A Randomized, Double-Blind, Placebo-Controlled, Single, Repeat Dose Escalation and Indomethacin Challenge Study to Evaluate Safety, Tolerability and Pharmacokinetics of GSK4381406 in Healthy Participants
Overview
- Phase
- Phase 1
- Intervention
- GSK4381406
- Conditions
- Colitis, Ulcerative
- Sponsor
- GlaxoSmithKline
- Locations
- 1
- Primary Endpoint
- Part 1 - Number of participants with adverse events (AEs) and serious adverse events (SAEs)
- Status
- Withdrawn
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a 3-part First Time in Human (FTIH) study to evaluate the safety, tolerability, and pharmacokinetics (PK) profile of GSK4381406 following administration of single ascending doses (Part 1), repeat ascending doses (Part 2), and repeat doses with an indomethacin challenge (Part 3) in healthy adult participants. Part 1 consists of 4 planned cohorts with up to 2 treatment periods in each and is expected to have 6 doses (but can accommodate up to 7 doses). The impact of food on PK of GSK4381406 will also be assessed. Part 2 will investigate 14 days of repeat dosing in 3 cohorts with 3 dose levels. Part 3 will evaluate the impact of repeat doses of GSK4381406 versus placebo on indomethacin induced changes in small intestinal permeability in healthy participants.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Body weight greater than (\>)50 kg and body mass index (BMI) within the range 18-29.9 kilogram per meter square (kg/m\^2) (inclusive)
- •Male and female participants
- •A female participant is eligible to participate if she is of non-childbearing potential
- •Capable of giving signed informed consent
Exclusion Criteria
- •Medical history of cardiovascular, cerebrovascular (including transient ischemic attack (TIA), ischemic and hemorrhagic stroke), respiratory, hepatic, renal (including chronic kidney disease), gastrointestinal (including IBD and IBS), endocrine, hematologic (including anemia and coagulopathies), or neurological disorders
- •Abnormal blood pressure (BP) (defined as systolic BP greater than or equal to \[≥\]130 millimetres of mercury (mmHg) or diastolic BP ≥85 mmHg) measured (based on the average of triplicate BP readings)
- •Medical history of antihypertensive drugs
- •Presence, or history within the past 14 days, of irregularities in bowel movements, including diarrhea (the passage of 3 or more loose or liquid stools per day) and constipation (3 or fewer bowel movements per week or requiring the use of laxatives).
- •Symptomatic herpes zoster within 3 months prior to screening.
- •Clinically significant multiple or severe drug allergies, intolerance to corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A \[IgA\] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
- •Any history or presence of malignancy except for basal cell or squamous epithelial carcinomas of the skin.
- •Alanine transaminase (ALT) \>1.5x Upper limit of normal (ULN)
- •Total bilirubin \>1.5x ULN (isolated total bilirubin \>1.5xULN is acceptable if total bilirubin is fractionated and direct bilirubin lesser than \[\<\]35 percentage \[%\]).
- •Current or chronic history of liver disease or known hepatic or biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones).
Arms & Interventions
Part 1: Cohort 1 - GSK4381406 or placebo
Participants in Part 1 Cohort 1 will receive a single dose of GSK4381406 dose level 1 or placebo in Treatment Period 1 in fasted state, followed by GSK4381406 dose level 3 or placebo in Treatment Period 2 in fasted state with washout period of at least 40 days between each dose.
Intervention: GSK4381406
Part 1: Cohort 1 - GSK4381406 or placebo
Participants in Part 1 Cohort 1 will receive a single dose of GSK4381406 dose level 1 or placebo in Treatment Period 1 in fasted state, followed by GSK4381406 dose level 3 or placebo in Treatment Period 2 in fasted state with washout period of at least 40 days between each dose.
Intervention: Placebo
Part 1: Cohort 2 - GSK4381406 or placebo
Participants in Part 1 Cohort 2 will receive a single dose of GSK4381406 dose level 2 or placebo in Treatment Period 1 in fasted state, followed by GSK4381406 dose level 4 or placebo in Treatment Period 2 in fasted state with washout period of at least 40 days between each dose.
Intervention: GSK4381406
Part 1: Cohort 2 - GSK4381406 or placebo
Participants in Part 1 Cohort 2 will receive a single dose of GSK4381406 dose level 2 or placebo in Treatment Period 1 in fasted state, followed by GSK4381406 dose level 4 or placebo in Treatment Period 2 in fasted state with washout period of at least 40 days between each dose.
