Last updated: 07/17/2024 17:32:16

Pharmacokinetic Study of Oral Gepotidacin (GSK2140944) in Subjects With Uncomplicated Urinary Tract Infection (Acute Cystitis)

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GSK study ID
206899
See study documents
Clinicaltrials.gov ID
NCT03568942
See results summary
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Overview
Eligibility
Locations
Study documents
Results summary
Plain language summaries
Additional information

Trial overview

Official title: A Phase IIa Single-Center, Open-Label Study Evaluating the Pharmacokinetics of Repeat Oral Doses of Gepotidacin (GSK2140944) in Adult Female Participants With Uncomplicated Urinary Tract Infection (Acute Cystitis)
Trial description: Gepotidacin (GSK2140944) is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor that is being developed for the treatment of uncomplicated urinary tract infections (UTIs; acute cystitis). This Phase IIa study will evaluate plasma and urine pharmacokinetics of gepotidacin in female subjects with acute cystitis. Eligible female subjects will receive twice daily (BID) dose of gepotidacin 1500 milligram (mg) for 5 days via oral route. Pre-treatment and post-treatment samples for pharmacokinetic (PK) assessments will be collected throughout the study. The total duration of the study is approximately 28 days.
Primary purpose:
Treatment
Trial design:
Single Group Assignment
Masking:
None (Open Label)
Allocation:
Not applicable
Primary outcomes:

Area under the concentration-time curve (AUC) from zero (predose) over the dosing interval (AUC[0-tau]) of gepotidacin

Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post-dose on Days 1 and 4.

Maximum plasma concentration (Cmax) of gepotidacin

Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post-dose on Days 1 and 4.

Time of occurrence of Cmax (tmax) of gepotidacin

Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post-dose on Days 1 and 4.

Apparent steady state clearance (CLss/F) of gepotidacin

Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 4.

Accumulation ratio (Ro) of gepotidacin

Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 4.

Plasma pre-dose concentration (Ctau) of gepotidacin

Timeframe: Pre-dose on Days 1, 2, 3, 4 and 5

Secondary outcomes:

Amount of drug excreted in urine over 12 hours (Ae 12h)

Timeframe: Pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose on Days 1 and 4

Amount of drug excreted in urine in a time interval (Ae[t1-t2])

Timeframe: Pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose on Days 1 and 4

Percentage of the given dose of drug excreted in urine (fe%)

Timeframe: Pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose on Days 1 and 4

Renal clearance (CLr) of gepotidacin

Timeframe: Pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose on Days 1 and 4

Urine pre-dose concentration (Ctau) on Days 1 through 5

Timeframe: Pre-dose on Days 1, 2, 3, 4 and 5

Number of subjects with treatment-emergent adverse events (AEs) and serious adverse events (SAEs)

Timeframe: Up to Day 31

Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)

Timeframe: Baseline and up to Day 13

Change from Baseline in temperature

Timeframe: Baseline and up to Day 13

Change from Baseline in pulse rate

Timeframe: Baseline and up to Day 13

Change from Baseline in electrocardiogram (ECG) measurement

Timeframe: Baseline and up to Day 4

Change from Baseline in neutrophil, lymphocyte, monocyte, eosinophil, basophil and platelet count

Timeframe: Baseline and up to Day 13

Change from Baseline in hemoglobin level

Timeframe: Baseline and up to Day 13

Change from Baseline in mean corpuscular hemoglobin (MCH)

Timeframe: Baseline and up to Day 13

Change from Baseline in mean corpuscular volume (MCV)

Timeframe: Baseline and up to Day 13

Change from Baseline in hematocrit level

Timeframe: Baseline and up to Day 13

Change from Baseline in red blood cell (RBC) count

Timeframe: Baseline and up to Day 13

Change from Baseline in albumin and total protein levels

Timeframe: Baseline and up to Day 13

Change from Baseline in creatinine, total bilirubin and direct bilirubin levels

Timeframe: Baseline and up to Day 13

Change from Baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels

Timeframe: Baseline and up to Day 13

Change from Baseline in blood urea nitrogen (BUN), glucose, chloride, potassium, sodium and calcium

