A First Time in Human Study to Evaluate the Safety and Tolerability of GSK4381406 in Healthy Participants

NCT05999708 | Withdrawn Phase 1 DMC

• 1 other identifier: 218680
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Colitis, Ulcerative

Keywords

Gastrointestinal (GI); Intestinal permeability; First time in human (FTIH); Safety; Pharmacokinetics; Indomethacin challenge; Food effect

Outcome Measures

Primary Outcomes (18)

• Part 1 - Number of participants with adverse events (AEs) and serious adverse events (SAEs)

  Up to Day 40

• Part 2 - Number of participants with adverse events (AEs) and serious adverse events (SAEs)

  Up to Day 54

• Part 3 - Number of participants with adverse events (AEs) and serious adverse events (SAEs)

  Up to Day 34

• Part 1 - Number of participants with clinically significant changes in hematology laboratory values

  Up to Day 40

• Part 2 - Number of participants with clinically significant changes in hematology laboratory values

  Up to Day 54

• Part 3 - Number of participants with clinically significant changes in hematology laboratory values

  Up to Day 34

• Part 1 - Number of participants with clinically significant changes in chemistry laboratory values

  Up to Day 40

• Part 2 - Number of participants with clinically significant changes in chemistry laboratory values

  Up to Day 54

• Part 3 - Number of participants with clinically significant changes in chemistry laboratory values

  Up to Day 34

• Part 1 - Number of participants with clinically significant changes in urinalysis

  Up to Day 40

• Part 2 - Number of participants with clinically significant changes in urinalysis

  Up to Day 54

• Part 3 - Number of participants with clinically significant changes in urinalysis

  Up to Day 34

• Part 1 - Number of participants with clinically significant changes in vital signs

  Up to Day 40

• Part 2 - Number of participants with clinically significant changes in vital signs

  Up to Day 54

• Part 3 - Number of participants with clinically significant changes in vital signs

  Up to Day 34

• Part 1 - Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) readings

  Up to Day 40

• Part 2 - Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) readings

  Up to Day 54

• Part 3 - Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) readings

  Up to Day 34

Secondary Outcomes (20)

• 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 - AUC from time zero to last quantifiable concentration [AUC(0-t)

  Up to Day 40

• Part 1 - AUC from time zero to infinity [AUC(0-inf)

  Up to Day 40

• Part 1 - Maximum observed plasma drug concentration (Cmax)

  Up to Day 40

• Part 1 - Time to maximum observed plasma drug concentration (tmax)

  Up to Day 40

Study Arms (8)

Part 1: Cohort 1 - GSK4381406 or placebo

EXPERIMENTAL

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.

Drug: GSK4381406; Drug: Placebo

Part 1: Cohort 2 - GSK4381406 or placebo

EXPERIMENTAL

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.

Drug: GSK4381406; Drug: Placebo

Part 1: Cohort 3 - GSK4381406 or placebo

EXPERIMENTAL

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.

Drug: GSK4381406; Drug: Placebo

Part 1: Cohort 4 - GSK4381406 or placebo

EXPERIMENTAL

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.

Drug: GSK4381406; Drug: Placebo

Part 2: Cohort 5 - GSK4381406 or placebo

EXPERIMENTAL

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.

Drug: GSK4381406; Drug: Placebo

Part 2: Cohort 6 - GSK4381406 or placebo

EXPERIMENTAL

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.

Drug: GSK4381406; Drug: Placebo

Part 2: Cohort 7 - GSK4381406 or placebo

EXPERIMENTAL

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.

Drug: GSK4381406; Drug: Placebo

Part 3 - GSK4381406 or Placebo and Indomethacin

EXPERIMENTAL

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.

Drug: GSK4381406; Drug: Placebo; Drug: Indomethacin

Interventions

GSK4381406 DRUG

GSK4381406 will be administered.

Part 1: Cohort 1 - GSK4381406 or placebo; Part 1: Cohort 2 - GSK4381406 or placebo; Part 1: Cohort 3 - GSK4381406 or placebo; Part 1: Cohort 4 - GSK4381406 or placebo; Part 2: Cohort 5 - GSK4381406 or placebo; Part 2: Cohort 6 - GSK4381406 or placebo; Part 2: Cohort 7 - GSK4381406 or placebo; Part 3 - GSK4381406 or Placebo and Indomethacin

Placebo DRUG

Placebo will be administered.

Part 1: Cohort 1 - GSK4381406 or placebo; Part 1: Cohort 2 - GSK4381406 or placebo; Part 1: Cohort 3 - GSK4381406 or placebo; Part 1: Cohort 4 - GSK4381406 or placebo; Part 2: Cohort 5 - GSK4381406 or placebo; Part 2: Cohort 6 - GSK4381406 or placebo; Part 2: Cohort 7 - GSK4381406 or placebo; Part 3 - GSK4381406 or Placebo and Indomethacin

Indomethacin DRUG

Indomethacin will be administered.

Part 3 - GSK4381406 or Placebo and Indomethacin

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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).
• QT interval corrected for heart rate according to Fridericia's formula (QTcF) \>450 millisecond (msec)
• Unable to refrain from the use of over-the-counter or prescription medication, including herbal medications and vitamins within 7 days or 5 half-lives (whichever is longer) prior to dosing until after follow-up visit, 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
• The use of NSAIDs, including aspirin, are not permitted throughout the study (except on Part 3 Indomethacin challenge) and should not have been taken within 14 days immediately preceding the first dose of study intervention. For analgesia, paracetamol (acetaminophen) at doses of less than or equal to (≤)4 gram per day (g/day) is permitted
• Unable to refrain from consumption of red wine, Seville oranges, grapefruit, or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to first dose of study intervention until completion of the follow up period

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, CB2 0GG, United Kingdom

Location

MeSH Terms

Conditions

Colitis, Ulcerative

Interventions

Indomethacin

Condition Hierarchy (Ancestors)

Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Inflammatory Bowel Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 11, 2023
• First Posted: August 21, 2023
• Study Start: October 31, 2023
• Primary Completion: December 5, 2024
• Study Completion: December 5, 2024
• Last Updated: December 15, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an 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 may be granted, when justified, for up to 6 months.

Locations

GB (1)