Safety, Tolerability and Pharmacokinetic Investigation of GSK3882347 in Healthy Participants.

A Double-Blind Randomized, Placebo-Controlled, Single and Repeated Oral Dose Escalation Study to Investigate the Safety, Tolerability, Pharmacokinetics (Including Food Effect) of GSK3882347 in Healthy Participants

This is a phase 1, 2-part, double-blind (sponsor-unblinded), randomized, placebo-controlled, first time in human (FTIH) study, that includes both single-ascending and multiple-ascending dose phase to assess the safety, tolerability, and pharmacokinetics (PK) of GSK3882347 in healthy adult men and Woman of Non Childbearing Potential (WONCBP). Part 1 will be the single ascending dose (SAD) phase and Part 2 will be the multiple ascending dose (MAD) phase. Each participant in the SAD cohort will receive a single dose of GSK3882347 or placebo (PBO) in 3:1 ratio and in Part 2 (MAD), participants will be randomized in a 4:1 ratio to receive active treatment and placebo. Part 1 will consist of two cohorts with a maximum of four-period for each cohort, the food effect evaluation will be conducted in last period (Period 4) in only one of the cohorts based on the observed human pharmacokinetics (PK). Part 2 will consist of maximum of four cohorts for each of the MAD dose or placebo.

Study Overview

• Status: Completed
• Conditions: Urinary Tract Infections
• Intervention / Treatment: Drug: GSK3882347; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB2 2GG
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent.
• Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. A participant with a clinical abnormality or laboratory parameter(s) not specifically listed in the exclusion or exclusion criteria that is outside the reference range for the population being studied may be included only if the investigator, in consultation with the Medical Monitor (if required), agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Participants with Body weight at least 50.0 kilograms (kg) (110 pound [lbs]) for males and 45.0 kg (99 lbs.) for females; and body mass index (BMI) within the range 18.5 - 32.0 kilograms per meter square (kg/m^2) (inclusive).
• Male and female participants; a female participant is eligible to participate if she is of WONCBP; Male participants are eligible to participate if they agree to the following during the intervention period for at least five days, corresponding to time needed to eliminate study intervention(s) (e.g. 5 terminal half-lives) after the last dose of study intervention), refrain from donating sperm, be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; must agree to use contraception/barrier, agree to use a male condom.
• Capable of giving signed informed consent as described in which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

• Participants with history or presence of cardiovascular, respiratory, hepatic, urological, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data
• Alanine transaminase (ALT) greater than 1.5 times upper limit of normal (ULN).
• Bilirubin greater than 1.5 times ULN (isolated bilirubin greater than1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin is less than 35%)
• Current or chronic history of liver disease or known hepatic or biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones).
• Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
• Male participants with heart rate of less than 45 or greater than 100 beats per minute (bpm), females with less than 50 or greater than 100 bpm.
• Participants with PR interval less than 120 or greater than 220 milliseconds (msec); QRS duration less than 70 msec or greater than 120 msec; QTcF interval greater than 450 msec.
• Evidence of previous myocardial infarction on ECG (does not include ST segment changes associated with re-polarization).
• Any conduction abnormality (including but not specific to left or right complete bundle branch block, atrioventricular (AV) block [2nd degree or higher], Wolff-Parkinson-White [WPW] syndrome).
• Sinus Pauses greater than 3 seconds.
• Any significant arrhythmia which, in the opinion of the Investigator or GSK Medical Monitor, will interfere with the safety for the individual participant.
• Non-sustained or sustained ventricular tachycardia (3 consecutive ventricular ectopic beats).
• Current or history of renal disease, or estimated creatinine clearance <90 milliliter (mL)/minute/1.73meter^2 or serum creatinine greater than ULN at screening.
• Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the first dose of study intervention, unless in the opinion of the Investigator and the GSK medical monitor, the medication will not interfere with the study procedures or compromise participant safety.
