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

NCT03305419 | Completed Phase 1 Results

• 2 other identifiers: 2051842017-002662-45
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

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

Keywords

Crossover; Sequential; GSK2982772; Safety; Pharmacokinetics; Healthy subjects

Outcome Measures

Primary Outcomes (12)

• Number of Subjects With Adverse Events (AEs) and Serious AEs (SAEs): Part A

  An AE is any untoward medical occurrence in a clinical study subjects, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.

  Up to Day 14

• Number of Participants With AEs and SAEs: Part B

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment were categorized as SAE.

  Up to Day 28

• Number of Participants With Worst Case Clinical Chemistry Parameters by Potential Clinical Importance Criteria: Part A

  Blood samples were collected from participants for the analysis of following clinical chemistry parameters: alanine amino transferase (ALT), albumin, alkaline phosphatase, aspartate amino transferase (AST), calcium, creatinine, glucose, potassium, sodium and total bilirubin. PCI ranges were \>=2 times Upper Limit of Normal (ULN) units per liter (U/L) for ALT, \<30 grams per liter (g/L) for albumin, \>=2 times ULN U/L for alkaline phosphatase, \>=2 times ULN U/L for AST, \<2 or \>2.75 millimoles per liter (mmol/L) for calcium, \>44.2 micromoles per liter (µmol/L) for creatinine, \<3 or \>9 mmol/L for glucose, \<3 or \>5.5 mmol/L for potassium, \<130 or \>150 mmol/L for sodium and \>=1.5 times ULN for total bilirubin. Participants were counted in the worst case category that their value changed to low, normal or high. If values were unchanged (example: High to High), or whose value became normal, were recorded in 'No Change' category.

  Up to Week 9

• Number of Participants With Worst Case Clinical Chemistry Parameters by Potential Clinical Importance Criteria: Part B

  Blood samples were collected from participants for the analysis of following clinical chemistry parameters: ALT, albumin, alkaline phosphatase, AST, calcium, creatinine, glucose, potassium, sodium and total bilirubin. PCI ranges were \>=2 times ULN U/L for ALT, \<30 g/L for albumin, \>=2 times ULN U/L for alkaline phosphatase, \>=2 times ULN U/L for AST, \<2 or \>2.75 mmol/L for calcium, \>44.2 µmol/L for creatinine, \<3 or \>9 mmol/L for glucose, \<3 or \>5.5 mmol/L for potassium, \<130 or \>150 mmol/L for sodium and \>=1.5 times ULN for total bilirubin. Participants were counted in the worst case category that their value changed to low, normal or high. If values were unchanged (example: High to High), or whose value became normal, were recorded in 'No Change' category.

  Up to Week 4

• Number of Participants With Worst Case Hematology Parameters by Potential Clinical Importance Criteria: Part A

  Blood samples were collected from participants for analysis of following hematology parameters; hematocrit, hemoglobin, lymphocytes, platelet count, total neutrophils and white blood cell (WBC) counts. PCI ranges were \>0.54 or \< 0.075 proportion of red blood cells (RBC) in blood for hematocrit, \<25 or \>180 g/L for hemoglobin, 0.8 x10\^9 cells/L for lymphocytes, \<1.5 x10\^9 cells/L for neutrophils, \<100 or \>550 x10\^9 cells/L for platelets and \<3 or 20\> x 10\^9 cells per liter WBC. Participants were counted in the worst case category that their value changed to low, normal or high. If values were unchanged (example: High to High), or whose value became normal, were recorded in 'No Change' category.

