Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of GSK3915393 in Healthy Participants and to Evaluate the Interaction Between GSK3915393 and Grapefruit Juice and Itraconazole

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT04604795

Collaborator

(none)

Enrollment

Location

Arms

7.8

Actual Duration (Months)

8.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a 3-part first time into human study (FTIH) study for GSK3915393. Parts A and B of the study will evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending and repeat oral doses of GSK3915393 in healthy adult participants. Part C will evaluate the impact of co-administration of GSK3915393 with grapefruit juice and itraconazole on the PK of GSK3915393.

Condition or Disease	Intervention/Treatment	Phase
Celiac Disease Coeliac Disease	Drug: GSK3915393 Capsules Drug: GSK3915393 Solution for Infusion Drug: Placebo capsules Drug: Itraconazole Other: Water Other: Grape fruit juice	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

65 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

This is a 3-part study. Parts A and C will have a 5 period crossover design Part B will be conducted as a parallel group dose escalation study.This is a 3-part study. Parts A and C will have a 5 period crossover design Part B will be conducted as a parallel group dose escalation study.

Masking:

Double (Participant, Investigator)

Masking Description:

Parts A and B will be double blind and Part C will be open label.

Primary Purpose:

Treatment

Official Title:

A Randomized, Placebo Controlled, Double Blind, Single and Repeat Dose Escalation Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of GSK3915393 in Healthy Participants and Open Label Assessment of Coadministration of GSK3915393 With Grapefruit Juice and Itraconazole on the Pharmacokinetics of GSK3915393

Actual Study Start Date :

Nov 4, 2020

Actual Primary Completion Date :

Jun 29, 2021

Actual Study Completion Date :