• Use of a systemic antimicrobial within 30 days of screening.
• Participation in the study would result in loss of blood or blood products in excess of 500 mL within 56 days.
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
• Current enrolment or past participation within the last 30 days before signing of consent in any other clinical study involving an investigational study intervention or any other type of medical research.
• Positive human immunodeficiency virus (HIV) antibody test.
• Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention.
• Positive Hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.
• Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study intervention.
• Positive pre-study drug/alcohol screen.
• Any history of substance abuse or a positive test for drugs of abuse at screening or admission.
• A positive highly sensitive pregnancy test (urine or serum as required by local regulations) at screening.
• A positive laboratory confirmation of COVID-19 infection, or high clinical index of suspicion for COVID-19.
• Part 1 (Food Effect): Participant must have no dietary restrictions (e.g., lactose intolerance) or inability to eat a high fat meal.
• Regular alcohol consumption within 6 months prior to the study defined as: An average weekly intake of greater than 21 units for males or greater than 14 units for females. One unit is equivalent to approximately (250 mL) of beer, (100 mL) of wine or (35 mL) measure of spirits.
• Positive smoke breathalyzer indicative of smoking history at screening and each in-house admission to the clinical research unit or regular use of tobacco- or nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 months prior to screening.
• Hypersensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 (SAD) Cohort 1:Participants receiving GSK3882347; In this single ascending dose phase, participants will receive GSK3882347 50 milligram (mg), 150 mg and 250 mg orally on Day 1 of period 1, 2 and 3 respectively. Period 4 will be conducted to assess food effect based on the observed human PK.	Drug: GSK3882347; Capsule of 10-200mg dose strength will be provided in labelled High Density Polyethylene (HDPE) bottles.
Placebo Comparator: Part 1 (SAD),Cohort 1:Participants receiving Placebo; In this single ascending dose phase, participants will receive matching Placebo orally on Day 1 of period 1, 2 and 3. Period 4 will be conducted to assess food effect based on the observed human PK.	Drug: Placebo; Matching strength placebo capsules will be provided
Experimental: Part 1 (SAD),Cohort 2: Participants receiving GSK3882347; In this single ascending dose phase, participants will receive GSK3882347 500 mg, 15 mg and 900 mg orally on Day 1 of period 1, 3 and 2 respectively.	Drug: GSK3882347; Capsule of 10-200mg dose strength will be provided in labelled High Density Polyethylene (HDPE) bottles.
Placebo Comparator: Part 1 (SAD),Cohort 2: Participants receiving Placebo; In this single ascending dose phase, participants will receive matching Placebo orally on Day 1 of period 1, 3 and 2.	Drug: Placebo; Matching strength placebo capsules will be provided
Experimental: Part 2 (MAD),Cohort 3: Participants receiving GSK3882347 50mg; In this multiple ascending dose phase, participants will receive GSK3882347 50 mg orally on Day 1 to Day 7 of the study. The dose to be administered may be changed based on clinical safety, tolerability and PK findings in Part 1.	Drug: GSK3882347; Capsule of 10-200mg dose strength will be provided in labelled High Density Polyethylene (HDPE) bottles.
Placebo Comparator: Part 2 (MAD),Cohort 3: Participants receiving Placebo; In this multiple ascending dose phase, participants will receive matching Placebo orally on Day 1 to Day 7 of the study.	Drug: Placebo; Matching strength placebo capsules will be provided
Experimental: Part 2 (MAD),Cohort 4: Participants receiving GSK3882347 150mg; GSK3882347 150 mg will be administered orally to the participants on Day 1 to day 7 of the study. This is a projected dose. The dose administered in Part 2, Cohort 4 will be based on PK/PD results from preceding dosing cohorts.	Drug: GSK3882347; Capsule of 10-200mg dose strength will be provided in labelled High Density Polyethylene (HDPE) bottles.
