A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of GSK3915393 in Healthy Participants and to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK3915393 in Participants With Celiac Disease (CeD)

Study Purpose

Celiac disease is a common T cell-mediated disorder triggered by dietary gluten with a worldwide prevalence estimated at one percent. GSK3915393 is being developed as an orally administered inhibitor of the enzyme transglutaminase 2 (TG2) for the treatment of participants with CeD. This study is the first time into human study (FTIH) for GSK3915393.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

Yes
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years - 50 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

For Healthy Participants (Parts A and B):
  • - 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 for inclusion: Two consecutive approved molecular tests (Polymerase chain reaction [PCR] or antigen test) separated by >24 hours.
At Screening or within 48 hours prior to start of Screening AND the second test ideally should be within 72 hours prior to admission to the unit. While awaiting test results participants should follow precautions as advised by the clinical unit.
  • - Body weight >=40 kilograms (kg) and body mass index (BMI) within the range 18.5-29.9 kilogram 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.
For Participants with CeD (Part C)
  • - Between 18 and 50 years of age inclusive, at the time of signing the informed consent.
  • - Participants with CeD who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
  • - Participants with a diagnosis of CeD: Documented diagnosis of CeD >=6 months before study entry, based on American College of Gastroenterology 2013 guideline on CeD diagnosis and management.
The confirmation of a diagnosis of CeD should be based on serology and upper endoscopy with histological analysis of a biopsy of the duodenum. A positive biopsy consistent with CeD. Every effort should be made to obtain the biopsy report to support the diagnosis of CeD. Prospective participants should not undergo biopsy for the sole purpose for participating in this trial. Participants for whom the biopsy report is not available may be enrolled in the study only after consultation with the GlaxoSmithKline Medical Monitor AND a positive gluten-specific serology to tissue transglutaminase (tTG) or endomysial antibodies (EMA), and/or gliadin-derived peptides (DGP). Every effort should be made to obtain the serology report. Participants for whom the serology report is not available may be enrolled in the study only if they have a report of duodenal biopsy confirming CeD. Participants with CeD must have been following a gluten-free diet for >= 6 months before study entry and be in remission defined as absence of symptoms typical of CeD for at least 2 months prior to the study and Immunoglobulin A (IgA) antibodies to tTG within normal limits at screening. Participants with weakly positive IgA antibodies to tTG may be included following discussion with the GlaxoSmithKline Medical Monitor; Human leukocyte antigen DQ (HLA-DQ) typing associated with CeD; No clinically significant abnormal laboratory test results other than those related to CeD as determined by the investigator.
  • - Negative COVID-19 test for inclusion: Two consecutive approved molecular tests (PCR or antigen test) separated by >24 hours.
At Screening or within 48 hours prior to start of Screening AND the second test ideally should be within 72 hours prior to admission to the unit. While awaiting test results participants should follow precautions as advised by the clinical unit.
  • - Body weight >=40 kg and body mass index (BMI) within the range 18.5-29.9 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 WONCBP OR Is a 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:

For Healthy Participants (Parts A and B):
  • - 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 Bazett'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.
  • - 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).
  • - 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.
For Participants with CeD (Part C):
  • - History or current evidence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 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; With the exception of CeD AND History of IBS and GERD in the past.
Participants with active, current symptoms of IBS or GERD are not eligible.
  • - 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.
  • - ALT >1.5 times 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 GI surgery (with exception of appendectomy).
  • - History of food allergy or food intolerance other than to gluten and lactose.
  • - Average QTcF >450 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.
  • - 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 or systemic corticosteroids within 3 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 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 mg at a time and no more than 2 g per day).
  • - Recent donation of blood or blood products such that participation in the study would result in loss of blood in excess of 500 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 RNA test result at screening or within 3 months prior to first dose of study treatment.
  • - A positive pre-study drug/alcohol screen.
  • - Positive HIV antibody test.
  • - History of drug abuse (as defined by the current version of the 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 defined as: 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.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT04604795
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

GlaxoSmithKline
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

GSK Clinical Trials
Principal Investigator Affiliation GlaxoSmithKline
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Industry
Overall Status Recruiting
Countries United Kingdom
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Celiac Disease
Arms & Interventions

Arms

Experimental: Part A:GSK3915393 DLs 1,3,4,microdose and placebo (Sequence A)

In Part A, participants will receive dose levels (DLs) 1, 3, 4, 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 pharmacokinetic data.

Experimental: Part A:GSK3915393 DLs 1,2,4,microdose and placebo (Sequence B)

In Part A, participants will receive dose levels 1, 2, 4, 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 pharmacokinetic data.

Experimental: Part A:GSK3915393 DLs 1,2,3,microdose and placebo (Sequence C)

In Part A, participants will receive dose levels 1, 2, 3, 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 pharmacokinetic data.

Experimental: Part A:GSK3915393 DLs 2,3,4,microdose and placebo (Sequence D)

In Part A, participants will receive dose levels 2, 3, 4, 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 pharmacokinetic data.

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 pharmacokinetic data from Part A.

Placebo Comparator: Part B: Cohort 1: Participants receiving placebo

Participants will receive placebo matching GSK3915393 dose level X during Part B of the study.

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 pharmacokinetic data from Part A and Part B.

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

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 pharmacokinetic data from Part A and Part B.

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.

Experimental: Part C: CeD participants receiving GSK3915393

Participants with CeD will receive GSK3915393 twice daily during Part C of the study. Dose will be determined based on safety, tolerability and pharmacokinetic data. Participants will also receive gluten daily on Days 8 to 10.

Placebo Comparator: Part C: CeD participants receiving placebo

Participants with CeD will receive placebo matching GSK3915393 twice daily during Part C of the study. Participants will also receive gluten daily on Days 8 to 10.

Interventions

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.

Other: - Gluten

The gluten will be given orally as slices of bread or as gluten flour mixed with water.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

GSK Investigational Site, London, United Kingdom

Status

Recruiting

Address

GSK Investigational Site

London, , NW10 7EW

Site Contact

US GSK Clinical Trials Call Center

GSKClinicalSupportHD@gsk.com

877-379-3718

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