Uncomplicated Urinary Tract Infections, Urinary Tract Infections
Conditions
Keywords
Microbiological response, Urinary tract infections (UTI), GSK3882347, Nitrofurantoin, Pharmacokinetics, Escherichia coli (E. coli)
Brief summary
This phase 1b study is a double-blind, double-dummy, nitrofurantoin-controlled study designed to evaluate microbiological response at the test of cure (ToC) visit along with safety, tolerability and pharmacokinetic (PK) response following oral dosing for 5 days of GSK3882347 in an adult female with uncomplicated urinary tract infections (uUTI). Comparator nitrofurantoin will be included in the study to ensure unbiased reporting of safety events. The study will be separated into 2 cohorts. Cohort 1 consists of an inpatient treatment period and PK analysis at frequent timepoints. Cohort 2 includes an outpatient treatment period and PK analysis conducted less frequently, at key trough timepoints.
Interventions
DRUGGSK3882347
GSK3882347 was administered.
DRUGNitrofurantoin
Nitrofurantoin was administered.
DRUGPlacebo
Placebo matching GSK3882347 or Nitrofurantoin was administered.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
This will be a randomized double-blind study with both participants and site staff blinded.
Intervention model description
This will be a randomized double-blind study and participants will be randomized to receive either GSK3882347 or nitrofurantoin in a 3:1 allocation ratio using an interactive response technology (IRT).
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Participants must be greater than or equal to (\>=)18 years of age and less than or equal to (\<=)70 years * The participant has 2 or more of the following clinical signs and symptoms of uncomplicated urinary tract infections (uUTI) with onset less than (\<) 96 hours of the screening assessment: dysuria, frequency, urgency, or lower abdominal pain * Participant has nitrite OR pyuria (≥ 10 white blood cells/ cubic millimeter \[WBC/mm\^3\], OR \> 5 WBC/high power field \[HPF\]) OR the presence of 2+ leukocyte esterase from a pre-treatment clean-catch midstream urine sample * Participants with body mass index (BMI) \>= 19.0 kilograms per square meter (kg/m\^2) * A female participant is eligible to participate who is not pregnant (as confirmed by a highly sensitive pregnancy test before the first dose of study intervention) or breastfeeding and one of the following conditions apply: 1) Woman participant of non-childbearing potential (WONCBP) Or 2) Woman participant of childbearing potential (WOCBP) using a contraceptive method that is highly effective, with a failure rate of \< 1 percentage (%), during the study intervention period and up to 5 days post intervention * 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 participant has a BMI \>= 40.0 kg/ m\^2 or a BMI \>=35.0 kg/ m\^2 with obesity related health conditions such as high blood pressure or uncontrolled diabetes (non-fasting glucose value \>300 milligram/deciliter \[mg/dL\]) * The participant is immunocompromised or has altered immune defenses that may predispose the participant to a higher risk of treatment failure and/or complications * The 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 * The 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 of the urinary tract, primary renal disease, or neurogenic bladder, or the participant has a history of anatomical or functional abnormalities of the urinary tract * The participant has an indwelling catheter, nephrostomy, ureteral stent, or other foreign material in the urinary tract * The participant 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 (°F) (\>=38 degree Celsius \[°C\]), flank pain, chills, or any other manifestations suggestive of upper UTI * The participant has anuria, oliguria, or significant impairment of renal function * The participant presents at enrollment with a suspected sexually transmitted infection * A positive confirmation of Coronavirus Disease 2019 (COVID-19) infection, or high clinical index of suspicion for COVID-19 * The participant has received treatment with other systemic antimicrobials or systemic antifungals within 1 week or 10 weeks for dalbavancin or oritavancin before study entry. * Regular alcohol consumption within 6 months prior to the study with an average weekly intake of \>14 units for females and one unit is equivalent to approximately 8 g of alcohol: a half-pint (250 mL) of beer, one glass (125 mL) of wine or one (35 mL) measure of spirits * Unable to take nitrofurantoin. E.g. hypersensitivity to the active substance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Microbiological Response at the Test of Cure (ToC) Visit | Day 10 to Day 13 (ToC Visit) | Microbiological response (success/failure) is used to measure microbiological efficacy. Microbiological success was defined as a reduction in E. coli count to less than (\<) 10\^3 colony-forming units (CFU) per milliliter (CFU/mL) for any E. coli at the ToC visit. Microbiological failure included all other microbiological outcomes (for example but not limited to \>=10\^3 CFU/mL for any E. coli identified at ToC visit, use of rescue medication prior to ToC, lost to follow-up before ToC, missing/unevaluable samples at ToC, etc). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | From the first dose of study intervention up to Follow-up Visit (up to Day 31) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. |
| Number of Participants With Serious AEs (SAEs) | From the signing of informed consent up to Follow-up Visit (up to Day 31) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is 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 or incapacity; is a congenital anomaly or birth defect; or any other situation according to the medical or scientific judgment of the investigator. |
| Number of Participants With Clinically Significant Changes in Vital Signs Findings | Up to Day 31 | Vital signs included tympanic-measured temperature, pulse and respiratory rate, systolic and diastolic blood pressure. Blood pressure and pulse measurements were assessed in a semi-supine or seated position with a completely automated device and were measured after at least 10 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of any change in vital signs was determined by the investigator. |
| Number of Participants With Clinically Significant Changes in Electrocardiograms (ECG) Findings | Up to Day 31 | Twelve-lead ECGs were obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. Clinical significance of any change in ECG findings was determined by the investigator. |
| Number of Participants With Clinically Significant Changes in Hematology Parameters | Up to Day 31 | Blood samples were collected for hematology parameters including platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, reticulocytes, white blood cell (WBC) count (neutrophils, lymphocytes, monocytes, eosinophils, basophils). Clinical significance of any change in hematology parameters was determined by the investigator. |
| Number of Participants With Clinically Significant Changes in Chemistry Parameters | Up to Day 31 | Blood samples were collected for chemistry parameters including blood urea nitrogen (BUN), creatinine (including estimated glomerular filtration rate \[eGFR\]), glucose (non-fasting), potassium, sodium, calcium, total and direct bilirubin, total protein, aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT), and alkaline phosphatase. Clinical significance of any change in clinical chemistry parameters was determined by the investigator. |
| Number of Participants With Clinically Significant Changes in Urinalysis Parameters | Up to Day 31 | Urine samples were collected for the analysis of urine parameters including specific gravity, potential of hydrogen (pH), glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase, microscopic examination (if blood or protein was abnormal), and protein/creatinine ratio. Clinical significance of any change in urinalysis parameters was determined by the investigator. |
| Cohort 1: Plasma Concentration at the End of the Dosing Interval Tau (Ctau) of GSK3882347 Post-dose on Day 1 and Day 5 | 24 hours post-dose on Day 1 and Day 5 | — |
| Cohort 1: Urine Concentration of GSK3882347 at 22-24-hour (h) Interval Collection Post-dose on Day 1 and Day 5 | 22-24 hour interval post-dose on Day 1 and Day 5 | — |
| Cohort 2: Plasma Ctau of GSK3882347 Post-dose on Day 1 and Day 5 | 24 hours post-dose on Day 1 and Day 5 | — |
| Cohort 2: Urine Concentration of GSK3882347 at 22-24h Interval Collection Post-dose on Day 1 and Day 5 | 22-24 hour interval post-dose on Day 1 and Day 5 | — |
Countries
United States
Contacts
STUDY_DIRECTORGSK Clinical Trials
GlaxoSmithKline
Participant flow
Pre-assignment details
140 participants were randomized to one of the study treatments. Due to potential data quality issues, 14 participants were excluded from the analyses presented.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 44.0 YEARS STANDARD_DEVIATION 14.89 |
| Race/Ethnicity, Customized Asian | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized White | 106 Participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 91 |
| other Total, other adverse events | 10 / 31 | 22 / 91 |
| serious Total, serious adverse events | 0 / 31 | 0 / 91 |
Outcome results
None listed