Intervention: Placebo
Part 1: Cohort 3 - GSK4381406 or placebo
Participants in Part 1 Cohort 3 will receive a single dose of GSK4381406 dose level 5 or placebo in Treatment Period 1 in fasted state, followed by GSK4381406 dose level 7 or placebo in Treatment Period 2 in fasted state with washout period of at least 40 days between each dose. Note: Requirement for Treatment Period 2 (dose level 7) will be determined by PK data of previous doses.
Intervention: GSK4381406
Part 1: Cohort 3 - GSK4381406 or placebo
Participants in Part 1 Cohort 3 will receive a single dose of GSK4381406 dose level 5 or placebo in Treatment Period 1 in fasted state, followed by GSK4381406 dose level 7 or placebo in Treatment Period 2 in fasted state with washout period of at least 40 days between each dose. Note: Requirement for Treatment Period 2 (dose level 7) will be determined by PK data of previous doses.
Intervention: Placebo
Part 1: Cohort 4 - GSK4381406 or placebo
Participants in Part 1 Cohort 4 will receive a single dose of GSK4381406 dose level 6 or placebo in Treatment Period 1 in fasted state, followed by GSK4381406 dose level 6 in Treatment Period 2 in fed state with washout period of at least 40 days between each dose.
Intervention: GSK4381406
Part 1: Cohort 4 - GSK4381406 or placebo
Participants in Part 1 Cohort 4 will receive a single dose of GSK4381406 dose level 6 or placebo in Treatment Period 1 in fasted state, followed by GSK4381406 dose level 6 in Treatment Period 2 in fed state with washout period of at least 40 days between each dose.
Intervention: Placebo
Part 2: Cohort 5 - GSK4381406 or placebo
Participants in Part 2 Cohort 5 will receive 14 days of once daily repeat dosing of GSK4381406 dose level A or placebo in fasted state.
Intervention: GSK4381406
Part 2: Cohort 5 - GSK4381406 or placebo
Participants in Part 2 Cohort 5 will receive 14 days of once daily repeat dosing of GSK4381406 dose level A or placebo in fasted state.
Intervention: Placebo
Part 2: Cohort 6 - GSK4381406 or placebo
Participants in Part 2 Cohort 6 will receive 14 days of once daily repeat dosing of GSK4381406 dose level B or placebo in fasted state.
Intervention: GSK4381406
Part 2: Cohort 6 - GSK4381406 or placebo
Participants in Part 2 Cohort 6 will receive 14 days of once daily repeat dosing of GSK4381406 dose level B or placebo in fasted state.
Intervention: Placebo
Part 2: Cohort 7 - GSK4381406 or placebo
Participants in Part 2 Cohort 7 will receive 14 days of once daily repeat dosing of GSK4381406 dose level C or placebo in fasted state.
Intervention: GSK4381406
Part 2: Cohort 7 - GSK4381406 or placebo
Participants in Part 2 Cohort 7 will receive 14 days of once daily repeat dosing of GSK4381406 dose level C or placebo in fasted state.
Intervention: Placebo
Part 3 - GSK4381406 or Placebo and Indomethacin
Participants in Part 3 will receive 3 days of once daily repeat dosing of GSK4381406 in Treatment Period 1 followed by placebo in Treatment Period 2, or placebo in Treatment Period 1 and GSK4381406 in Treatment Period 2 in a cross-over design with a washout period of at least 14 days between each dosing period. Participants will be dosed in fasted state. The participants will be challenged with indomethacin during the final 2 days of each dosing period.
Intervention: GSK4381406
Part 3 - GSK4381406 or Placebo and Indomethacin
Participants in Part 3 will receive 3 days of once daily repeat dosing of GSK4381406 in Treatment Period 1 followed by placebo in Treatment Period 2, or placebo in Treatment Period 1 and GSK4381406 in Treatment Period 2 in a cross-over design with a washout period of at least 14 days between each dosing period. Participants will be dosed in fasted state. The participants will be challenged with indomethacin during the final 2 days of each dosing period.