Jun 29, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A:GSK3915393 DLs 1,3,4,intravenous (IV) microdose and placebo (Sequence A) In Part A, participants will receive dose levels (DLs) 1, 3, 4, IV microdose of GSK3915393, and placebo in a pre-determined sequence (Sequence A). There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data.	Drug: GSK3915393 Capsules GSK3915393 capsules will be given orally. Drug: GSK3915393 Solution for Infusion GSK3915393 solution for infusion will be administered intravenously. Drug: Placebo capsules Placebo matching GSK3915393 capsules will be given orally.
Experimental: Part A:GSK3915393 DLs 1,2,4,IV microdose and placebo (Sequence B) In Part A, participants will receive dose levels 1, 2, 4, IV microdose of GSK3915393 and placebo in a pre-determined sequence (Sequence B). There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data.	Drug: GSK3915393 Capsules GSK3915393 capsules will be given orally. Drug: GSK3915393 Solution for Infusion GSK3915393 solution for infusion will be administered intravenously. Drug: Placebo capsules Placebo matching GSK3915393 capsules will be given orally.
Experimental: Part A:GSK3915393 DLs 1,2,3,IV microdose and placebo (Sequence C) In Part A, participants will receive dose levels 1, 2, 3, IV microdose of GSK3915393 and placebo in a pre-determined sequence (Sequence C). There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data.	Drug: GSK3915393 Capsules GSK3915393 capsules will be given orally. Drug: GSK3915393 Solution for Infusion GSK3915393 solution for infusion will be administered intravenously. Drug: Placebo capsules Placebo matching GSK3915393 capsules will be given orally.
Experimental: Part A:GSK3915393 DLs 2,3,4,IV microdose and placebo (Sequence D) In Part A, participants will receive dose levels 2, 3, 4, IV microdose of GSK3915393 and placebo in a pre-determined sequence (Sequence D). There will be a washout period of at least 7 days between each dose. Oral dose levels will be determined based on safety, tolerability and PK data.	Drug: GSK3915393 Capsules GSK3915393 capsules will be given orally. Drug: GSK3915393 Solution for Infusion GSK3915393 solution for infusion will be administered intravenously. Drug: Placebo capsules Placebo matching GSK3915393 capsules will be given orally.
Experimental: Part B: Cohort 1: Participants receiving GSK3915393 DL X Participants will receive GSK3915393 dose level X twice daily during Part B of the study. Dose levels will be determined based on safety, tolerability and PK data from Part A.	Drug: GSK3915393 Capsules GSK3915393 capsules will be given orally.
Placebo Comparator: Part B: Cohort 1: Participants receiving placebo Participants will receive placebo matching GSK3915393 dose level X during Part B of the study.	Drug: Placebo capsules Placebo matching GSK3915393 capsules will be given orally.
Experimental: Part B: Cohort 2: Participants receiving GSK3915393 DL Y Participants will receive GSK3915393 dose level Y twice daily during Part B of the study. Dose levels will be determined based on safety, tolerability and PK data from Part A and Part B.	Drug: GSK3915393 Capsules GSK3915393 capsules will be given orally.
Placebo Comparator: Part B: Cohort 2: Participants receiving placebo Participants will receive placebo matching GSK3915393 dose level Y twice daily during Part B of the study	Drug: Placebo capsules Placebo matching GSK3915393 capsules will be given orally.
Experimental: Part B: Cohort 3: Participants receiving GSK3915393 DL Z Participants will receive GSK3915393 dose level Z twice daily during Part B of the study. Dose levels will be determined based on safety, tolerability and PK data from Part A and Part B.	Drug: GSK3915393 Capsules GSK3915393 capsules will be given orally.
Placebo Comparator: Part B: Cohort 3: Participants receiving placebo Participants will receive placebo matching GSK3915393 dose level Z twice daily during Part B of the study.	Drug: Placebo capsules Placebo matching GSK3915393 capsules will be given orally.
Experimental: Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+water/GSK3915393+GFJ/GSK3915393+ITZ (Sequence A) Participants will receive GSK3915393 IV microdose in period 1 followed by combination of GSK3915393 IV microdose and itraconazole (ITZ) in period 2. Participants will then receive oral GSK3915393 plus water in period 3, oral GSK3915393 plus grape fruit juice (GFJ) in period 4 and oral GSK3915393 plus ITZ in period 5.	Drug: GSK3915393 Capsules GSK3915393 capsules will be given orally. Drug: GSK3915393 Solution for Infusion GSK3915393 solution for infusion will be administered intravenously. Drug: Itraconazole Participants will be administered with GSK3915393 along with ITZ orally Other: Water Participants will be administered with GSK3915393 along with water orally Other: Grape fruit juice Participants will be administered with GSK3915393 along with GFJ orally
Experimental: Part C: GSK3915393 IV/GSK3915393 IV+ITZ/GSK3915393+GFJ/GSK3915393+water/GSK3915393+ITZ (Sequence B) Participants will receive GSK3915393 IV microdose in period 1 followed by combination of GSK3915393 IV microdose and ITZ in period 2. Participants will then receive oral GSK3915393 plus GFJ in period 3, oral GSK3915393 plus water in period 4 and oral GSK3915393 plus ITZ in period 5.	Drug: GSK3915393 Capsules GSK3915393 capsules will be given orally. Drug: GSK3915393 Solution for Infusion GSK3915393 solution for infusion will be administered intravenously. Drug: Itraconazole Participants will be administered with GSK3915393 along with ITZ orally Other: Water Participants will be administered with GSK3915393 along with water orally Other: Grape fruit juice Participants will be administered with GSK3915393 along with GFJ orally

Outcome Measures

Primary Outcome Measures

Part A: Number of participants with adverse events (AEs), serious AEs (SAEs), and treatment related AEs following oral dosing [Up to Week 11]
AEs, SAEs and treatment related AEs will be collected.
Part B: Number of participants with AEs, SAEs and treatment related AEs [Up to Week 4]
AEs, SAEs and treatment related AEs will be collected.
Part A: Number of participants with clinically significant changes in physical examination, vital signs, laboratory parameters and 12-lead electrocardiogram (ECG) following oral dosing [Up to Week 11]
Participants with clinically significant changes in physical examination, vital signs, laboratory parameters and 12-lead ECG will be assessed.
Part B: Number of participants with clinically significant changes in physical examination, vital signs, laboratory parameters and 12-lead ECG [Up to Week 4]
Participants with clinically significant changes in physical examination, vital signs, laboratory parameters and 12-lead ECG will be assessed.
Part C: Maximum observed plasma drug concentration (Cmax) of GSK3915393 [Pre-dose to Day 3 in Treatment Periods 1, 2, 3, 4 and 5 (Period 1, 3 and 4 are 3 days each, Period 2 and 5 are 6 days each)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part C: Time to maximum observed plasma drug concentration (Tmax) of GSK3915393 [Pre-dose to Day 3 in Treatment Periods 1, 2, 3, 4 and 5 (Period 1, 3 and 4 are 3 days each, Period 2 and 5 are 6 days each)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part C: Area under the plasma drug concentration versus time curve from time zero to last quantifiable concentration (AUC[0-t]) of GSK3915393 [Pre-dose to Day 3 in Treatment Periods 1, 2, 3, 4 and 5 (Period 1, 3 and 4 are 3 days each, Period 2 and 5 are 6 days each)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part C: AUC from time zero to infinity (AUC[0-inf]) of GSK3915393 [Pre-dose to Day 3 in Treatment Periods 1 and 2 (Period 1 is 3 days and Period 2 is 6 days]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part C: Apparent terminal half-life (t1/2) of GSK3915393 [Pre-dose to Day 3 in Treatment Periods 1 and 2, (Period 1 is 3 days and Period 2 is 6 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.

