A First Time in Human (FTIH) Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Repeat Doses of GSK3884464 in Healthy Participants

Overview

This will be a FTIH study which aims to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and repeat oral doses of GSK3884464 administered to healthy participants.

Full Title of Study: “A Two-Part First Time in Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeat Oral Doses of GSK3884464 in a Randomized, Double Blind, Placebo-Controlled, Dose Escalation Study in Healthy Participants”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: October 18, 2022

Interventions

  • Drug: GSK3884464
    • GSK3884464 will be administered
  • Drug: Placebo
    • Placebo to match GSK3884464 will be administered.

Arms, Groups and Cohorts

  • Experimental: Part 1 Cohort 1
    • Participants will be randomized in one of 3 treatment sequences in a 1:1:1 ratio. Within each period, allocation to GSK3884464 and placebo will be 2:1. In period 1, participants will receive GSK3884464 (Dose 1) + Placebo; in period 2: GSK3884464 (Dose 2) + Placebo and in period 3: GSK3884464 (Dose 3) + Placebo. There will be a minimum of 7 days washout period between dosing in each session.
  • Experimental: Part 1 Cohort 2
    • Participants will be randomized in one of 3 treatment sequences in a 1:1:1 ratio. Within each period, allocation to GSK3884464 and placebo will be 2:1. In period 1, participants will receive GSK3884464 (Dose 4) + Placebo; in period 2: GSK3884464 (Dose 5) + Placebo and in period 3: GSK3884464 (Dose 6) + Placebo. There will be a minimum of 7 days washout period between dosing in each session.
  • Experimental: Part 1 Cohort 3
    • Participants will be randomized in one of 3 treatment sequences in a 1:1:1 ratio. Within each period, allocation to GSK3884464 and placebo will be 2:1. In period 1, participants will receive GSK3884464 (Dose 7) + Placebo; in period 2: GSK3884464 (Dose 8) + Placebo and in period 3: GSK3884464 (Dose 9) + Placebo. There will be a minimum of 7 days washout period between dosing in each session.
  • Experimental: Part 2 Cohort 4
    • Participants will be randomized to receive either GSK3884464 (Dose X) or placebo in sequential design according to randomization schedule. Participants will receive repeat daily doses of the study intervention or placebo based on PK data obtained in Part 1.
  • Experimental: Part 2 Cohort 5
    • Participants will be randomized to receive either GSK3884464 (Dose Y) or placebo in sequential design according to randomization schedule. Participants will receive repeat daily doses of the study intervention or placebo based on PK data obtained in Part 1 and ongoing PK data in Part 2.
  • Experimental: Part 2 Cohort 6
    • Participants will be randomized to receive either GSK3884464 (Dose Z) or placebo in sequential design according to randomization schedule. Participants will receive repeat daily doses of the study intervention or placebo based on PK data obtained in Part 1 and ongoing PK data in Part 2.

