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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04020341
Recruitment Status : Recruiting
First Posted : July 16, 2019
Last Update Posted : June 28, 2022
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Urinary Tract Infections Drug: Gepotidacin Drug: Placebo matching nitrofurantoin Drug: Nitrofurantoin Drug: Placebo matching gepotidacin Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 17, 2019
Estimated Primary Completion Date : March 13, 2024
Estimated Study Completion Date : March 13, 2024


Arm Intervention/treatment
Experimental: Gepotidacin
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
Drug: Gepotidacin
Gepotidacin will be available as tablets containing 750 mg gepotidacin. Each dose should be taken with water after consumption of food.

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

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.
Drug: Nitrofurantoin
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.

Drug: Placebo matching gepotidacin
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.




Primary Outcome Measures :
  1. Number of participants with therapeutic response (combined per participant clinical and microbiological response) at the Test-of-Cure (TOC) visit [ Time Frame: Days 10 to 13 ]
    A therapeutic success refers to participants who have 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). All other combinations (other than clinical success + microbiological success) are deemed failures for therapeutic response.


Secondary Outcome Measures :
  1. Number of participants with clinical outcome and response at the TOC visit [ Time Frame: Days 10 to 13 ]
    Clinical success (response) is defined as clinical resolution. Clinical resolution (outcome) is defined as 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.

  2. Number of participants with clinical outcome and response at the follow-up visit [ Time Frame: Days 25 to 31 ]
    Clinical success (response) is defined as sustained clinical resolution. Sustained clinical resolution (outcome) is defined as resolution of signs and symptoms of acute cystitis demonstrated at the TOC Visit persist at the Follow-up Visit (and no new signs and symptoms), without the participant receiving other systemic antimicrobials before the Follow-up visit.

  3. Number of participants with per participant microbiological outcome and response at the TOC visit [ Time Frame: Days 10 to 13 ]
    Participant-level microbiological success (response) is defined as microbiological eradication. Microbiological eradication (outcome) is defined as reduction of all qualifying bacterial uropathogens [>=10^5 CFU/mL] recovered at Baseline to <10^3 CFU/mL as observed on quantitative urine culture without the participant receiving other systemic antimicrobials before the TOC Visit.

  4. Number of participants with per participant microbiological outcome and response at the follow-up visit [ Time Frame: Days 25 to 31 ]
    Participant-level microbiological success (response) is defined as sustained microbiological eradication. Sustained microbiological eradication (outcome) is defined as reduction of all qualifying bacterial uropathogens [>=10^5 CFU/mL] recovered at Baseline to <10^3 CFU/mL as observed on quantitative urine culture, following microbiological eradication at the TOC Visit, without the participant receiving other systemic antimicrobials before the TOC Visit.

  5. Number of participants with therapeutic response (combined per participant clinical and microbiological response) at the follow-up visit [ Time Frame: Days 25 to 31 ]
    A therapeutic success refers to participants who have been deemed both a "microbiological success" (sustained microbiological eradication) and a "clinical success" (sustained symptom resolution). All other combinations (other than clinical success + microbiological success) will be deemed failures for therapeutic response.

  6. Plasma concentration of gepotidacin [ Time Frame: Up to Day 5 ]
  7. Urine concentration of gepotidacin [ Time Frame: Up to Day 5 ]
  8. Number of participants with Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) [ Time Frame: Up to Day 31 ]
  9. Change from Baseline in hematology parameters: neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count and platelet count (Giga cells per Liter) [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  10. Change from Baseline in hematology parameter: hemoglobin level [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  11. Change from Baseline in hematology parameter: hematocrit level [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  12. Change from Baseline in hematology parameter: Red blood cell (RBC) count [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  13. Change from Baseline in hematology parameter: Mean corpuscular hemoglobin (MCH) [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  14. Change from Baseline in hematology parameter: Mean corpuscular volume (MCV) [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  15. Change from Baseline in clinical chemistry parameters: Blood urea nitrogen (BUN), glucose non-fasting, calcium, chloride, sodium, magnesium, phosphorus and potassium levels (Millimoles per Liter) [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  16. Change from Baseline in clinical chemistry parameters: Total bilirubin, direct bilirubin and creatinine levels (Micromoles per Liter) [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  17. Change from Baseline in clinical chemistry parameters: Albumin and total protein levels (Gram per Liter) [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  18. Change from Baseline in clinical chemistry parameters: Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase levels (International units per Liter) [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  19. Number of participants with abnormal urinalysis Dipstick results [ Time Frame: Days 10 to 13 ]
  20. Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (Millimeters of mercury [mmHg]) [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  21. Change from Baseline in pulse rate [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]
  22. Change from Baseline in body temperature [ Time Frame: Baseline, On-Therapy (Days 2 to 4), and Test of cure (Days 10 to 13) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04020341


Contacts
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Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

Locations
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Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT04020341    
Other Study ID Numbers: 204989
First Posted: July 16, 2019    Key Record Dates
Last Update Posted: June 28, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
Acute cystitis
Efficacy
Gepotidacin
Nitrofurantoin
Urinary Tract Infection
Simple cystitis
Additional relevant MeSH terms:
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Infections
Communicable Diseases
Urinary Tract Infections
Disease Attributes
Pathologic Processes
Urologic Diseases
Nitrofurantoin
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Anti-Bacterial Agents