Secondary Outcome Measures

Part A: Maximum observed plasma drug concentration (Cmax) following single oral dose of GSK3915393 [Pre-dose to Day 2 in Treatment Periods 1, 2, 4 and 5 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: Cmax following single intravenous (IV) dose of GSK3915393 [Pre-dose to Day 1 in Treatment Period 3 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: Time to maximum observed plasma concentration (Tmax) following single oral dose of GSK3915393 [Pre-dose to Day 2 in Treatment Periods 1, 2, 4 and 5 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: Tmax following single IV dose of GSK3915393 [Pre-dose to Day 1 in Treatment Period 3 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: AUC(0 to t) following single oral dose of GSK3915393 [Pre-dose to Day 2 in Treatment Periods 1, 2, 4 and 5 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: AUC(0 to t) following single IV dose of GSK3915393 [Pre-dose to Day 1 in Treatment Period 3 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: AUC(0 to inf) following single oral dose of GSK3915393 [Pre-dose to Day 2 in Treatment Periods 1, 2, 4 and 5 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: AUC(0 to inf) following single IV dose of GSK3915393 [Pre-dose to Day 1 in Treatment Period 3 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: T1/2 following single IV dose of GSK3915393 [Pre-dose to Day 1 in Treatment Period 3 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: Clearance (CL) following single IV dose of GSK3915393 [Pre-dose to Day 1 in Treatment Period 3 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: Volume of distribution (Vd) following single IV dose of GSK3915393 [Pre-dose to Day 1 in Treatment Period 3 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: Absolute bioavailability (F) following single oral dose of GSK3915393 [Pre-dose to Day 2 in Treatment Periods 1, 2, 4 and 5 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: Fraction of drug escaping hepatic metabolism [Pre-dose to Day 2 in Treatment Periods 1, 2, 4 and 5 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: Product of fraction of drug absorbed and fraction of drug escaping gut [Pre-dose to Day 2 in Treatment Periods 1, 2, 4 and 5 (Each period is 4 days)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part A: Number of participants with AEs and SAEs following IV dosing [Up to Week 11]
AEs, SAEs and treatment related AEs will be collected.
Part A: Number of participants with clinically significant changes in physical examination, vital signs, laboratory parameters and ECG following IV dosing [Up to Week 11]
Participants with clinically significant changes in physical examination, , vital signs, laboratory parameters and ECG will be assessed.
Part B: Cmax of GSK3915393 [Pre-dose and up to 24 hours post-dose on Days 1 and 14; Pre-dose and up to 10 hours post-dose on Days 3, 5, and 7]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part B: Tmax of GSK3915393 [Pre-dose and up to 24 hours post-dose on Days 1 and 14; Pre-dose and up to 10 hours post-dose on Days 3, 5, and 7]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part B: AUC (0-t) of GSK3915393 [Pre-dose and up to 24 hours post-dose on Days 1 and 14; Pre-dose and up to 10 hours post-dose on Days 3, 5, and 7]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part B: AUC over the dosing interval (AUC[0 to tau]) of GSK3915393 [Pre-dose and up to 24 hours post-dose on Days 1 and 14; Pre-dose and up to 10 hours post-dose on Days 3, 5, and 7]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part B: Cmax following first dose of GSK3915393 [Pre-dose and up to 10 hours post-dose on Days 1, 3, 5, 7 and 15]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part B: Tmax following first dose of GSK3915393 [Pre-dose and up to 10 hours post-dose on Days 1, 3, 5, 7 and 15]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part B: AUC(0 to tau) following first dose of GSK3915393 [Pre-dose and up to 10 hours post-dose on Days 1, 3, 5, 7 and 15]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part B: Trough concentration (Ctrough) following repeat dose of GSK3915393 [Pre first dose on Days 2, 3, 5, 7 and 14]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part C: Number of participants with AEs, SAEs and treatment related AEs [Up to Week 10]
AEs, SAEs and treatment related AEs will be collected.
Part C: Number of participants with clinically significant changes in physical examination, vital signs, laboratory parameters and ECG [Up to Week 10]
Participants with clinically significant changes in physical examination, vital signs, laboratory parameters and 12-lead ECG will be assessed.
Part C: Fraction of drug escaping hepatic metabolism [Pre-dose to Day 3 in Treatment Periods 1, 2, 3, 4 and 5 (Period 1, 3 and 4 are 3 days each, Period 2 and 5 are 6 days each)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.
Part C: Product of fraction of drug absorbed [Pre-dose to Day 3 in Treatment Periods 1, 2, 3, 4 and 5 (Period 1, 3 and 4 are 3 days each, Period 2 and 5 are 6 days each)]
Blood samples will be collected at the indicated time points for PK analysis of GSK3915393.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Between 18 and 50 years of age inclusive, at the time of signing the informed consent.
Healthy participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
Negative coronavirus disease of 2019 (COVID-19) test on admission.
Body weight >=40 kilograms (kg) and body mass index (BMI) within the range 18.5-29.9 kilograms per square meter (kg/m^2) (inclusive).
Male or females: No restrictions for male participants. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: Is a woman of non-childbearing potential (WONCBP) OR Is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method from 30 days prior to first dose until follow up visit. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated in relationship to the first dose of study intervention). A WOCBP must have a negative highly sensitive pregnancy test (serum) at screening and on admission to the clinical unit. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Capable of giving signed informed consent.

