Clinical trial NCT04488770: Safety, Tolerability and Pharmacokinetic Investigation of GSK3882347 in Healthy Participants.
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Urinary Tract Infections
Keywords: SAD
MAD
FTIH
Pharmacokinetics
Urinary Tract Infections
GSK3882347
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Department of Health and Human Services
name: Wellcome Trust
First posted: 2020-07-28
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Part 1 will consist of two cohorts (Cohorts 1 and 2) with a maximum of four periods in a cross-over design conducted in two separate cohorts. Part 2 consists of a maximum of four ascending repeat-dose cohorts (Cohorts 3 to 6) for which participants, will receive a single oral dose of GSK3882347 or placebo for 7 days.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Part 1: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 3 months
measure: Part 2: Number of Participants With Non-serious AEs and SAEs
timeFrame: Up to 26 days
measure: Part 1: Number of Participants With Treatment Related AEs
timeFrame: Up to 3 months
measure: Part 2: Number of Participants With Treatment Related AEs
timeFrame: Up to 26 days
measure: Part 1: Number of Participants With Worst-case Hematology Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline
timeFrame: Up to 3 months
measure: Part 2: Number of Participants With Worst-case Hematology Results Relative to PCI Criteria Post-Baseline Relative to Baseline
timeFrame: Up to 26 days
measure: Part 1: Number of Participants With Worst-case Clinical Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline
timeFrame: Up to 3 months
measure: Part 2: Number of Participants With Worst-case Clinical Chemistry Results Relative to PCI Criteria Post-Baseline Relative to Baseline
timeFrame: Up to 26 days
measure: Part 1: Number of Participants With Worst Case Urinalysis Results Post Baseline Relative to Baseline
timeFrame: Up to 3 months
measure: Part 2: Number of Participants With Worst Case Urinalysis Results Post Baseline Relative to Baseline
timeFrame: Up to 26 days
measure: Part 1: Number of Participants With Worst Case Vital Signs Results Relative to PCI Criteria Post Baseline Relative to Baseline
timeFrame: Up to 3 months
measure: Part 2: Number of Participants With Worst Case Vital Signs Results Relative to PCI Criteria Post Baseline Relative to Baseline
timeFrame: Up to 26 days
measure: Part 1: Number of Participants With Worst Case Abnormal Electrocardiogram (ECG) Results Post Baseline Relative to Baseline
timeFrame: Up to 3 months
measure: Part 2: Number of Participants With Worst Case Abnormal ECG Results Post Baseline Relative to Baseline
timeFrame: Up to 26 days
measure: Part 1: Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) After Single Dose Administration of GSK3882347
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose in each treatment period
measure: 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
timeFrame: 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
measure: Part 1: Area Under the Concentration-time Curve Extrapolated From Time Zero to Infinity (AUC[0-infinity]) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 1: Maximum Plasma Concentration (Cmax) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 1: Plasma Concentrations at 24 Hours (C24h) After Single Dose Administration of GSK3882347
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose in each treatment period
measure: Part 1: Time to Cmax (Tmax) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 1: Lag Time for Absorption (Tlag) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 1: Terminal Elimination Half-life (T1/2) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 2: Area Under the Concentration-time Curve Over the Dosing Interval Tau (AUC[0-tau]) After Repeat Dose Administration of GSK3882347
timeFrame: Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
measure: Part 2: Cmax After Repeat Dose Administration of GSK3882347
timeFrame: Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
measure: Part 2: Tmax After Repeat Dose Administration of GSK3882347
timeFrame: Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
measure: Part 2: Plasma Concentrations Over the Dosing Interval (Ctau) After Repeat Dose Administration of GSK3882347
timeFrame: Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
measure: Part 1: Urine Concentration Between 22-24 Hours (C22-24) After Single Dose Administration of GSK3882347
timeFrame: Day 1: 22-24 hours post-dose in each treatment period
measure: Part 2: Urine Concentration Between 22-24 Hours (C22-24) After Repeat Dose Administration of GSK3882347
timeFrame: Day 1 and Day 7: 22-24 hours post-dose
measure: Part 1: Amount of Drug Excreted in Urine of Unchanged Drug (Ae Total) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 2: Amount of Drug Excreted in Urine of Unchanged Drug (Ae Total) After Repeat Dose Administration of GSK3882347
timeFrame: Days 1 and 7: At 0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-22, 22-24 hours post-dose
measure: Part 1: Percentage of the Given Dose of Drug Excreted in Urine (%fe Total) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 2: Percentage of the Given Dose of Drug Excreted in Urine (%fe Total) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 1: Renal Clearance of Drug (CLr) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 2: Renal Clearance of Drug (CLr) After Repeat Dose Administration of GSK3882347
timeFrame: 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 outcomes:
measure: Part 1: Area Under the Concentration-time Curve From Time Zero to 12 Hours (AUC[0-12]) After Single Dose Administration of GSK3882347
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8 and 12 hours post-dose in each treatment period
measure: Part 1: Plasma Concentrations at 12 Hours (C12) After Single Dose Administration of GSK3882347
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8 and 12 hours post-dose in each treatment period
measure: Part 1: Apparent Oral Clearance (CL/F) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 1: Apparent Volume of Distribution After Oral Administration (Vz/F) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 1: Mean Residence Time (MRT) After Single Dose Administration of GSK3882347
timeFrame: 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
measure: Part 2: Area Under the Concentration-time Curve From Time Zero to 12 Hours (AUC[0-12]) After Repeat Dose Administration of GSK3882347
timeFrame: Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8 and 12 hours post-dose
measure: Part 2: Plasma Concentrations at 12 Hours (C12) After Repeat Dose Administration of GSK3882347
timeFrame: Days 1 and 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8 and 12 hours post-dose
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: Part 2: Dose Proportionality of GSK3882347 for Dose Levels 50 mg to 900 mg Using AUC(0-tau) After Repeat Dose Administration of GSK3882347
timeFrame: Day 1 and Day 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
measure: Part 2: Dose Proportionality of GSK3882347 for Dose Levels 50 mg to 900 mg Using Cmax After Repeat Dose Administration of GSK3882347
timeFrame: Day 1 and Day 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
measure: Part 2: Observed Accumulation Ratio (Ro) Using AUC(0-tau) After Repeat Dose Administration of GSK3882347
timeFrame: Day 1 and Day 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
measure: Part 2: Time Invariance of GSK3882347
timeFrame: Day 1 and Day 7: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24 hours post-dose
measure: Part 2: Pre-dose Plasma Concentrations After Repeat Dose Administration of GSK3882347 From Days 3 to 7
timeFrame: Days 3, 4, 5, 6 and 7: Pre-dose
measure: 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
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose
measure: 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
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose
measure: 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
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose
measure: Part 1: Maximum Plasma Concentration (Cmax) After Single Dose Administration of GSK3882347 250 mg Under Fasted and Fed Conditions for Assessment of Food Effect
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose
measure: 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
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose
measure: Part 1: Tmax After Single Dose Administration of GSK3882347 250 mg Under Fasted and Fed Conditions for Assessment of Food Effect
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose
measure: Part 1: Tlag After Single Dose Administration of GSK3882347 250 mg Under Fasted and Fed Conditions for Assessment of Food Effect
timeFrame: Pre-dose, 15, 30 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 32, 48, 72 and 96 hours post-dose
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: