A Safety and Pharmacokinetic (PK) Study of GSK2982772 in Healthy Subjects

NCT ID: NCT03305419

Last Updated: 2023-10-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-11
• Study Completion Date: 2018-10-15

Brief Summary

This study is designed to evaluate the safety, tolerability and PK of GSK2982772, in repeat oral doses in healthy subjects. This study is being conducted to support administration of higher dose levels of GSK2982772 than initially studied in the First Time in Human (FTiH) study. This study will also assess the impact of food during the repeat doses of GSK2982772. This will be a two part study; Part A and Part B. Part A (cohort 1) - single ascending dose, randomized, placebo-controlled, 3-way crossover. Part B (cohorts 2, 3, 4 and 5) - repeat dose, randomized, placebo-controlled, sequential-group. Subjects will be randomized in 3:1 ratio to receive GSK2982772 or placebo in crossover manner on Day 1 of each of the three periods in Part A. Subjects will be randomized in 3:1 ratio to receive GSK2982772 or placebo in sequential groups for 14 days in cohort 2 of Part B and in 9:5 ratio to receive GSK2982772 or placebo in sequential groups for 14 days in cohorts 3, 4 and 5 of Part B. Approximately 66 subjects will be included in this study. The study duration, including screening and follow-up, will not be expected to exceed 13 weeks for Part A and 8 weeks for Part B.

Conditions

Autoimmune Diseases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Subjects receiving treatment sequence ABC in cohort 1: Part A

Eligible subjects will be randomized to receive treatment sequence ABC in Part A; A= GSK2982772 120 mg TID, B= GSK2982772 240 mg TID, and C= GSK2982772 360 mg BID. Subjects will receive oral capsule of GSK2982772 or placebo on Day 1 in each of the 3 treatment periods followed by a wash-out period of at least 7 days between dosing regimens.

Group Type: EXPERIMENTAL

GSK2982772 capsule

Intervention Type: DRUG

GSK2982772 will be available as size 00, white, opaque capsule containing white to almost white Solid (120 mg maximum fill per capsule). It will be administered orally with water to receive total dose of 120 mg, 240 mg or 360 mg per randomization.

Placebo capsule

Intervention Type: DRUG

Placebo will be available as size 00, white, opaque capsule containing white to almost white Solid. It will be administered orally with water.

Subjects receiving treatment sequence ABP in cohort 1: Part A

Eligible subjects will be randomized to receive treatment sequence ABP in Part A; A= GSK2982772 120 mg TID, B= GSK2982772 240 mg TID, and P= Placebo. Subjects will receive oral capsule of GSK2982772 or placebo on Day 1 in each of the 3 treatment periods followed by a wash-out period of at least 7 days between dosing regimens.

Group Type: EXPERIMENTAL

GSK2982772 capsule

Intervention Type: DRUG

GSK2982772 will be available as size 00, white, opaque capsule containing white to almost white Solid (120 mg maximum fill per capsule). It will be administered orally with water to receive total dose of 120 mg, 240 mg or 360 mg per randomization.

Placebo capsule

Intervention Type: DRUG

Placebo will be available as size 00, white, opaque capsule containing white to almost white Solid. It will be administered orally with water.

Subjects receiving treatment sequence APC in cohort 1: Part A

Eligible subjects will be randomized to receive treatment sequence APC in Part A; A= GSK2982772 120 mg TID, P= Placebo and C= GSK2982772 360 mg BID. Subjects will receive oral capsule of GSK2982772 or placebo on Day 1 in each of the 3 treatment periods followed by a wash-out period of at least 7 days between dosing regimens.

Group Type: EXPERIMENTAL

GSK2982772 capsule

Intervention Type: DRUG

GSK2982772 will be available as size 00, white, opaque capsule containing white to almost white Solid (120 mg maximum fill per capsule). It will be administered orally with water to receive total dose of 120 mg, 240 mg or 360 mg per randomization.

Placebo capsule

Intervention Type: DRUG

Placebo will be available as size 00, white, opaque capsule containing white to almost white Solid. It will be administered orally with water.

