Clinical trial NCT03568942: Pharmacokinetic Study of Oral Gepotidacin (GSK2140944) in Subjects With Uncomplicated Urinary Tract Infection (Acute Cystitis)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infections, Bacterial
Keywords: gepotidacin
GSK2140944
acute cystitis
pharmacokinetics
urinary tract infections
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Biomedical Advanced Research and Development Authority
First posted: 2018-06-26
Enrollment: 22
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Subjects will receive 1500 mg gepotidacin tablets BID via oral route for 5 days.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: Area Under the Plasma Concentration-time Curve (AUC) From Zero (Pre-dose) Over the Dosing Interval (AUC[0-tau]) of Gepotidacin
timeFrame: Days 1 and 4: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose
measure: Maximum Plasma Concentration (Cmax) of Gepotidacin
timeFrame: Days 1 and 4: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose
measure: Time of Occurrence of Cmax (Tmax) of Gepotidacin
timeFrame: Days 1 and 4: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose
measure: Apparent Steady State Clearance (CLss/F) of Gepotidacin
timeFrame: Day 4: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose
measure: Accumulation Ratio (Ro) of Gepotidacin
timeFrame: Days 1 and 4: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose
measure: Plasma Pre-dose Concentration (Ctau) of Gepotidacin
timeFrame: Days 1 to 5: Pre-dose
Secondary outcomes:
measure: Amount of Drug Excreted Over 12 Hours (Ae12hours) of Gepotidacin
timeFrame: Days 1 and 4: Pre-dose and at 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours post-dose
measure: Amount of Drug Excreted in Urine in a Time Interval (Ae[t1-t2]) of Gepotidacin
timeFrame: Days 1 and 4: Pre-dose and at 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours post-dose
measure: Percentage of the Given Dose of Drug Excreted in Urine (fe%) of Gepotidacin
timeFrame: Days 1 and 4: Pre-dose and at 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours post-dose
measure: Renal Clearance (CLr) of Gepotidacin
timeFrame: Days 1 and 4: Pre-dose and at 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours, and 10 to 12 hours post-dose
measure: Urine Pre-dose Concentration (Ctau) of Gepotidacin
timeFrame: Days 1 to 5: Pre-dose
measure: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious AEs (SAEs)
timeFrame: Up to Day 31
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline, Day 2, Day 3, Day 4, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline, Day 2, Day 3, Day 4, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Body Temperature
timeFrame: Baseline, Day 2, Day 3, Day 4, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Electrocardiogram (ECG) Parameters: PR Interval, QRS Duration, QT Interval, Corrected QT Interval Using Bazett's Formula (QTcB) and Corrected QT Interval Using Fridericia's Formula (QTcF)
timeFrame: Baseline; Day 1: 2 hours; Day 4: pre-dose and 2 hours
measure: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet Counts
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Hematology Parameter: Hemoglobin
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Hemoglobin
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Volume
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Hematology Parameter: Red Blood Cell Count
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Clinical Chemistry Parameters: Creatinine and Bilirubin
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (ALP)
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Change From Baseline in Clinical Chemistry Parameters: Glucose, Calcium, Chloride, Potassium, Sodium and Urea
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Number of Participants With Urinalysis Dipstick Results: Glucose and Nitrites
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Number of Participants With Urinalysis Dipstick Results: Ketones
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Number of Participants With Urinalysis Dipstick Results: Leukocyte Esterase
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Number of Participants With Urinalysis Dipstick Results: Occult Blood
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Number of Participants With Urinalysis Dipstick Results: Protein
timeFrame: Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit)
measure: Number of Participants With Abnormal Physical Examination Findings
timeFrame: Up to Day 31
Other outcomes:
Locations:
city: La Mesa
country: United States
facility: GSK Investigational Site
state: California
Study officials:
affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Overcash JS, Tiffany CA, Scangarella-Oman NE, Perry CR, Tao Y, Hossain M, Barth A, Dumont EF. Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants with Uncomplicated Urinary Tract Infection (Acute Uncomplicated Cystitis). Antimicrob Agents Chemother. 2020 Jun 23;64(7):e00199-20. doi: 10.1128/AAC.00199-20. Print 2020 Jun 23.
citation: Nuzzo A, Van Horn S, Traini C, Perry CR, Dumont EF, Scangarella-Oman NE, Gardiner DF, Brown JR. Microbiome recovery in adult females with uncomplicated urinary tract infections in a randomised phase 2A trial of the novel antibiotic gepotidacin (GSK140944). BMC Microbiol. 2021 Jun 15;21(1):181. doi: 10.1186/s12866-021-02245-8.