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

Study Overview
=================
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.

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)

Conditions
-----------------
Infections, Bacterial

Intervention / Treatment
-----------------
* Drug: Gepotidacin


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Subjects will receive 1500 mg gepotidacin tablets BID via oral route for 5 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Female subjects with acute cystitis<br>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<br>* Gepotidacin tablets will be available at a dose strength of 750 mg. Tablets will be administered BID with water after consumption of food.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of Drug Excreted Over 12 Hours (Ae12hours) of Gepotidacin | Urine samples were collected to evaluate the PK of gepotidacin at the indicated time points. The PK parameters were calculated by standard non-compartmental analysis. Ae12hours was calculated by adding all the fractions of drug collected over all the allotted time intervals. | 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 | Ae(t1-t2) measure the amount of drug excreted in urine in a time intervals 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 on Days 1 and 4. The PK parameters were calculated by standard non-compartmental analysis. | 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 | Urine samples were collected to evaluate the PK of gepotidacin at the indicated time points. fe% was calculated as fe% = (Ae 12 hours/Dose) multiply by 100. The PK parameters were calculated by standard non-compartmental analysis. | 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 | Urine samples were collected to evaluate the PK of gepotidacin at the indicated time points. CLr was calculated as CLr = Ae 12 hours/AUC(0-tau). The PK parameters were calculated by standard non-compartmental analysis. | 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 | Urine 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 | 
| Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious AEs (SAEs) | An AEs is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; and other important medical events which may require medical or surgical intervention. Safety Population consisted of all participants who received at least 1 dose of gepotidacin. | Up to Day 31 | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Vital signs including SBP and DBP were measured in semi-supine position after 5 minutes of rest for the participants in a quiet setting without distractions. Baseline was defined as the latest non-missing value at Day -1 or at Day 1 pre-dose. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 2, Day 3, Day 4, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Pulse Rate | Vital sign including pulse rate was measured in semi-supine position after 5 minutes of rest for the participants in a quiet setting without distractions. Baseline was defined as the latest non-missing value at Day -1 or at Day 1 pre-dose. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 2, Day 3, Day 4, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Body Temperature | Vital sign including body temperature was measured in semi-supine position after 5 minutes of rest for the participants in a quiet setting without distractions. Baseline was defined as the latest non-missing value at Day -1 or at Day 1 pre-dose. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 2, Day 3, Day 4, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| 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) | A 12-lead ECG was measured in semi-supine position using an ECG machine that measured PR interval, QRS duration, QT interval, QTcB and QTcF. Baseline was defined as the latest non-missing value at Day -1 or at Day 1 pre-dose. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. | Baseline; Day 1: 2 hours; Day 4: pre-dose and 2 hours | 
| Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet Counts | Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and Platelet counts. Baseline was defined as Day -1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Hematology Parameter: Hemoglobin | Blood samples were collected to analyze the hematology parameter: Hemoglobin. Baseline was defined as Day -1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Hematology Parameter: Hematocrit | Blood samples were collected to analyze the hematology parameter: Hematocrit. Baseline was defined as Day -1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Hemoglobin | Blood samples were collected to analyze the hematology parameter: Erythrocyte Mean Corpuscular Hemoglobin. Baseline was defined as Day -1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Volume | Blood samples were collected to analyze the hematology parameter: Erythrocyte Mean Corpuscular Volume. Baseline was defined as Day -1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Hematology Parameter: Red Blood Cell Count | Blood samples were collected to analyze the hematology parameter: Red blood cell count. Baseline was defined as Day -1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein | Blood samples were collected to analyze the chemistry parameters: Albumin and Protein. Baseline was defined as Day -1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Clinical Chemistry Parameters: Creatinine and Bilirubin | Blood samples were collected to analyze the chemistry parameters: Creatinine and Bilirubin. Baseline was defined as Day -1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (ALP) | Blood samples were collected to analyze the chemistry parameters: ALT, AST and ALP. Baseline was defined as Day -1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Change From Baseline in Clinical Chemistry Parameters: Glucose, Calcium, Chloride, Potassium, Sodium and Urea | Blood samples were collected to analyze the chemistry parameters: Glucose, Calcium, Chloride, Potassium, Sodium and Urea. Baseline was defined as Day -1. Change from Baseline was calculated by subtracting the post-dose visit value from the Baseline value. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Number of Participants With Urinalysis Dipstick Results: Glucose and Nitrites | Urine samples were collected at indicated time points to analyze parameters including glucose and nitrites by dipstick. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative and positive in the urine sample. Baseline was defined as Day -1. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. Only categories with significant values have been presented. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Number of Participants With Urinalysis Dipstick Results: Ketones | Urine samples were collected at indicated time points to analyze parameter including ketones by dipstick. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative, 5 indicates 5 milligrams per deciliter (mg/dL) and 20 indicates 20 mg/dL in the urine sample. Baseline was defined as Day -1. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. Only categories with significant values have been presented. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Number of Participants With Urinalysis Dipstick Results: Leukocyte Esterase | Urine samples were collected at indicated time points to analyze parameter including leukocyte esterase by dipstick. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative, Trace indicates 15 Leukocytes per microliter (Leuko/mcL), Small indicates 70 Leuko/mcL, Moderate indicates 125 Leuko/mcL and Large indicates 500 Leuko/mcL in the urine sample. Baseline was defined as Day -1. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. Only categories with significant values have been presented. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Number of Participants With Urinalysis Dipstick Results: Occult Blood | Urine samples were collected at indicated time points to analyze parameter including occult blood by dipstick. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative, Small indicates 25 Erythrocytes per microliter (Ery/mcL), Moderate indicates 50 Ery/mcL and Large indicates 250 Ery/mcL in the urine sample. Baseline was defined as Day -1. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. Only categories with significant values have been presented. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Number of Participants With Urinalysis Dipstick Results: Protein | Urine samples were collected at indicated time points to analyze parameter including protein by dipstick. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative indicates <10 mg/dL, 1+ indicates 30 mg/dL and 2+ indicates 100 mg/dL in the urine sample. Baseline was defined as Day -1. Assessment at Test-of-cure visit was conducted between any day of Days 10 to 13. Only categories with significant values have been presented. | Baseline, Day 3, Day 5 and Days 10 to 13 (Test-of-cure visit) | 
| Number of Participants With Abnormal Physical Examination Findings | Physical examinations included assessments of the respiratory, cardiovascular, abdominal, gastrointestinal, neurological and urogenital systems. This analysis was planned but data was not collected and captured in the database. | Up to Day 31 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
gepotidacin, GSK2140944, acute cystitis, pharmacokinetics, urinary tract infections