  Up to Week 9

• Number of Participants With Worst Case Hematology Parameters by Potential Clinical Importance Criteria: Part B

  Blood samples were collected from participants for analysis of following hematology parameters; hematocrit, hemoglobin, lymphocytes, platelet count, total neutrophils and WBC counts. PCI ranges were \>0.54 or \< 0.075 proportion of RBC in blood for hematocrit, \<25 or \>180 g/L for hemoglobin, 0.8 x10\^9 cells/L for lymphocytes, \<1.5 x10\^9 cells/L for neutrophils, \<100 or \>550 x10\^9 cells/L for platelets and \<3 or 20\> x 10\^9 cells per liter WBC. Participants were counted in the worst case category that their value changed to low, normal or high. If values were unchanged (example: High to High), or whose value became normal, were recorded in 'No Change' category.

  Up to Week 4

• Number of Participants With Worst Case Urinalysis Results: Part A

  Urine samples were collected from participants for analysis of following parameters: cellular casts, granular casts, hyaline casts, RBC and WBC and were counted as cells per high-power field (cells/HPF). The number of participants with cells in urine has been presented.

  Up to Week 9

• Number of Participants With Worst Case Urinalysis Results: Part B

  Urine samples were collected from participants for analysis of following parameters: cellular casts, granular casts, hyaline casts, RBC and WBC and were counted as cells per high-power field (cells/HPF). The number of participants with cells in urine has been presented.

  Up to Week 4

• Number of Participants With Abnormal Vital Signs: Part A

  Vital signs were measured in a supine position after 5 minutes rest. The PCI criteria for vital signs included: systolic blood pressure \<85 and \>160 millimeters of mercury \[mmHg\]), diastolic blood pressure \<45 mmHg and \>100 mmHg, heart rate \<40 and \>100 beats per minute, body temperature \<=35.5 and \>=37.8 degrees Celsius and respiration rate \<=8 and \>=20 breaths per minute. Data of participants with potential clinical importance has been reported.

  Up to Week 9

• Number of Participants With Abnormal Vital Signs: Part B

  Vital signs were measured in a supine position after 5 minutes rest. The PCI criteria for vital signs included: systolic blood pressure \<85 and \>160 mmHg, diastolic blood pressure \<45 mmHg and \>100 mmHg, heart rate \<40 and \>100 beats per minute, body temperature \<=35.5 and \>=37.8 degrees Celsius and respiration rate \<=8 and \>=20 breaths per minute. Data of participants with potential clinical importance has been reported.

  Up to Week 4

• Number of Participants With Abnormal Electrocardiogram (ECG) Findings: Part A

  12-lead ECG's were obtained in the supine position after 5 minutes of rest using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT and QT duration corrected for heart rate by Fridericia's formula (QTcF) intervals. Clinically significant and not clinically significant abnormal ECG findings have been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

  Up to Day 4

• Number of Participants With Abnormal ECG Findings: Part B

  12-lead ECG's were obtained in the supine position after 5 minutes of rest using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT and QT duration corrected for heart rate by Fridericia's formula (QTcF) intervals. Clinically significant and not clinically significant abnormal ECG findings have been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

  Up to Week 4

Secondary Outcomes (40)

• Area Under the Concentration-time Curve (AUC) From Time Zero to 24 Hours (AUC[0-24]) Following TID Dosing of GSK2982772: Part A

  Pre-dose, 20, 40minutes, 1 hour, 1hr 30min, 2, 3, 5, 7hour, 7hr 20min,and 7hr 40 min, 8hr, 8hr 30min, 9hr, 10hr, 12hr, 14hr, 14hr 20min, 14hr 40 min, 15hr, 15hr 30min, 16hr, 17hr, 19hr, 22hr, 24hours post dose on Day1

• AUC(0-24) Following BID Dosing of GSK2982772: Part A

  Pre-dose, 20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 4hr, 6hr, 8hr, 10hr, 12hr, 12hr 20min, 12hr 40min, 13hr, 13hr 30min, 14hr, 15hr, 16hr, 19hr, 22hr, 24hr post dose on Day 1.

