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

• ClinicalTrials.gov Identifier: NCT05999708
• Recruitment Status: Withdrawn
• First Posted: August 21, 2023
• Last Update Posted: December 15, 2023
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Colitis, Ulcerative	Drug: GSK4381406; Drug: Placebo; Drug: Indomethacin	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Estimated Study Start Date: October 31, 2023
• Estimated Primary Completion Date: December 5, 2024
• Estimated Study Completion Date: December 5, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: GSK4381406; GSK4381406 will be administered.; Drug: Placebo; Placebo will be administered.
Experimental: 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.	Drug: GSK4381406; GSK4381406 will be administered.; Drug: Placebo; Placebo will be administered.
Experimental: 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.	Drug: GSK4381406; GSK4381406 will be administered.; Drug: Placebo; Placebo will be administered.
Experimental: 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.	Drug: GSK4381406; GSK4381406 will be administered.; Drug: Placebo; Placebo will be administered.
Experimental: 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.	Drug: GSK4381406; GSK4381406 will be administered.; Drug: Placebo; Placebo will be administered.
Experimental: 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.	Drug: GSK4381406; GSK4381406 will be administered.; Drug: Placebo; Placebo will be administered.
Experimental: 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.	Drug: GSK4381406; GSK4381406 will be administered.; Drug: Placebo; Placebo will be administered.
Experimental: 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.	Drug: GSK4381406; GSK4381406 will be administered.; Drug: Placebo; Placebo will be administered.; Drug: Indomethacin; Indomethacin will be administered.

Outcome Measures

Primary Outcome Measures :

1. Part 1 - Number of participants with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to Day 40 ]
2. Part 2 - Number of participants with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to Day 54 ]
3. Part 3 - Number of participants with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to Day 34 ]
4. Part 1 - Number of participants with clinically significant changes in hematology laboratory values [ Time Frame: Up to Day 40 ]
5. Part 2 - Number of participants with clinically significant changes in hematology laboratory values [ Time Frame: Up to Day 54 ]
6. Part 3 - Number of participants with clinically significant changes in hematology laboratory values [ Time Frame: Up to Day 34 ]
7. Part 1 - Number of participants with clinically significant changes in chemistry laboratory values [ Time Frame: Up to Day 40 ]
8. Part 2 - Number of participants with clinically significant changes in chemistry laboratory values [ Time Frame: Up to Day 54 ]
9. Part 3 - Number of participants with clinically significant changes in chemistry laboratory values [ Time Frame: Up to Day 34 ]
10. Part 1 - Number of participants with clinically significant changes in urinalysis [ Time Frame: Up to Day 40 ]
11. Part 2 - Number of participants with clinically significant changes in urinalysis [ Time Frame: Up to Day 54 ]
12. Part 3 - Number of participants with clinically significant changes in urinalysis [ Time Frame: Up to Day 34 ]
13. Part 1 - Number of participants with clinically significant changes in vital signs [ Time Frame: Up to Day 40 ]
14. Part 2 - Number of participants with clinically significant changes in vital signs [ Time Frame: Up to Day 54 ]
15. Part 3 - Number of participants with clinically significant changes in vital signs [ Time Frame: Up to Day 34 ]
16. Part 1 - Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) readings [ Time Frame: Up to Day 40 ]
17. Part 2 - Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) readings [ Time Frame: Up to Day 54 ]
18. Part 3 - Number of participants with clinically significant changes in 12-lead Electrocardiogram (ECG) readings [ Time Frame: Up to Day 34 ]

Secondary Outcome Measures :