Clinical Trial Outcome Measures

Primary Measures

  • Parts 1 and 2: Number of participants with adverse events (AEs)
    • Time Frame: Day 1 through Week 10
  • Part 1: Number of participants with clinically significant changes in laboratory values, vital signs and 12-lead Electrocardiogram (ECG)
    • Time Frame: Up to Week 10
  • Part 1: Number of participants with clinically significant changes in continuous telemetry
    • Time Frame: Day 1 through Day 3
  • Part 2: Cohorts 4 and 5: Number of participants with clinically significant changes in laboratory values, vital signs, 12-lead ECG and echocardiogram
    • Time Frame: Day 1 through Week 9
  • Part 2: Cohort 6: Number of participants with clinically significant changes in laboratory values, vital signs, 12-lead ECG and echocardiogram
    • Time Frame: Day 1 through Week 10
  • Part 2: Cohorts 4 and 5: Number of participants with clinically significant changes in continuous telemetry
    • Time Frame: Day 1 through Day 14
  • Part 2: Cohort 6: Number of participants with clinically significant changes in continuous telemetry
    • Time Frame: Day 1 through Day 21
  • Part 1: Area under the plasma concentration curve from time zero to last time of quantifiable concentration (AUC[0-t]) of GSK3884464 following single dose administration
    • Time Frame: Day 1 pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 1: AUC from time zero to infinity (AUC[0-inf]) of GSK3884464 following single dose administration
    • Time Frame: Day 1 pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 1: Maximum observed plasma concentration (Cmax) of GSK3884464 following single dose administration
    • Time Frame: Day 1 pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 1: Time to maximum observed plasma drug concentration (Tmax) of GSK3884464 following single dose administration
    • Time Frame: Day 1 pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 1: Terminal half-life (T1/2) of GSK3884464 following single dose administration
    • Time Frame: Day 1 pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohorts 4 and 5: AUC over the dosing interval (AUC[tau]) of GSK3884464 following repeat dose administration
    • Time Frame: Day 1: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4 and Day 11: pre-dose; Day 7: pre-dose, 6 and 12 hours post-dose; Day 14: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohort 6: AUC(tau) of GSK3884464 following repeat dose administration
    • Time Frame: Day 1:pre-dose,30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4, Day 11 and Day 18:pre-dose; Day 7:pre-dose,6 and 12 hours post-dose; Day 21:pre-dose, 30 minutes,1, 1.5, 2, 3, 4, 6, 8, 12, 18,24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohorts 4 and 5: Cmax of GSK3884464 following repeat dose administration
    • Time Frame: Day 1: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4 and Day 11: pre-dose; Day 7: pre-dose, 6 and 12 hours post-dose; Day 14: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohort 6: Cmax of GSK3884464 following repeat dose administration
    • Time Frame: Day 1:pre-dose,30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4, Day 11 and Day 18:pre-dose; Day 7:pre-dose,6 and 12 hours post-dose; Day 21:pre-dose, 30 minutes,1, 1.5, 2, 3, 4, 6, 8, 12, 18,24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohorts 4 and 5: Trough plasma concentration (Ctau) of GSK3884464 following repeat dose administration
    • Time Frame: Day 1: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4 and Day 11: pre-dose; Day 7: pre-dose, 6 and 12 hours post-dose; Day 14: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohort 6: Ctau of GSK3884464 following repeat dose administration
    • Time Frame: Day 1:pre-dose,30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4, Day 11 and Day 18:pre-dose; Day 7:pre-dose,6 and 12 hours post-dose; Day 21:pre-dose, 30 minutes,1, 1.5, 2, 3, 4, 6, 8, 12, 18,24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohorts 4 and 5: Tmax of GSK3884464 following repeat dose administration
    • Time Frame: Day 1: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4 and Day 11: pre-dose; Day 7: pre-dose, 6 and 12 hours post-dose; Day 14: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohort 6: Tmax of GSK3884464 following repeat dose administration
    • Time Frame: Day 1:pre-dose,30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4, Day 11 and Day 18:pre-dose; Day 7:pre-dose,6 and 12 hours post-dose; Day 21:pre-dose, 30 minutes,1, 1.5, 2, 3, 4, 6, 8, 12, 18,24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohorts 4 and 5: T1/2 of GSK3884464 following repeat dose administration
    • Time Frame: Day 1: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4 and Day 11: pre-dose; Day 7: pre-dose, 6 and 12 hours post-dose; Day 14: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohort 6: T1/2 of GSK3884464 following repeat dose administration
    • Time Frame: Day 1:pre-dose,30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4, Day 11 and Day 18:pre-dose; Day 7:pre-dose,6 and 12 hours post-dose; Day 21:pre-dose, 30 minutes,1, 1.5, 2, 3, 4, 6, 8, 12, 18,24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohorts 4 and 5: Accumulation ratio based on AUC(tau) (RAUC) of GSK3884464 following repeat dose administration
    • Time Frame: Day 1: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4 and Day 11: pre-dose; Day 7: pre-dose, 6 and 12 hours post-dose; Day 14: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohort 6: RAUC of GSK3884464 following repeat dose administration
    • Time Frame: Day 1:pre-dose,30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4, Day 11 and Day 18:pre-dose; Day 7:pre-dose,6 and 12 hours post-dose; Day 21:pre-dose, 30 minutes,1, 1.5, 2, 3, 4, 6, 8, 12, 18,24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohorts 4 and 5: Accumulation ratio based on Cmax (RCmax) of GSK3884464 following repeat dose administration
    • Time Frame: Day 1: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4 and Day 11: pre-dose; Day 7: pre-dose, 6 and 12 hours post-dose; Day 14: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohort 6: RCmax of GSK3884464 following repeat dose administration
    • Time Frame: Day 1:pre-dose,30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4, Day 11 and Day 18:pre-dose; Day 7:pre-dose,6 and 12 hours post-dose; Day 21:pre-dose, 30 minutes,1, 1.5, 2, 3, 4, 6, 8, 12, 18,24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohorts 4 and 5: Accumulation ratio based on Ctau (RCtau) of GSK3884464 following repeat dose administration
    • Time Frame: Day 1: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4 and Day 11: pre-dose; Day 7: pre-dose, 6 and 12 hours post-dose; Day 14: pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96 and 120 hours post-dose
  • Part 2: Cohort 6: RCtau of GSK3884464 following repeat dose administration
    • Time Frame: Day 1:pre-dose,30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours post-dose; Day 4, Day 11 and Day 18:pre-dose; Day 7:pre-dose,6 and 12 hours post-dose; Day 21:pre-dose, 30 minutes,1, 1.5, 2, 3, 4, 6, 8, 12, 18,24, 36, 48, 72, 96 and 120 hours post-dose