• AUC[0-24] Following TID Dosing of GSK2982772: Part B

  Pre-dose, 20, 40minutes, 1 hour, 1hr 30min, 2, 3, 5, 7hour, 7hr 20min,and 7hr 40 min, 8hr, 8hr 30min, 9hr, 10hr, 12hr, 14hr, 14hr 20min, 14hr 40 min, 15hr, 15hr 30min, 16hr, 17hr, 19hr, 22hr, 24hours post dose on Day14

• AUC (0-7) Following TID Dosing of GSK2982772 : Part A

  Pre-dose, 20 and 40 minutes, 1 and 1 hour 30 minutes, 2, 3, 5, 7 hours on Day 1

• AUC (7-14) Following TID Dosing of GSK2982772 : Part A

  7 hours, 7 hours 20 and 40 minutes, 8 hours, 8 hours 30 minutes, 9, 10, 12, 14 hours on Day 1

Study Arms (12)

Subjects receiving treatment sequence ABC in cohort 1: Part A

EXPERIMENTAL

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.

Drug: GSK2982772 capsule; Drug: Placebo capsule

Subjects receiving treatment sequence ABP in cohort 1: Part A

EXPERIMENTAL

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.

Drug: GSK2982772 capsule; Drug: Placebo capsule

Subjects receiving treatment sequence APC in cohort 1: Part A

EXPERIMENTAL

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.

Drug: GSK2982772 capsule; Drug: Placebo capsule

Subjects receiving treatment sequence PBC in cohort 1: Part A

EXPERIMENTAL

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.

Drug: GSK2982772 capsule; Drug: Placebo capsule

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

EXPERIMENTAL

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

Drug: GSK2982772 capsule

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

EXPERIMENTAL

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

Drug: GSK2982772 capsule

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

EXPERIMENTAL

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

Drug: GSK2982772 capsule

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

EXPERIMENTAL

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

Drug: GSK2982772 capsule

Subjects receiving placebo in cohort 2 : Part B

PLACEBO COMPARATOR

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

Drug: Placebo capsule

Subjects receiving placebo in cohort 3 : Part B

PLACEBO COMPARATOR

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

Drug: Placebo capsule

Subjects receiving placebo in cohort 4 : Part B

PLACEBO COMPARATOR

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

Drug: Placebo capsule

Subjects receiving placebo in cohort 5: Part B

PLACEBO COMPARATOR

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

Drug: Placebo capsule

Interventions

GSK2982772 capsule 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 2 : Part B; Subjects receiving GSK2982772 120 mg TID in cohort 3 : Part B; Subjects receiving GSK2982772 240 mg TID in cohort 4: Part B; Subjects receiving GSK2982772 360 mg BID in cohort 5: Part B; Subjects receiving treatment sequence ABC in cohort 1: Part A; Subjects receiving treatment sequence ABP in cohort 1: Part A; Subjects receiving treatment sequence APC in cohort 1: Part A; Subjects receiving treatment sequence PBC in cohort 1: Part A

Placebo capsule 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 2 : Part B; Subjects receiving placebo in cohort 3 : Part B; Subjects receiving placebo in cohort 4 : Part B; Subjects receiving placebo in cohort 5: Part B; Subjects receiving treatment sequence ABC in cohort 1: Part A; Subjects receiving treatment sequence ABP in cohort 1: Part A; Subjects receiving treatment sequence APC in cohort 1: Part A; Subjects receiving treatment sequence PBC in cohort 1: Part A

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 33165774 DERIVED

MeSH Terms

Conditions

Autoimmune Diseases

Interventions

GSK2982772

Condition Hierarchy (Ancestors)

Immune System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This will be a double-blind study. Subjects and investigator will be masked.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This study will consist of two parts; Part A and Part B. Part A will be a 3-way crossover design and Part B will be a sequential-group design.

Study Record Dates

• First Submitted: October 4, 2017
• First Posted: October 10, 2017
• Study Start: October 11, 2017
• Primary Completion: October 15, 2018
• Study Completion: October 15, 2018
• Last Updated: October 10, 2023
• Results First Posted: November 1, 2019

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Anonymized IPD is 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)