Placebo Comparator: Part 2 (MAD),Cohort 4: Participants receiving Placebo; In this multiple ascending dose phase, participants will receive matching Placebo orally on Day 1 to Day 7 of the study.	Drug: Placebo; Matching strength placebo capsules will be provided
Experimental: Part 2(MAD),Cohort 5: Participants receiving GSK3882347 500mg; GSK3882347 500 mg will be administered orally to the participants on Day 1 to day 7 of the study. This is a projected dose. The dose administered in Part 2, Cohort 5 will be based on PK/PD results from preceding dosing cohorts.	Drug: GSK3882347; Capsule of 10-200mg dose strength will be provided in labelled High Density Polyethylene (HDPE) bottles.
Placebo Comparator: Part 2 (MAD),Cohort 5: Participants receiving Placebo; In this multiple ascending dose phase, participants will receive matching Placebo orally on Day 1 to Day 7 of the study.	Drug: Placebo; Matching strength placebo capsules will be provided
Experimental: Part 2(MAD),Cohort 6: Participants receiving GSK3882347 900mg; GSK3882347 900 mg will be administered orally to the participants on Day 1 to day 7 of the study. This is a projected dose. The dose administered in Part 2, Cohort 6 will be based on PK/PD results from preceding dosing cohorts.	Drug: GSK3882347; Capsule of 10-200mg dose strength will be provided in labelled High Density Polyethylene (HDPE) bottles.
Placebo Comparator: Part 2(MAD),Cohort 6: Participants receiving Placebo; In this multiple ascending dose phase, participants will receive matching Placebo orally on Day 1 to Day 7 of the study.	Drug: Placebo; Matching strength placebo capsules will be provided

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)	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/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Number of participants with common (greater than or equal to [>=]5 percent [%]) non-serious AEs is presented.	Up to 3 months
Part 2: Number of Participants With Non-serious AEs and SAEs	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/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Number of participants with common (>=5%) non-serious AEs is presented.	Up to 26 days
Part 1: Number of Participants With Treatment Related AEs	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 treatment related AEs is presented.	Up to 3 months
Part 2: Number of Participants With Treatment Related AEs	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 treatment related AEs is presented.	Up to 26 days
Part 1: Number of Participants With Worst-case Hematology Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline	Blood samples were collected to analyze hematocrit,hemoglobin,leukocytes,lymphocytes,neutrophils and platelets. PCI ranges were <0.075 or >0.54 proportion of red blood cells in blood for hematocrit, <25 or >180 grams per liter(g/L) for hemoglobin,<3 or >20 x10^9 cells per liter(cells/L) for leukocytes,<0.8 x10^9 cells/L for lymphocytes,<1.5 x10^9 cells/L for neutrophils and <100 or >550 x10^9 cells/L for platelets.Participants were counted in worst case category that their value changes to(low,within range or no change or high),unless there is no change in their category.Participants whose laboratory value category was unchanged(for example[e.g.],High to High),or whose value became within range, were recorded in"To within Range or No Change" category.Participants were counted twice if the participant has values that changed 'To Low' and 'To High',so the percentages may not add to 100%.Baseline=latest pre-dose assessment with a non-missing value, including those from unscheduled visits	Up to 3 months
Part 2: Number of Participants With Worst-case Hematology Results Relative to PCI Criteria Post-Baseline Relative to Baseline	Blood samples were collected to analyze hematocrit,hemoglobin,leukocytes,lymphocytes,neutrophils and platelets. PCI ranges were <0.075 or >0.54 proportion of red blood cells in blood for hematocrit, <25 or >180 grams per liter(g/L) for hemoglobin,<3 or >20 x10^9 cells per liter(cells/L) for leukocytes,<0.8 x10^9 cells/L for lymphocytes,<1.5 x10^9 cells/L for neutrophils and <100 or >550 x10^9 cells/L for platelets.Participants were counted in worst case category that their value changes to(low,within range or no change or high),unless there is no change in their category.Participants whose laboratory value category was unchanged(e.g.,High to High),or whose value became within range, were recorded in"To within Range or No Change" category.Participants were counted twice if the participant has values that changed 'To Low' and 'To High',so the percentages may not add to 100%.Baseline=latest pre-dose assessment with a non-missing value, including those from unscheduled visits	Up to 26 days
Part 1: Number of Participants With Worst-case Clinical Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline	Blood samples were collected to analyze PCI ranges: >=2 times Upper limit of Normal(ULN) Units per Liter(U/L) for Alanine aminotransferase(ALT),>=2 times ULN U/L for alkaline phosphatase(ALP), >=2 times ULN U/L for aspartate aminotransferase(AST),>=1.5 times ULN micromoles/L for bilirubin,<2 or >2.75 millimoles/L (mmol/L) for calcium,<3 or >9 mmol/L for glucose,<3 or >5.5 mmol/L for potassium and <130 or >150 mmol/L for sodium.Participants were counted in worst case category that their value changes to(low,within range or no change or high),unless there is no change in their category.Participants whose laboratory value category was unchanged(e.g.,High to High),or whose value became within range,were recorded in"To within Range or No Change" category.Participants were counted twice if the participant has values that changed 'To Low' and 'To High',so the percentages may not add to 100%.Baseline=latest pre-dose assessment with a non-missing value,including those from unscheduled visits	Up to 3 months
Part 2: Number of Participants With Worst-case Clinical Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline	Blood samples were collected to analyze PCI ranges: >=2 times ULN U/L for Alanine aminotransferase(ALT),>=2 times ULN U/L for alkaline phosphatase(ALP), >=2 times ULN U/L for aspartate aminotransferase(AST),>=1.5 times ULN micromoles/L for bilirubin,<2 or >2.75 mmol/L for calcium,<3 or >9 mmol/L for glucose,<3 or >5.5 mmol/L for potassium and <130 or >150 mmol/L for sodium.Participants were counted in worst case category that their value changes to(low,within range or no change or high),unless there is no change in their category.Participants whose laboratory value category was unchanged(e.g.,High to High),or whose value became within range,were recorded in"To within Range or No Change" category.Participants were counted twice if the participant has values that changed 'To Low' and 'To High',so the percentages may not add to 100%.Baseline=latest pre-dose assessment with a non-missing value,including those from unscheduled visits.	Up to 26 days
Part 1: Number of Participants With Worst Case Urinalysis Results Post Baseline Relative to Baseline	Urine samples were collected for the analysis of urine parameters including occult blood and protein by dipstick. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters were recorded as no change/decreased, increase to positive for urine occult blood and protein indicating proportional concentrations in the urine sample. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Number of participants with worst case urinalysis results Post Baseline relative to Baseline is presented.	Up to 3 months
Part 2: Number of Participants With Worst Case Urinalysis Results Post Baseline Relative to Baseline	Urine samples were collected for the analysis of urine parameters including occult blood and protein by dipstick. The dipstick test gave results in a semi-quantitative manner (proportional concentrations in urine samples), and results for urinalysis parameters were recorded as no change/decreased, increase to positive for urine occult blood and protein. 'No change/decreased' indicates no change from Baseline results or decreased in results from Baseline including change in negative results. 'Increase to positive' indicates increase in result from Baseline. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Number of participants with worst case urinalysis results Post Baseline relative to Baseline is presented.	Up to 26 days
Part 1: Number of Participants With Worst Case Vital Signs Results Relative to PCI Criteria Post Baseline Relative to Baseline	Vital signs were assessed including Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate (PR). PCI ranges were <85 (Low), 85-160 (Normal) and >160 (High) for SBP; <45 (Low), 45-100 (Normal), >100 (High) for DBP; <40 (Low), 40-110 (Normal), >110 (High) for pulse rate. Participants were counted in worst case category that their value changes to(low,within range or no change, high),unless there is no change in their category.Participants whose laboratory value category was unchanged(e.g.,High to High),or whose value became within range, were recorded in"To within Range or No Change" category.Participants were counted twice if the participant has values that changed 'To Low' and 'To High',so the percentages may not add to 100%.Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits	Up to 3 months