Secondary Measures

  • Part 1: Change from Baseline in NAD(P)H dehydrogenase Quinone 1 (NQO1) messenger Ribonucleic acid (mRNA) in whole blood post treatment with GSK3884464
    • Time Frame: Baseline (Day 1) pre-dose, 2, 6, 12 and 24 hours post-dose
  • Part 2: Cohorts 4 and 5: Change from Baseline in NQO1 mRNA in whole blood post treatment with GSK3884464
    • Time Frame: Baseline (Day 1), Days 7 and 14: pre-dose, 6 and 12 hours post-dose
  • Part 2: Cohort 6: Change from Baseline in NQO1 mRNA in whole blood post treatment with GSK3884464.
    • Time Frame: Baseline (Day 1), Days 7 and 21: pre-dose, 6 and 12 hours post-dose

Participating in This Clinical Trial

Inclusion Criteria

  • Healthy as determined by the experienced investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring/assessment. – Part 1: Body weight greater than or equal to (>=)50 kilograms (kg), body mass index (BMI) >=18 and less than or equal to (<=)30 kilograms per square meter (kg/m^2) (inclusive). Part 2: Body weight >=50 kg, BMI >=22 and <=30 kg/m^2 (inclusive). – Participants with 18 to 50 years of age inclusive at the time of signing the informed consent. – Male or females of non-childbearing potential. – Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Exclusion criteria:

  • History or presence of significant cardiovascular, respiratory, hepatic, renal, gastrointestinal (Gastroesophageal reflux disease [GERD], nausea, vomiting or dysphagia), endocrine, hematological or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data. – History of current or past significant renal diseases. – Clinically significant high blood pressure and/or history of hypertension as determined by the investigator. – Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. – Breast cancer within the past 10 years. – Any clinically relevant abnormality on the screening medical assessments. – Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). – Unable to refrain from the use of prescription or non-prescription drug. – A positive laboratory confirmation of Coronavirus Disease-2019 (COVID-19) infection, or high clinical index of suspicion for COVID-19. – Participants with Glycated hemoglobin (HbA1c) greater than (>)48 millimoles per mol (mmol/mol) at screening. – Presence of Hepatitis B surface antigen at screening. – Positive Hepatitis C antibody test result at screening. – Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment. – Positive pre-study drug/alcohol screen. – Positive Human immunodeficiency virus (HIV) antibody test. – Screening urine albumin to creatinine ratio >30 milligrams/grams (mg/gm) (>3 mg/mmol). – Regular use of known drugs of abuse. – Regular alcohol consumption within six months prior to the study defined as: An average weekly intake of >=14 units for males >=14 units for females. One unit is equivalent to 8 gm of alcohol: a half-pint (approximately 240 milliliters [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. – Smokelyzer test levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products (for example [e.g.] nicotine patches or vaporizing devices) within 3 months prior to screening. – Participants with a history or current evidence of depression, bipolar disorder, suicidal ideation and behavior, or a lifetime history of suicide attempt will be excluded.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 50 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • GlaxoSmithKline
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • GSK Clinical Trials, Study Director, GlaxoSmithKline
  • Overall Contact(s)
    • US GSK Clinical Trials Call Center, 877-379-3718, GSKClinicalSupportHD@gsk.com

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