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

NCT03568942 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 206899
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

Infections, Bacterial

Keywords

gepotidacin; GSK2140944; acute cystitis; pharmacokinetics; urinary tract infections

Outcome Measures

Primary Outcomes (6)

• Area Under the Plasma Concentration-time Curve (AUC) From Zero (Pre-dose) Over the Dosing Interval (AUC[0-tau]) of Gepotidacin

  Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. PK Parameter Population consisted of all participants who received gepotidacin 1500 mg BID through the completion of all PK collections for whom valid and evaluable plasma PK parameters were derived for gepotidacin.

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

• Maximum Plasma Concentration (Cmax) of Gepotidacin

  Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.

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

• Time of Occurrence of Cmax (Tmax) of Gepotidacin

  Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.

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

• Apparent Steady State Clearance (CLss/F) of Gepotidacin

  Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. CLss/F was calculated as Dose divided by AUC(0-tau).

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

• Accumulation Ratio (Ro) of Gepotidacin

  Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. Accumulation ratio (Ro) was calculated as ratio of AUC(0-tau) at Day 4 to AUC(0-tau) at Day 1.

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

• Plasma Pre-dose Concentration (Ctau) of Gepotidacin

  Blood samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis.

  Days 1 to 5: Pre-dose

Secondary Outcomes (26)

• Amount of Drug Excreted Over 12 Hours (Ae12hours) of Gepotidacin

  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

• Amount of Drug Excreted in Urine in a Time Interval (Ae[t1-t2]) of Gepotidacin

  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

• Percentage of the Given Dose of Drug Excreted in Urine (fe%) of Gepotidacin

  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

• Renal Clearance (CLr) of Gepotidacin

  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

• Urine Pre-dose Concentration (Ctau) of Gepotidacin

  Days 1 to 5: Pre-dose

Study Arms (1)

Female subjects with acute cystitis

EXPERIMENTAL

Adult female subjects with suspected acute cystitis based on clinical presentation and pyuria (\>=10 WBC/mm\^3 or presence of leukocyte esterase) and/or nitrite will be included. Subjects will be administered 1500 mg gepotidacin BID for 5 days via the oral route.

Drug: Gepotidacin

Interventions

Gepotidacin DRUG

Gepotidacin tablets will be available at a dose strength of 750 mg. Tablets will be administered BID with water after consumption of food.

Female subjects with acute cystitis

Eligibility Criteria

• Age: 18 Years - 65 Years
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Biomedical Advanced Research and Development Authority: collaborator

Study Sites (1)

GSK Investigational Site

La Mesa, California, 91942, United States

Location

Related Publications (2)

• 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.

  PMID: 32284384 BACKGROUND

• 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.

  PMID: 34130619 DERIVED

Related Links

• Related Info
• Related Info

MeSH Terms

Conditions

Bacterial Infections; Urinary Tract Infections

Interventions

gepotidacin

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subjects will receive 1500 mg gepotidacin tablets BID via oral route for 5 days.

Study Record Dates

• First Submitted: June 11, 2018
• First Posted: June 26, 2018
• Study Start: July 23, 2018
• Primary Completion: January 7, 2019
• Study Completion: January 7, 2019
• Last Updated: June 29, 2020
• Results First Posted: January 7, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• 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.

Locations

US (1)