Phase I Study of GSK2982772 in Japanese Healthy Male Participants

NCT03590613 | Completed Phase 1 Results

• 1 other identifier: 205037
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

The study plans to enroll approximately 12 subjects. The main objective of the study is to assess the safety, tolerability and pharmacokinetics (PK) of the three times a day (TID), dosing of GSK2982772, in Japanese healthy male subjects. The study will comprise of four study periods each at least 7 days in duration with subjects in-house for 4 nights (through 72 hrs after the first dose). During each treatment period (TP), subjects will be admitted to the unit the day before dosing and will be discharged after completion of the 72 hours post-dose assessments. There will be a washout of atleast 7-days between the TP doses for each individual, post which there will be 7-days follow-up. The dose range proposed in this study is based on a low starting dose, which will be escalated to the highest dose that is intended for the Phase 2b dose range study. The decision to proceed to the next dose-level, of GSK2982772 within the study will be made by principal investigator and GSK Medical Monitor per each dosing periods. The study duration is approximately 22 weeks.

Conditions

Autoimmune Diseases

Keywords

Sentinel-dosing; GSK2982772; Japnese; Dose-ascending; Crossover; Healthy

Outcome Measures

Primary Outcomes (25)

• Number of Participants Reporting Adverse Events (AEs) and Serious Adverse Events (SAEs)

  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. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgement. Safety population comprised of all participants who have received at least one dose of study treatment. This population was used for the safety analyses.

  From the day of first dose to 39 days

• Change From Baseline in Clinical Chemistry Parameters

  Blood samples were collected for the analysis of clinical chemistry parameters including: glucose, calcium, cholesterol, chloride, high density lipoprotein (HDL) cholesterol, potassium, low density lipoprotein (LDL) cholesterol, phosphate, sodium, triglycerides and urea. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each treatment period

• Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein

  Blood samples were collected for the analysis of clinical chemistry parameters including: albumin and protein. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Clinical Chemistry Parameters: Alkaline Phosphate (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatinine Kinase (CK), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrognase (LDH)

  Blood samples were collected for the analysis of clinical chemistry parameters including: ALP, ALT, AST, CK, GGT and LDH. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Clinical Chemistry Parameter: Amylase

  Blood samples were collected for the analysis of clinical chemistry parameter: amylase. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine and Urate (Uric Acid)

  Blood samples were collected for the analysis of clinical chemistry parameters:direct bilirubin, bilirubin, creatinine and urate. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Clinical Chemistry Parameter: C-reactive Protein (CRP) of TID Doses for One Day of GSK2982772

  Blood samples were collected for the analysis of clinical chemistry parameter: CRP. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Hematology Parameter: Hematocrit

  Blood samples were collected for the analysis of hematology parameter: hematocrit. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Hematology Parameter: Hemoglobin

  Blood samples were collected for the analysis of hematology parameter: hemoglobin. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Hemoglobin (MCH)

  Blood samples were collected for the analysis of hematology parameter: erythrocyte MCH. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Volume (MCV)

  Blood samples were collected for the analysis of hematology parameter: erythrocyte MCV. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Hematology Parameter: Erythrocytes

  Blood samples were collected for the analysis of hematology parameter: erythrocytes. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Hematology Parameter: Reticulocytes/Erythrocytes

  Blood samples were collected for the analysis of hematology parameter: percentage reticulocytes. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Hematology Parameters: Platelets and Leukocytes of TID Doses for One Day of GSK2982772

  Blood samples were collected for the analysis of hematology parameters including platelet count and leukocytes. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Hematology Parameters of TID Doses for One Day of GSK2982772

  Blood samples were collected for the analysis of hematology parameters including neutrophils/leukocytes, lymphocytes/leukocytes, monocytes/leukocytes, eosinophils/leukocytes and basophils/leukocytes. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Urine Potential of Hydrogen (pH)

  Urine samples were collected for analysis of urine pH. pH is calculated on a scale of 0 to 14, values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH of less than 7 is acidic and a pH of greater than 7 is basic. Normal urine has a slightly acidic pH (5.0-6.0). Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Change From Baseline in Urine Specific Gravity

  Urine samples were collected for analysis of urine specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. The urinary specific gravity measurement is a routine part of urinalysis. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 72 hours at each Treatment Period

• Number of Participants With Abnormal Urinalysis Results by Dipstick Method

  Urine samples were collected to assess urine bilirubin, urine glucose, urine ketones, urine occult blood, urine protein and urine urobilinogen by dipstick test. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameter of urine bilirubin, urine occult blood, urine glucose, urine ketones, urine protein and urine urobilinogen can be read as negative (-) and trace (+-) indicating proportional concentrations in the urine sample.