Exclusion Criteria:

History or current evidence of cardiovascular, respiratory, hepatic, renal, gastrointestinal (Irritable bowel syndrome [IBS], Gastroesophageal reflux disease [GERD], nausea, vomiting or dysphagia), endocrine, hematological, neurological, or psychiatric 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.
Current evidence of active infection.
Participants with signs/symptoms suggestive of COVID-19 (i.e. fever, cough, etc) within the past 14 days prior to screening and admission to clinical unit.
Participants with known COVID-19 positive contacts in the past 14 days prior to screening and admission to clinical unit.
Any history of suicidal behavior within the past 6 months or any history of attempted suicide in a participant's lifetime.
Alanine transaminase (ALT) >1.5 times upper limit of normal (ULN).
Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
History of gastrointestinal (GI) surgery (with exception of appendectomy).
Average QT interval corrected using Fridericia's formula (QTcF) >450 milliseconds (msec) at screening.
Any clinically relevant abnormality on the screening medical assessment, laboratory examination, or electrocardiogram.
History of QTc prolongation, symptomatic cardiac arrhythmias or cardiac arrest.
For Part C only, history of liver toxicity resulting from drug administration.
For Part C only, history of intolerance to itraconazole.
History of sensitivity to any of the study medication, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline Medical Monitor, contraindicates their participation.
Use of any immunosuppressive medications within 6 months prior to entry.
Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, probiotics, antacids, herbal and dietary supplements (including Saint [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) prior to the first dose of study medication for each dosing, unless in the opinion of the Investigator and GlaxoSmithKline Medical Monitor the medication will not interfere with the study procedures or compromise participant safety. (Paracetamol is acceptable at a dose of no more than 500 milligrams [mg] at a time and no more than 2 grams [g] per day).
Participants who have received a COVID-19 vaccine within 7 days of admission (or readmission) to the clinical unit or who are demonstrating signs/symptoms attributed to a COVID-19 vaccination that occurred greater than 7 days earlier.
Recent donation of blood or blood products such that participation in the study would result in loss of blood in excess of 500 milliliter (mL) within 56 days.
The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day.
Unwillingness or inability to follow the procedures outlined in the protocol or any other type of medical research within 30 days of randomization.
Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study treatment.
Positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment.
A positive pre-study drug/alcohol screen.
Positive human immunodeficiency virus (HIV) antibody test.
History of drug abuse (as defined by the current version of the Diagnostic and Statistical Manual [DSM]) within 2 years before dosing, or a positive drug screen reflecting consumption of illicit drugs.
Regular alcohol consumption within 6 months prior to screening: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
Urinary cotinine levels indicative of smoking or use of tobacco or nicotine-containing products (e.g. nicotine patches or vaporizing devices) at screening or on admission to the unit.