1. Part 1 - Area under the plasma concentration-time curve (AUC) from time zero to 24-hour post-dose [AUC(0-24) [ Time Frame: Up to 24 hours post dose ]
2. Part 1 - AUC from time zero to last quantifiable concentration [AUC(0-t) [ Time Frame: Up to Day 40 ]
3. Part 1 - AUC from time zero to infinity [AUC(0-inf) [ Time Frame: Up to Day 40 ]
4. Part 1 - Maximum observed plasma drug concentration (Cmax) [ Time Frame: Up to Day 40 ]
5. Part 1 - Time to maximum observed plasma drug concentration (tmax) [ Time Frame: Up to Day 40 ]
6. Part 1 - Time of last quantifiable concentration (tlast) [ Time Frame: Up to Day 40 ]
7. Part 1 - Apparent terminal phase half-life (t½) [ Time Frame: Up to Day 40 ]
8. Part 2 - AUC from time zero to last quantifiable concentration [AUC(0-t) [ Time Frame: Day 1 and Day 14 ]
9. Part 2 - AUC over the dosing interval [AUC(0-tau) [ Time Frame: Day 1 and Day 14 ]
10. Part 2 - Maximum observed plasma drug concentration (Cmax) [ Time Frame: Day 1 and Day 14 ]
11. Part 2 - Time to maximum observed plasma drug concentration (tmax) [ Time Frame: Day 1 and Day 14 ]
12. Part 2 - AUC from time zero to infinity [AUC(0-inf) [ Time Frame: Day 14 to Day 54 ]
13. Part 2 - Apparent terminal phase half-life (t½) [ Time Frame: Day 14 to Day 54 ]
14. Part 2 - Pre-dose (trough) plasma concentrations (Ctau) [ Time Frame: Day 1 to Day 14 ]
15. Part 2 - Accumulation ratios for Cmax (R) [ Time Frame: Day 1 and Day 14 ]
16. Part 2 - Accumulation ratios for AUC(0-tau) (Ro) [ Time Frame: Day 1 and Day 14 ]
17. Part 1: Cohort 4 - AUC from time zero to infinity [AUC(0-inf) [ Time Frame: Up to Day 40 ]
18. Part 1: Cohort 4 - Maximum observed plasma drug concentration (Cmax) [ Time Frame: Up to Day 40 ]
19. Part 1: Cohort 4 - Time to maximum observed plasma drug concentration (tmax) [ Time Frame: Up to Day 40 ]
20. Part 3 - Lactulose:rhamnose ratio over 0-5 hour in urine [ Time Frame: At Day 1, 3, 17 and 20 ]
    Lactulose and rhamnose concentrations in urine will be collected over 0-2 hour and 2-5 hour, which will be used to derive the ratio over 0-5 hour

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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).
• 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
• Live vaccine(s) within 1 month prior to screening or plans to receive such vaccines during the study
• Participation in the study would result in loss of blood or blood products in excess of 450 millilitre (mL) within the last 3 months prior to the Screening Visit. Blood donation during the study is not permitted
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day
• Current enrolment or past participation in another investigational study in which an investigational intervention (e.g., drug, vaccine, invasive device) was administered within the last 40 days or 5 half-lives, whichever is longer, before the first day of dosing (Day 1)
• 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 ribo nucleic acid (RNA) test result at screening or within 3 months prior to first dose of study intervention.
• Positive pre-study drug/alcohol screen
• Regular use of known drugs of abuse, including tetrahydrocannabinol.
• Positive human immunodeficiency virus (HIV) antibody test.
• Evidence of active or latent tuberculosis (TB) as documented by medical history and examination, and TB testing: a positive (not indeterminate) TB test such as QuantiFERON-TB Gold Plus test
• Positive smoke breathalyzer levels 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.
• Estimated glomerular filtration rate (eGFR) of <90 millilitre per minute per 1.73 meter square (mL/min/1.73 m^2) and / or UACR of >30 milligram per gram (mg/g) (>3 milligram per millimoles [mg/mmol]) at screening.
• Electrocardiogram (ECG) evidence of ischemic heart disease as determined by the Investigator.
• Positive test for Coronavirus disease 2019 (COVID-19) infection or signs and symptoms suggestive of COVID-19
• Regular excess alcohol consumption within 6 months prior to the study defined as an average weekly intake of >14 units for males and females
• 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 Additional exclusions for part 3 cohort only -
• Medical history of NSAIDs hypersensitivities, bronchial asthma, psychiatric and neurologic disorders, gastrointestinal disorders (including gastroesophageal reflux disease [GORD], gastritis, peptic ulcer disease and previous GI bleeding), cardiac or renal disease, coagulation defects and who are not on concomitant medication that may potentiate the potential harmful effects of indomethacin.
• Medical history of diabetes, defined as an HbA1c >5.6%, >39 mmol/mol.
• History of severe lactose intolerance or galactosaemia

Contacts and Locations

Locations

United Kingdom

GSK Investigational Site

Cambridge, United Kingdom, CB2 0GG

Sponsors and Collaborators

GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

More Information

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT05999708
• Other Study ID Numbers: 218680
• First Posted: August 21, 2023
• Last Update Posted: December 15, 2023
• Last Verified: December 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (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.
• URL: https://www.gsk.com/en-gb/innovation/trials/data-transparency/

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by GlaxoSmithKline:

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

Additional relevant MeSH terms:

Colitis, Ulcerative; Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Indomethacin; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Gout Suppressants; Tocolytic Agents; Reproductive Control Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action