  At 72 hours of each Treatment Period

• Change From Baseline in Electrocardiogram (ECG) Finding: Mean Heart Rate

  Full 12-lead ECGs were recorded in participant using an automated ECG machine. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each Treatment Period

• Change From Baseline in ECG Findings of TID Doses for One Day of GSK2982772

  Full 12-lead ECGs were recorded in participants using an automated ECG machine and measured PR, QRS, QT and QTcF intervals. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each Treatment Period

• Number of Participants With Abnormal Not Clinically Significant Cardiac Telemetry

  Continuous cardiac telemetry was performed and number of participants with abnormal clinically significant and not clinically significant values are presented.

  Up to 24 hours at each Treatment Period

• Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

  Blood pressure of participants were measured at indicated time points in supine position after 5 minutes rest. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each treatment period

• Change From Baseline in Pulse Rate of TID Doses for One Day of GSK2982772

  Pulse rate of participants were measured at indicated time points in supine position after 5 minutes rest. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each Treatment Period

• Change From Baseline in Body Temperature of TID Doses for One Day of GSK2982772

  Temperature of participants were measured at indicated time points in supine position after 5 minutes rest. Baseline value was the latest pre-dose (Day -1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each Treatment Period

• Number of Participants With Abnormal Neurological Examinations of TID Doses for One Day of GSK2982772

  Neurological examinations including: mental status, gait, balance, coordination, cranial nerves, motor power, reflexes, and sensory system (light touch and pain) were assessed in participants specified time points.

  Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each Treatment Period

Secondary Outcomes (4)

• Area Under the Plasma Drug Concentration Versus Time Curve Over 24 Hours (AUC[0-24]) and AUC Over Each Dose Interval of TID Doses for One Day of GSK2982772

  Pre-dose, 20 and 40 minutes, 1, 1.5, 2, 3, 5, 7 hours, 7 hours 20 minutes, 7 hours 40 minutes, 8, 8.5, 9, 10, 12, 14 hours, 14 hours 20 minutes, 14 hours 40 minutes, 15, 15.5, 16, 17, 19, 22 and 24 hours post-dose at each Treatment Period

• Maximum Observed Plasma Concentration (Cmax) and Observed Trough Drug Plasma Concentrations Following Each TID Doses for One Day of GSK2982772

  Pre-dose,20 and 40 minutes, 1, 1.5, 2, 3, 5, 7 hours,7 hours 20 minutes,7 hours 40 minutes,8, 8.5, 9, 10, 12, 14 hours,14 hours 20 minutes,14 hours40 minutes, 15, 15.5, 16, 17, 19, 22, 24, 28, 32, 36, 48, 60 and 72 hours post-dose at each Treatment Period

• Terminal Half Life (t1/2) After the Third TID Dose for One Day of GSK2982772

  Pre-dose,20 and 40 minutes, 1, 1.5, 2, 3, 5, 7 hours,7 hours 20 minutes,7 hours 40 minutes,8, 8.5, 9, 10, 12, 14 hours,14 hours 20 minutes,14 hours40 minutes, 15, 15.5, 16, 17, 19, 22, 24, 28, 32, 36, 48, 60 and 72 hours post-dose at each Treatment Period

• Time to Maximum Observed Plasma Drug Concentration (Tmax) of Each TID Doses for One Day of GSK2982772

  Pre-dose,20 and 40 minutes, 1, 1.5, 2, 3, 5, 7 hours,7 hours 20 minutes,7 hours 40 minutes,8, 8.5, 9, 10, 12, 14 hours,14 hours 20 minutes,14 hours40 minutes, 15, 15.5, 16, 17, 19, 22, 24, 28, 32, 36, 48, 60 and 72 hours post-dose at each Treatment Period

Study Arms (4)

Sequence 1: Placebo TID then 60 TID then 120 TID then 240 TID

EXPERIMENTAL

The eligible subjects in this arm will receive placebo TID in TP1, GSK2982772 60 mg TID in TP2, GSK2982772 120mg TID in TP3 and GSK2982772 240 mg TID in TP4. GSK2982772 or placebo will be administered at 0 hour (the first dosing), 7 hours (the second dosing) and 14 hours (the third dosing) on Day 1 in each TP. Subjects will fast overnight for 8 hours before first dose. Each TP will be followed by a washout period of at least 7 days, for each subject.

Drug: GSK2982772; Drug: Placebo

Sequence 2: 60 TID then Placebo TID then 120 TID then 240 TID

EXPERIMENTAL

The eligible subjects in this arm will receive GSK2982772 60 mg TID in TP1, placebo TID in TP2, GSK2982772 120mg TID in TP3 and GSK2982772 240 mg TID in TP4. GSK2982772 or placebo will be administered at 0 hour (the first dosing), 7 hours (the second dosing) and 14 hours (the third dosing) on Day 1 in each TP. Subjects will fast overnight for 8 hours before first dose. Each TP will be followed by a washout period of at least 7 days, for each subject.