Timeframe: Baseline and up to Day 13

Change from Baseline in specific gravity of urine

Timeframe: Baseline and up to Day 13

Change from Baseline in potential of hydrogen (pH) of urine

Timeframe: Baseline and up to Day 13

Change from Baseline in glucose, protein, blood, ketone, nitrite and leukocyte esterase levels in urine

Timeframe: Baseline and up to Day 13

Number of subjects with abnormal physical examination results

Timeframe: Up to Day 13

Interventions:
  • Drug: Gepotidacin
    • Enrollment:
    22
    Primary completion date:
    2019-07-01
    Observational study model:
    Not applicable
    Time perspective:
    Not applicable
    Clinical publications:
    J. Scott Overcash, Courtney Tiffany, Nicole Scangarella-Oman, Caroline Perry, Yu Tao, Mohammad Hossain, Aline Barth, Etienne Dumont. Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants With Uncomplicated Urinary Tract Infection (Acute Cystitis). Antimicrob Agents Chemother. 2020 DOI: 10.1128/AAC.00199-20
    Medical condition
    Infections, Bacterial
    Product
    gepotidacin
    Collaborators
    BARDA
    Study date(s)
    July 2018 to January 2019
    Type
    Interventional
    Phase
    2

    Participation criteria

    Sex
    Female
    Age
    18 - 65 years
    Accepts healthy volunteers
    No
    • Subject must be >=18 to <=65 years of age inclusive, at the time of signing the informed consent.
    • The subject has 2 or more of the following clinical signs and symptoms of acute cystitis with onset <=72 hours of the screening assessment: dysuria, frequency, urgency, or lower abdominal pain.
    • The subject resides in a nursing home or dependent care-type facility.
    • The subject has a body mass index >=40.0 kilogram per square meter (kg/m^2) or a body mass index >=35.0 kg/m^2 with obesity-related health conditions such as high blood pressure or uncontrolled diabetes.
    Inclusion and exclusion criteria
    Inclusion criteria:
    • Subject must be >=18 to <=65 years of age inclusive, at the time of signing the informed consent.
    • The subject has 2 or more of the following clinical signs and symptoms of acute cystitis with onset <=72 hours of the screening assessment: dysuria, frequency, urgency, or lower abdominal pain.
    • The subject has pyuria (>=10 white blood cells per cubic millimeters [WBC/mm^3] or the presence of leukocyte esterase) and/or nitrite from a pretreatment clean-catch midstream urine sample based on local laboratory procedures.
    • The subject is female. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: a) Not a woman of childbearing potential (WOCBP) OR b) A WOCBP who agrees to follow the contraceptive guidance from the Baseline Visit through completion of the Test of Cure (TOC) Visit.
    • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.
    Exclusion criteria:
    • The subject resides in a nursing home or dependent care-type facility.
    • The subject has a body mass index >=40.0 kilogram per square meter (kg/m^2) or a body mass index >=35.0 kg/m^2 with obesity-related health conditions such as high blood pressure or uncontrolled diabetes.
    • The subject 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 subject is immunocompromised or has altered immune defenses that may predispose the subject to a higher risk of treatment failure and/or complications (e.g., renal transplant recipients, subjects with clinically significant persistent granulocytopenia [absolute neutrophil count <1000/microliter (µL)], and subjects receiving immunosuppressive therapy, including corticosteroid therapy [>40 mg/day prednisolone or equivalent for >1 week or >=20 milligrams per day (mg/day) prednisolone or equivalent for >6 weeks; or prednisolone or equivalent >=10 mg/day for >6 weeks]). Subjects with a known cluster of differentiation 4 (CD4) count of <200 cells/mm^3 should not be enrolled.
    • The subject has uncontrolled diabetes, defined as a non-fasting glucose value >300 milligrams per deciliter (mg/dL) or based on investigator judgment.
    • The subject has any of the following: A medical condition that requires medication that may be aggravated by inhibition of acetylcholinesterase, such as: a) Poorly controlled asthma or chronic obstructive pulmonary disease at Baseline and, in the opinion of the investigator, not stable on current therapy; b) Acute severe pain, uncontrolled with conventional medical management; c) Active peptic ulcer disease; d) Parkinson disease; e) Myasthenia gravis; f) 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 drug (e.g., ileostomy or malabsorption syndrome). Subjects who have had a gastric bypass or a cholecystectomy are excluded from the study OR Hemoglobin value <12 grams per deciliter (g/dL) or a known uncorrected iron deficiency.