Part 2: Number of Participants With Worst Case Vital Signs Results Relative to PCI Criteria Post Baseline Relative to Baseline	Vital signs were assessed including Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate (PR). PCI ranges were <85 (Low), 85-160 (Normal) and >160 (High) for SBP; <45 (Low), 45-100 (Normal), >100 (High) for DBP; <40 (Low), 40-110 (Normal), >110 (High) for pulse rate. Participants were counted in worst case category that their value changes to(low,within range or no change, high),unless there is no change in their category.Participants whose laboratory value category was unchanged(e.g.,High to High),or whose value became within range, were recorded in"To within Range or No Change" category.Participants were counted twice if the participant has values that changed 'To Low' and 'To High',so the percentages may not add to 100%.Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits	Up to 26 days
Part 1: Number of Participants With Worst Case Abnormal Electrocardiogram (ECG) Results Post Baseline Relative to Baseline	A 12-lead ECG was recorded with the participant in a semi-supine position after a rest of at least 10 minutes. Twelve lead ECGs were obtained by using an automated ECG machine that measured PR, QRS, QT, and corrected QT (QTc) intervals and calculated heart rate. Data for abnormal not clinically significant (NCS) and clinically significant (CS) ECG findings are presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits.	Up to 3 months
Part 2: Number of Participants With Worst Case Abnormal ECG Results Post Baseline Relative to Baseline	A 12-lead ECG was recorded with the participant in a semi-supine position after a rest of at least 10 minutes. Twelve lead ECGs were obtained by using an automated ECG machine that measured PR, QRS, QT, and corrected QT (QTc) intervals and calculated heart rate. Data for abnormal not clinically significant (NCS) and clinically significant (CS) ECG findings are presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits.	Up to 26 days
Part 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose in each treatment period
Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC[0-t]) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 1: Area Under the Concentration-time Curve Extrapolated From Time Zero to Infinity (AUC[0-infinity]) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 1: Maximum Plasma Concentration (Cmax) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 1: Plasma Concentrations at 24 Hours (C24h) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose in each treatment period
Part 1: Time to Cmax (Tmax) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 1: Lag Time for Absorption (Tlag) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 1: Terminal Elimination Half-life (T1/2) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 2: Area Under the Concentration-time Curve Over the Dosing Interval Tau (AUC[0-tau]) After Repeat Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
Part 2: Cmax After Repeat Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
Part 2: Tmax After Repeat Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
Part 2: Plasma Concentrations Over the Dosing Interval (Ctau) After Repeat Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
Part 1: Urine Concentration Between 22-24 Hours (C22-24) After Single Dose Administration of GSK3882347	Urine samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Day 1: 22-24 hours post-dose in each treatment period
Part 2: Urine Concentration Between 22-24 Hours (C22-24) After Repeat Dose Administration of GSK3882347	Urine samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Day 1 and Day 7: 22-24 hours post-dose
Part 1: Amount of Drug Excreted in Urine of Unchanged Drug (Ae Total) After Single Dose Administration of GSK3882347	Urine samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	At 0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-22, 22-24, 24-26, 26-32, 32-38, 38-48, 48-60, 60-72, 72-84, 84-96 hours post-dose in each treatment period
Part 2: Amount of Drug Excreted in Urine of Unchanged Drug (Ae Total) After Repeat Dose Administration of GSK3882347	Urine samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Days 1 and 7: At 0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-22, 22-24 hours post-dose
Part 1: Percentage of the Given Dose of Drug Excreted in Urine (%fe Total) After Single Dose Administration of GSK3882347	Urine samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis. %fe was calculated as: (Ae total/Dose)*100 percent (%).	At 0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-22, 22-24, 24-26, 26-32, 32-38, 38-48, 48-60, 60-72, 72-84, 84-96 hours post-dose in each treatment period