Intervention: Placebo
Part 3 - GSK4381406 or Placebo and Indomethacin
Participants in Part 3 will receive 3 days of once daily repeat dosing of GSK4381406 in Treatment Period 1 followed by placebo in Treatment Period 2, or placebo in Treatment Period 1 and GSK4381406 in Treatment Period 2 in a cross-over design with a washout period of at least 14 days between each dosing period. Participants will be dosed in fasted state. The participants will be challenged with indomethacin during the final 2 days of each dosing period.
Intervention: Indomethacin
Outcomes
Primary Outcomes
Part 1 - Number of participants with adverse events (AEs) and serious adverse events (SAEs)
Time Frame: Up to Day 40
Part 3 - Number of participants with adverse events (AEs) and serious adverse events (SAEs)
Time Frame: Up to Day 34
Part 2 - Number of participants with clinically significant changes in chemistry laboratory values
Time Frame: Up to Day 54
Part 3 - Number of participants with clinically significant changes in vital signs
Time Frame: Up to Day 34
Part 2 - Number of participants with adverse events (AEs) and serious adverse events (SAEs)
Time Frame: Up to Day 54
Part 1 - Number of participants with clinically significant changes in hematology laboratory values
Time Frame: Up to Day 40
Part 1 - Number of participants with clinically significant changes in chemistry laboratory values
Time Frame: Up to Day 40
Part 1 - Number of participants with clinically significant changes in urinalysis
Time Frame: Up to Day 40
Part 1 - Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) readings
Time Frame: Up to Day 40
Part 3 - Number of participants with clinically significant changes in urinalysis
Time Frame: Up to Day 34
Part 3 - Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) readings
Time Frame: Up to Day 34
Part 2 - Number of participants with clinically significant changes in hematology laboratory values
Time Frame: Up to Day 54
Part 1 - Number of participants with clinically significant changes in vital signs
Time Frame: Up to Day 40
Part 3 - Number of participants with clinically significant changes in hematology laboratory values
Time Frame: Up to Day 34
Part 3 - Number of participants with clinically significant changes in chemistry laboratory values
Time Frame: Up to Day 34
Part 2 - Number of participants with clinically significant changes in urinalysis
Time Frame: Up to Day 54
Part 2 - Number of participants with clinically significant changes in vital signs
Time Frame: Up to Day 54
Part 2 - Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) readings
Time Frame: Up to Day 54
Secondary Outcomes
- Part 2 - AUC from time zero to last quantifiable concentration [AUC(0-t)(Day 1 and Day 14)
- Part 1 - Time to maximum observed plasma drug concentration (tmax)(Up to Day 40)
- Part 1 - AUC from time zero to last quantifiable concentration [AUC(0-t)(Up to Day 40)
- Part 1: Cohort 4 - Time to maximum observed plasma drug concentration (tmax)(Up to Day 40)
- Part 2 - AUC over the dosing interval [AUC(0-tau)(Day 1 and Day 14)
- Part 1 - AUC from time zero to infinity [AUC(0-inf)(Up to Day 40)
- Part 1 - Time of last quantifiable concentration (tlast)(Up to Day 40)
- Part 1 - Apparent terminal phase half-life (t½)(Up to Day 40)
- Part 2 - AUC from time zero to infinity [AUC(0-inf)(Day 14 to Day 54)
- Part 1 - Area under the plasma concentration-time curve (AUC) from time zero to 24-hour post-dose [AUC(0-24)(Up to 24 hours post dose)
- Part 1 - Maximum observed plasma drug concentration (Cmax)(Up to Day 40)
- Part 2 - Maximum observed plasma drug concentration (Cmax)(Day 1 and Day 14)
- Part 2 - Time to maximum observed plasma drug concentration (tmax)(Day 1 and Day 14)
- Part 2 - Apparent terminal phase half-life (t½)(Day 14 to Day 54)
- Part 1: Cohort 4 - AUC from time zero to infinity [AUC(0-inf)(Up to Day 40)
- Part 2 - Pre-dose (trough) plasma concentrations (Ctau)(Day 1 to Day 14)
- Part 2 - Accumulation ratios for Cmax (R)(Day 1 and Day 14)
- Part 2 - Accumulation ratios for AUC(0-tau) (Ro)(Day 1 and Day 14)
- Part 1: Cohort 4 - Maximum observed plasma drug concentration (Cmax)(Up to Day 40)
- Part 3 - Lactulose:rhamnose ratio over 0-5 hour in urine(At Day 1, 3, 17 and 20)