Palm Springs
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state: Florida
city: Pembroke Pines
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state: Florida
city: Plant City
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state: Florida
city: Sweetwater
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
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facility: GSK Investigational Site
state: Florida
city: West Palm Beach
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state: Florida
city: Blackfoot
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state: Idaho
city: Boise
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state: Idaho
city: Meridian
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state: Idaho
city: Hanover
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facility: GSK Investigational Site
state: Maryland
city: Fall River
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state: Massachusetts
city: Butte
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state: Montana
city: Lincoln
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state: Nebraska
city: East Orange
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state: New Jersey
city: Lawrenceville
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city: Mount Laurel
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state: New Jersey
city: Bronx
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state: New York
city: Brooklyn
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state: New York
city: New York
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facility: GSK Investigational Site
state: New York
city: New York
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facility: GSK Investigational Site
state: New York
city: Cary
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facility: GSK Investigational Site
state: North Carolina
city: Wilmington
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state: North Carolina
city: Winston-Salem
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city: Fargo
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state: North Dakota
city: Cincinnati
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state: Ohio
city: Columbus
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facility: GSK Investigational Site
state: Ohio
city: Columbus
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facility: GSK Investigational Site
state: Ohio
city: Columbus
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facility: GSK Investigational Site
state: Ohio
city: Dayton
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facility: GSK Investigational Site
state: Ohio
city: Eugene
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facility: GSK Investigational Site
state: Oregon
city: Bala-Cynwyd
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facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
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facility: GSK Investigational Site
state: Pennsylvania
city: Greenville
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state: South Carolina
city: Lancaster
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state: South Carolina
city: Union
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facility: GSK Investigational Site
state: South Carolina
city: Milan
country: United States
facility: GSK Investigational Site
state: Tennessee
city: New Tazewell
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Katy
country: United States
facility: GSK Investigational Site
state: Texas
city: Mesquite
country: United States
facility: GSK Investigational Site
state: Texas
city: Missouri City
country: United States
facility: GSK Investigational Site
state: Texas
city: North Richland Hills
country: United States
facility: GSK Investigational Site
state: Texas
city: Plano
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Bountiful
country: United States
facility: GSK Investigational Site
state: Utah
city: Saint George
country: United States
facility: GSK Investigational Site
state: Utah
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Richmond
country: United States
facility: GSK Investigational Site
state: Virginia
city: Richmond
country: United States
facility: GSK Investigational Site
state: Virginia
city: Maroubra
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Sydney
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Tarragindi
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Gabrovo
country: Bulgaria
facility: GSK Investigational Site
city: Haskovo
country: Bulgaria
facility: GSK Investigational Site
city: Kyustendil
country: Bulgaria
facility: GSK Investigational Site
city: Montana
country: Bulgaria
facility: GSK Investigational Site
city: Pleven
country: Bulgaria
facility: GSK Investigational Site
city: Ruse
country: Bulgaria
facility: GSK Investigational Site
city: Shumen
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Stara Zagora
country: Bulgaria
facility: GSK Investigational Site
city: Targovisthe
country: Bulgaria
facility: GSK Investigational Site
city: Aurangabad
country: India
facility: GSK Investigational Site
city: Chandrapur
country: India
facility: GSK Investigational Site
city: Hyderabad
country: India
facility: GSK Investigational Site
city: Mumbai
country: India
facility: GSK Investigational Site
city: Nagpur
country: India
facility: GSK Investigational Site
city: Nagpur
country: India
facility: GSK Investigational Site
city: Nashik
country: India
facility: GSK Investigational Site
city: New Delhi
country: India
facility: GSK Investigational Site
city: Pune
country: India
facility: GSK Investigational Site
city: Rajkot
country: India
facility: GSK Investigational Site
city: Surat
country: India
facility: GSK Investigational Site
city: Ansan-si
country: Korea, Republic of
facility: GSK Investigational Site
city: Goyang-si, Gyeonggi-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Hwasun-gun, Jeollanam-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Incheon
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Suwon
country: Korea, Republic of
facility: GSK Investigational Site
city: Katowice
country: Poland
facility: GSK Investigational Site
city: Ostrowiec Swietokrzyski
country: Poland
facility: GSK Investigational Site
city: Swidnik
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
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.