Subjects receiving treatment sequence PBC in cohort 1: Part A

Eligible subjects will be randomized to receive treatment sequence PBC in Part A; P= Placebo, B= GSK2982772 240 mg TID and C= GSK2982772 360 mg BID. Subjects will receive oral capsule of GSK2982772 or placebo on Day 1 in each of the 3 treatment periods followed by a wash-out period of at least 7 days between dosing regimens.

Group Type: EXPERIMENTAL

GSK2982772 capsule

Intervention Type: DRUG

GSK2982772 will be available as size 00, white, opaque capsule containing white to almost white Solid (120 mg maximum fill per capsule). It will be administered orally with water to receive total dose of 120 mg, 240 mg or 360 mg per randomization.

Placebo capsule

Intervention Type: DRUG

Placebo will be available as size 00, white, opaque capsule containing white to almost white Solid. It will be administered orally with water.

Subjects receiving GSK2982772 120 mg TID in cohort 2 : Part B

Eligible subjects will receive GSK2982772 oral capsule with a dose of 120 mg TID for 14 days in Part B.

Group Type: EXPERIMENTAL

GSK2982772 capsule

Intervention Type: DRUG

GSK2982772 will be available as size 00, white, opaque capsule containing white to almost white Solid (120 mg maximum fill per capsule). It will be administered orally with water to receive total dose of 120 mg, 240 mg or 360 mg per randomization.

Subjects receiving GSK2982772 120 mg TID in cohort 3 : Part B

Eligible subjects will receive GSK2982772 oral capsule with a dose of 120 mg TID for 14 days in Part B.

Group Type: EXPERIMENTAL

GSK2982772 capsule

Intervention Type: DRUG

GSK2982772 will be available as size 00, white, opaque capsule containing white to almost white Solid (120 mg maximum fill per capsule). It will be administered orally with water to receive total dose of 120 mg, 240 mg or 360 mg per randomization.

Subjects receiving GSK2982772 240 mg TID in cohort 4: Part B

Eligible subjects will receive GSK2982772 oral capsule with a dose of 240 mg TID for 14 days in Part B.

Group Type: EXPERIMENTAL

GSK2982772 capsule

Intervention Type: DRUG

GSK2982772 will be available as size 00, white, opaque capsule containing white to almost white Solid (120 mg maximum fill per capsule). It will be administered orally with water to receive total dose of 120 mg, 240 mg or 360 mg per randomization.

Subjects receiving GSK2982772 360 mg BID in cohort 5: Part B

Eligible subjects will receive GSK2982772 oral capsule with a dose of 360 mg BID for 14 days in Part B.

Group Type: EXPERIMENTAL

GSK2982772 capsule

Intervention Type: DRUG

GSK2982772 will be available as size 00, white, opaque capsule containing white to almost white Solid (120 mg maximum fill per capsule). It will be administered orally with water to receive total dose of 120 mg, 240 mg or 360 mg per randomization.

Subjects receiving placebo in cohort 2 : Part B

Subjects will receive placebo oral capsule for 14 days in Part B.

Group Type: PLACEBO_COMPARATOR

Placebo capsule

Intervention Type: DRUG

Placebo will be available as size 00, white, opaque capsule containing white to almost white Solid. It will be administered orally with water.

Subjects receiving placebo in cohort 3 : Part B

Subjects will receive placebo oral capsule for 14 days in Part B.

Group Type: PLACEBO_COMPARATOR

Placebo capsule

Intervention Type: DRUG

Placebo will be available as size 00, white, opaque capsule containing white to almost white Solid. It will be administered orally with water.

Subjects receiving placebo in cohort 4 : Part B

Subjects will receive placebo oral capsule for 14 days in Part B.

Group Type: PLACEBO_COMPARATOR

Placebo capsule

Intervention Type: DRUG

Placebo will be available as size 00, white, opaque capsule containing white to almost white Solid. It will be administered orally with water.

Subjects receiving placebo in cohort 5: Part B

Subjects will receive placebo oral capsule for 14 days in Part B.

Group Type: PLACEBO_COMPARATOR

Placebo capsule

Intervention Type: DRUG

Placebo will be available as size 00, white, opaque capsule containing white to almost white Solid. It will be administered orally with water.