Part 2: Percentage of the Given Dose of Drug Excreted in Urine (%fe Total) After Single Dose Administration of GSK3882347	Urine samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis. %fe was calculated as: (Ae total/Dose)*100%.	Day 1 and Day 7: At 0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-22, 22-24 hours post-dose
Part 1: Renal Clearance of Drug (CLr) After Single Dose Administration of GSK3882347	Urine samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis. CLr was calculated as: Ae total/AUC(0-t)	At 0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-22, 22-24, 24-26, 26-32, 32-38, 38-48, 48-60, 60-72, 72-84, 84-96 hours post-dose in each treatment period
Part 2: Renal Clearance of Drug (CLr) After Repeat Dose Administration of GSK3882347	Urine samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis. CLr was calculated as: Ae total/AUC(0-t).	Day 1 and Day 7: At 0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-22, 22-24 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Area Under the Concentration-time Curve From Time Zero to 12 Hours (AUC[0-12]) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8 and 12 hours post-dose in each treatment period
Part 1: Plasma Concentrations at 12 Hours (C12) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8 and 12 hours post-dose in each treatment period
Part 1: Apparent Oral Clearance (CL/F) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 1: Apparent Volume of Distribution After Oral Administration (Vz/F) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 1: Mean Residence Time (MRT) After Single Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 2: Area Under the Concentration-time Curve From Time Zero to 12 Hours (AUC[0-12]) After Repeat Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8 and 12 hours post-dose
Part 2: Plasma Concentrations at 12 Hours (C12) After Repeat Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis.	Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8 and 12 hours post-dose
Part 1: Dose Proportionality of GSK3882347 for Dose Levels 15 mg to 900 mg Using AUC(0-infinity) After Single Dose Administration of GSK3882347 Under Fasted Condition	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis. Dose proportionality was assessed using Power model. Log-e(dose) was fitted as fixed effect and participant was fitted as random effect. Kenward and Roger method and unstructured covariance structure was used. Slope and 90% confidence interval (CI) for the slope are presented. The SD 250 mg fed treatment was not considered in the analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 1: Dose Proportionality of GSK3882347 for Dose Levels 15 mg to 900 mg Using Cmax After Single Dose Administration of GSK3882347 Under Fasted Condition	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis. Dose proportionality was assessed using Power model. Log-e(dose) was fitted as fixed effect and participant was fitted as random effect. Kenward and Roger method and unstructured covariance structure was used. Slope and 90% CI for the slope are presented. The SD 250 mg fed treatment was not considered in the analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose in each treatment period
Part 2: Dose Proportionality of GSK3882347 for Dose Levels 50 mg to 900 mg Using AUC(0-tau) After Repeat Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis. Dose proportionality was assessed using Power model. Log-e(dose) was fitted as fixed effect and participant was fitted as random effect. Kenward and Roger method and unstructured covariance structure was used. Slope and 90% CI for the slope are presented.	Day 1 and Day 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
Part 2: Dose Proportionality of GSK3882347 for Dose Levels 50 mg to 900 mg Using Cmax After Repeat Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis. Dose proportionality was assessed using Power model. Log-e(dose) was fitted as fixed effect and participant was fitted as random effect. Kenward and Roger method and unstructured covariance structure was used. Slope and 90% CI for the slope are presented.	Day 1 and Day 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