    • The subject, in the judgment of the investigator, would not be able or willing to comply with the protocol or complete study follow-up.
    • The subject has a serious underlying disease that could be imminently life threatening, or the subject is unlikely to survive for the duration of the study period.
    • The subject 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 [E. coli]) as the contributing pathogen.
    • The subject has symptoms known or suspected to be caused by another disease process such as asymptomatic bacteriuria or chronic interstitial cystitis.
    • The subject has an anatomical or physiological anomaly that predisposes the subject 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 subject has a history of anatomical or functional abnormalities of the urinary tract (e.g., chronic vesico-ureteral reflux, detrusor insufficiency).
    • The subject has an indwelling catheter, nephrostomy, ureter stent, or other foreign material in the urinary tract.
    • The subject who, in the opinion of the investigator, has an otherwise complicated UTI, an active upper UTI (e.g., pyelonephritis, urosepsis), signs and symptoms onset >=96 hours before the Screening assessment, or a temperature >=101 degree Fahrenheit, flank pain, chills, or any other manifestations suggestive of upper UTI.
    • The subject has anuria, oliguria, or significant impairment of renal function (creatinine clearance <30 milliliters per minute [mL/min] or clinically significant elevated serum creatinine).
    • The subject presents with vaginal discharge at Baseline (e.g., suspected sexually transmitted disease).
    • The subject has congenital long QT syndrome or known prolongation of the corrected QT (QTc) interval.
    • The subject has uncompensated heart failure, defined as New York Heart Association Class >=III.
    • The subject has severe left ventricular hypertrophy.
    • The subject has a family history of QT prolongation or sudden death.
    • The subject has a recent history of vasovagal syncope or episodes of symptomatic bradycardia or bradyarrhythmia within the last 12 months.
    • The subject is taking QT-prolonging drugs or drugs known to increase the risk of torsades de points (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 subject is taking a strong cytochrome P450 enzyme 3A4 (CYP3A4) inhibitor or a strong P-glycoprotein (P-gp) inhibitor.
    • The subject has a QT interval corrected for heart rate (QTc) >450 milliseconds (msec) or a QTc >480 msec for subjects with bundle-branch block.
    • The subject has a known ALT value >2 times upper limit of normal (ULN).
    • The subject 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%).
    • The subject 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).
    • The subject has received treatment with other systemic antimicrobials or systemic antifungals within 1 week before study entry.
    • The subject must agree not to use the medications or nondrug therapies from the Baseline Visit through the TOC Visit.
    • The subject has been previously enrolled in this study or has previously been treated with gepotidacin.
    • The subject has participated in a clinical trial and has received an investigational product within 30 days or 5 half-lives, whichever is longer.

    Trial location(s)

    Location
    Status
    Contact us
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    Location
    GSK Investigational Site
    La Mesa, California, United States, 91942
    Status
    Study Complete
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    Study documents

    Protocol
    Available language(s): English
    Download document(s)
    Statistical analysis plan
    Available language(s): English
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    If you wish to request for full study report, please contact - [email protected]

    Results overview

    Results posted on ClinicalTrials.gov

    Recruitment status
    Study complete
    Actual primary completion date
    2019-07-01
    Actual study completion date
    2019-07-01

    Plain language summaries

    Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.

    Additional information about the trial

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