Interventions

GSK2982772 capsule

GSK2982772 will be available as size 00, white, opaque capsule containing white to almost white Solid (120 mg maximum fill per capsule). It will be administered orally with water to receive total dose of 120 mg, 240 mg or 360 mg per randomization.

Intervention Type: DRUG

Placebo capsule

Placebo will be available as size 00, white, opaque capsule containing white to almost white Solid. It will be administered orally with water.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Subject must be 18 to 65 years of age inclusive, at the time of signing the informed consent.

Exclusion Criteria

• Body weight >=50 kilograms (kg) and body mass index (BMI) within the range 19 - 30 kg per square meter (kg/m^2) (inclusive).
• A male subject with a female partner of reproductive potential must agree to use contraception during the treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance for a minimum of 28 days prior to the treatment period and for at least 30 days after the last administration of study drug. A WOCBP using a hormonal method of highly effective contraception must also agree to partner use of a male condom during the treatment period and for at least 30 days after the last administration of study drug.
• Capable of giving signed informed consent.

• History or presence of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological 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.
• History of herpes zoster (shingles) reactivation.
• Evidence of active or latent tuberculosis (TB) as documented by medical history and examination, chest x-rays (posterior anterior and lateral), and TB testing: either a positive tuberculin skin test (TST; defined as a skin induration >5 millimeter (mm) at 48 to 72 hours, regardless of Bacillus Calmette-Guerin (BCG) or other vaccination history) or a positive (not indeterminate) QuantiFERON-TB Gold test.
• 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%).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• ECG QT interval corrected for heart rate (QTc) >450 millisecond (msec).
• History of serious or recurrent infections or has had an active infection within 14 days of receiving study medication.
• History of diagnosis of obstructive sleep apnoea or significant respiratory disorder. Childhood asthma that has fully resolved is permitted.
• Part A: History of active suicidal ideation behavior (SIB) within the past 6 months or any history of attempted suicide in a subject's lifetime.
• History of current evidence of febrile seizures, epilepsy, convulsions, significant head injury, or other significant neurologic conditions.
• Past or intended use of over-the-counter or prescription medication, including herbal medications, within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is the longest) prior to dosing.
• Subject received a vaccine (either live attenuated or now-live) within 30 days prior to randomization, or plans to receive a live attenuated vaccine within 30 days + 5 half-lives (32 days) of the last dose of study medication.
• Participation in the study would result in loss of blood or blood products in excess of 500 milliliters (mL) within a 56-day period.
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
• The subject 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).
• Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C antibody test result at screening.
• Positive pre-study drug/alcohol screen.
• Positive human immunodeficiency virus (HIV1 and 2) antibody test.
• Regular use of known drugs of abuse.
• Subjects with impaired renal function defined as Chronic Kidney Disease Epidemiology Collaboration (CKS-EPI) Creatinine > 1.6 mg/deciliter (mg/dL) with an age appropriate glomerular filtration rate (GFR) <= 60 (mL/minute/1.73 m^2) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
• An elevated C-reactive protein (CRP) outside of the normal reference range.
• Regular alcohol consumption within 6 months prior to the study defined as: For United Kingdom (UK) - an average weekly intake of >14 units for males and females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• Cotinine or carbon monoxide levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
• Unwilling or unable to swallow multiple size 00 capsules as part of study participation.

• History of SIB as measured using the Columbia Suicide Severity Rating Scale (C-SSRS) or a history of attempted suicide.
• A positive anti-nuclear antibody (ANA) outside of the normal reference range.
• Fasting total cholesterol >=300 mg/dL or triglycerides >=250 mg/dL.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Cambridge, , United Kingdom

Countries

United Kingdom

References

Tompson DJ, Davies C, Scott NE, Cannons EP, Kostapanos M, Gross AS, Powell M, Ino H, Shimamura R, Ogura H, Nagakubo T, Igarashi H, Nakano A. Comparison of the Pharmacokinetics of RIPK1 Inhibitor GSK2982772 in Healthy Western and Japanese Subjects. Eur J Drug Metab Pharmacokinet. 2021 Jan;46(1):71-83. doi: 10.1007/s13318-020-00652-2.

Reference Type: DERIVED

PMID: 33165774 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2017-002662-45

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

205184

Identifier Type: -

Identifier Source: org_study_id