Drug: GSK2982772; Drug: Placebo

Sequence 3: 60 TID then 120 TID then Placebo TID then 240 TID

EXPERIMENTAL

The eligible subjects in this arm will receive GSK2982772 60 mg TID in TP1, GSK2982772 120mg TID in TP2, placebo TID in TP3 and GSK2982772 240 mg TID in TP4. GSK2982772 or placebo will be administered at 0 hour (the first dosing), 7 hours (the second dosing) and 14 hours (the third dosing) on Day 1 in each TP. Subjects will fast overnight for 8 hours before first dose. Each TP will be followed by a washout period of at least 7 days, for each subject.

Drug: GSK2982772; Drug: Placebo

Sequence 4: 60 TID then 120 TID then 240 TID then Placebo TID

EXPERIMENTAL

The eligible subjects in this arm will receive GSK2982772 60 mg TID in TP1, GSK2982772 120mg TID in TP2, GSK2982772 240 mg TID in TP3 and placebo TID in TP4. GSK2982772 or placebo will be administered at 0 hour (the first dosing), 7 hours (the second dosing) and 14 hours (the third dosing) on Day 1 in each TP. Subjects will fast overnight for 8 hours before first dose. Each TP will be followed by a washout period of at least 7 days, for each subject.

Drug: GSK2982772; Drug: Placebo

Interventions

GSK2982772 DRUG

GSK2982772 will be available as white to almost white, round, film coated tablets to be administered via oral route

Sequence 1: Placebo TID then 60 TID then 120 TID then 240 TID; Sequence 2: 60 TID then Placebo TID then 120 TID then 240 TID; Sequence 3: 60 TID then 120 TID then Placebo TID then 240 TID; Sequence 4: 60 TID then 120 TID then 240 TID then Placebo TID

Placebo DRUG

Placebo matching GSK2982772 will be available as white to almost white, round, film coated tablets to be administered via oral route.

Sequence 1: Placebo TID then 60 TID then 120 TID then 240 TID; Sequence 2: 60 TID then Placebo TID then 120 TID then 240 TID; Sequence 3: 60 TID then 120 TID then Placebo TID then 240 TID; Sequence 4: 60 TID then 120 TID then 240 TID then Placebo TID

Eligibility Criteria

• Age: 20 Years - 64 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject must be 20 to 64 years of age inclusive, at the time of signing the informed consent.

You may not qualify if:

• Body weight \>= 50 kilogram (kg) and body mass index (BMI) within the range 18.5-24.9 kg/meter square (inclusive).
• Japanese male subjects must agree to use contraception as detailed in protocol during the treatment period and until follow up visit.
• Capable of giving informed consent as described in the protocol.
• History or presence of 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.
• Abnormal blood pressure as determined by the investigators.
• Symptomatic herpes zoster within 3 months prior to screening.
• Evidence of active or latent Tuberculosis (TB) as documented by medical history and examination, chest X-rays (anterior and lateral), and TB testing (T Spot. TB)
• 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).
• History of active infections within 14 days of first receiving study medication.
• Corrected Q-T interval (QTc) obtained using the Fridericia's formula (QTcF) \> 450 millisecond.
• History or diagnosis of obstructive sleep apnoea, or a significant respiratory disorder. Childhood asthma that was fully resolved is permitted.
• History of active Suicidal Ideation Behavior within the past 6 months or any history of attempted suicide in a subject's lifetime.
• History or current evidence of febrile seizures, epilepsy, convulsions, significant head injury, or other significant neurologic conditions.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Fukuoka, 812-0025, Japan

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: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: It is a double-blinded study, where the subjects, investigators and the site-staff will be blinded.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Study will comprise of four TPs, each of at least 7 days in duration with subjects in-house for 4 nights (through 72 hours after the first dose). During each TP, subjects will be admitted to the unit, day before dosing and will be discharged after completion of 72 hours post-dose assessments. dose will be administered TID, in an ascending manner. Every individual subject will receive placebo and GSK2982772 (60, 120,240 mg TID) as per assigned sequence. For TID dosing, GSK2982772 or placebo will be administered at 0 hour (the first dosing), 7 hour (the second dosing) and 14 hour (the third dosing) on Day 1 in each period. On Day 1, subjects will fast 8hour overnight prior to first dose. breakfast will be served approximately 2hour after first dose. Lunch and dinner will be served between 2 to 3hour prior to second and third doses, respectively. A washout of atleast 7-days between the TP doses for each individual subject.

Study Record Dates

• First Submitted: July 6, 2018
• First Posted: July 18, 2018
• Study Start: July 19, 2018
• Primary Completion: September 21, 2018
• Study Completion: September 26, 2018
• Last Updated: October 4, 2023
• Results First Posted: September 17, 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

JP (1)