Safety, Tolerability, Pharmacokinetic and Microbiological Investigation of GSK3882347 in Female Participants With Urinary Tract Infections

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).

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 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.

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.

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.

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.

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.

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.

Clinical symptom score (CSS) measures 4 uncomplicated urinary tract infection (uUTI) symptoms: dysuria, frequency, urgency, and lower abdominal/suprapubic pain. Each symptom is scored from 0 (no symptoms) to 3 (severe). Individual symptom scores are added for a cumulative total score (range 0-12), with higher scores indicating greater severity. Clinical outcome for a visit is categorized based on change of total score from baseline (BL): Clinical Resolution (CR) - Total score decreases from BL to 0; Clinical Improvement (CI) - Total score decreases from BL but is greater than (>) 0; Clinical Worsening (CW) - Total score increases or has no change from BL; or Indeterminate (Ind) - Participant (par.) failed to attend the visit, achieved CR/CI but received systemic antibacterials between BL and the visit day being assessed, or BL score is missing. For a clinical outcome of CR/CI, the par. must not have received another systemic antibacterials between BL and the visit being assessed.

CSS measures 4 uUTI symptoms: dysuria, frequency, urgency, and lower abdominal/suprapubic pain. Each symptom is scored from 0 (no symptoms) to 3 (severe). Individual symptom scores are added for a cumulative total score (range 0-12), with higher scores indicating greater severity. Clinical outcome at ToC is categorized based on change of total score from BL: CR - Total score decreases from BL to 0; CI - Total score decreases from BL but is >0; CW - Total score increases or has no change from BL; Ind - Par. refused a clinical examination, failed to attend the ToC visit, achieved CR or CI but received another systemic antibacterial before ToC, or BL score is missing. For a clinical outcome of CR or CI, the par. must not have received another systemic antibacterial between BL and ToC visit. Clinical response at ToC is defined as "Clinical Success" for an outcome of CR, and "Clinical Failure" for any other outcome (CI, CW, or Ind).

CSS measures 4 uUTI symptoms: dysuria, frequency, urgency, and lower abdominal/suprapubic pain. Individual symptoms (each scored 0 to 3) are added for a total score (0-12), with higher scores indicating greater severity. Clinical outcome at FU is categorized based on change of total score from ToC: Sustained CR (SCR) - ToC and FU=0; Delayed CR (DCR) - FU=0, after >0 at ToC; CI - Total score at FU and ToC>0, with score at FU<ToC; CW - Total score at FU and ToC>0, with score at FU>ToC; Clinical Recurrence (CRr) - Total score >0 at FU after ToC=0; Ind - Par. refused a clinical exam, failed to attend FU, achieved SCR/DCR/CI but received another systemic antibacterials before ToC, or BL score is missing. For a clinical outcome of SCR/DCR/CI, the par. must not have received any systemic antibacterials between BL and FU. Clinical response at FU is defined as "Clinical Success" for an outcome of SCR, and "Clinical Failure" for any other outcome (DCR, CI, CW, CRr, or Ind).

The investigators were asked to record their impression of the clinical status of the participant with regard to the presenting uUTI (resolved/unresolved). Clinical resolution outcome was reported as Clinically Resolved if, in the opinion of the investigator, there was resolution of signs and symptoms of the uUTI present at Baseline (and no worsening and no new signs and symptoms) and no requirement for the use of other antibacterial therapy. Refusal to consent to a clinical examination at a required in-person visit or failure to attend the visit had an outcome of Indeterminate.

The investigators were asked to record their impression of the clinical status of the participant with regard to the presenting uUTI (resolved/unresolved). Clinical resolution response at ToC visit was defined as "Clinical Resolution Success (CRS)" when, in the opinion of the investigator, there was resolution of signs and symptoms of the uUTI present at Baseline (and no worsening and no new signs and symptoms) and no requirement for the use of other antibacterial therapy. "Clinical Resolution Failure (CRF)" was defined when investigator's assessment was Clinically Unresolved/Clinical Worsening or Indeterminate at ToC. Indeterminate was defined as refusal to consent to a clinical examination or failure to attend the ToC visit.

The investigators were asked to record their impression of the clinical status of the participant with regard to the presenting uUTI (resolved/unresolved). Clinical resolution response at FU was defined as "CRS" when investigator's assessment was Clinically Resolved at both ToC and FU (SCR), i.e., resolution of signs and symptoms of the uUTI present at BL (and no worsening and no new signs and symptoms) and no requirement for the use of other antibacterials. "CRF" was defined when investigator's assessment was: Clinically Unresolved at ToC but Clinically Resolved at FU (DCR); Clinically Resolved at ToC but Clinically Unresolved at FU (CRr); Clinically Unresolved at both ToC and FU (CU/CW); or when participants refused to consent to a clinical exam, failed to attend the FU, or achieved SCR/DCR but received other systemic antibacterials before FU (Ind).