Part 2: Observed Accumulation Ratio (Ro) Using AUC(0-tau) After Repeat Dose Administration of GSK3882347	Blood samples were collected at indicated time points for PK analysis of GSK3882347. PK parameters were analyzed using standard non-compartmental analysis. Accumulation ratio was calculated as AUC(0-tau) at Day 7 divided by AUC(0-tau) at Day 1 for GSK3882347. Mixed effect model was used to assess accumulation ratio for the log transformed parameters. Treatment, day and the interaction of treatment and day were fitted as fixed effect. Participant was fitted as random effect. Kenward and Roger method and unstructured covariance structure was used.	Day 1 and Day 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
Part 2: Time Invariance of GSK3882347	Blood samples were collected at indicated time points for the analysis of time invariance. Time invariance was calculated as AUC(0-tau) at Day 7 divided by AUC(0-infinity) at Day 1 for GSK3882347. Mixed effect ANOVA model was used to assess time invariance for the log transformed parameters. Treatment, day and the interaction of treatment and day were fitted as fixed effect. Participant was fitted as random effect. Kenward and Roger method and unstructured covariance structure was used.	Day 1 and Day 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
Part 2: Pre-dose Plasma Concentrations After Repeat Dose Administration of GSK3882347 From Days 3 to 7	Blood samples were collected at indicated time points for PK analysis of GSK3882347.	Days 3, 4, 5, 6 and 7: Pre-dose
Part 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) After Single Dose Administration of GSK3882347 250 mg Under Fasted and Fed Conditions for Assessment of Food Effect	Blood samples were collected at indicated time points for PK analysis of GSK3882347 250 mg under fasted and fed conditions for assessment of food effect. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose
Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUC [0-t]) After Single Dose Administration of GSK3882347 250 mg Under Fasted and Fed Conditions for Assessment of Food Effect	Blood samples were collected at indicated time points for PK analysis of GSK3882347 250 mg under fasted and fed conditions for assessment of food effect. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose
Part 1: Area Under the Concentration-time Curve Extrapolated From Time Zero to Infinity (AUC [0-infinity]) After Single Dose Administration of GSK3882347 250 mg Under Fasted and Fed Conditions for Assessment of Food Effect	Blood samples were collected at indicated time points for PK analysis of GSK3882347 250 mg under fasted and fed conditions for assessment of food effect. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose
Part 1: Maximum Plasma Concentration (Cmax) After Single Dose Administration of GSK3882347 250 mg Under Fasted and Fed Conditions for Assessment of Food Effect	Blood samples were collected at indicated time points for PK analysis of GSK3882347 250 mg under fasted and fed conditions for assessment of food effect. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose
Part 1: Plasma Concentrations at 24 Hours (C24h) After Single Dose Administration of GSK3882347 250 mg Under Fasted and Fed Conditions for Assessment of Food Effect	Blood samples were collected at indicated time points for PK analysis of GSK3882347 250 mg under fasted and fed conditions for assessment of food effect. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose
Part 1: Tmax After Single Dose Administration of GSK3882347 250 mg Under Fasted and Fed Conditions for Assessment of Food Effect	Blood samples were collected at indicated time points for PK analysis of GSK3882347 250 mg under fasted and fed conditions for assessment of food effect. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose
Part 1: Tlag After Single Dose Administration of GSK3882347 250 mg Under Fasted and Fed Conditions for Assessment of Food Effect	Blood samples were collected at indicated time points for PK analysis of GSK3882347 250 mg under fasted and fed conditions for assessment of food effect. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Collaborators: Wellcome Trust; Department of Health and Human Services

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2020
• Primary Completion (Actual): May 14, 2021
• Study Completion (Actual): May 14, 2021

Study Registration Dates

• First Submitted: July 23, 2020
• First Submitted That Met QC Criteria: July 23, 2020
• First Posted (Actual): July 28, 2020

Study Record Updates

• Last Update Posted (Actual): February 17, 2023
• Last Update Submitted That Met QC Criteria: May 10, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Pharmacokinetics; SAD; MAD; Urinary Tract Infections; FTIH; GSK3882347
• Additional Relevant MeSH Terms: Infections; Urologic Diseases; Urinary Tract Infections
• Other Study ID Numbers: 212148; 2020-000680-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No