Clinical trial NCT03590613: Phase I Study of GSK2982772 in Japanese Healthy Male Participants
Official title: A Single-centre, Randomized, Double-blind, Dose-ascending, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral TID Doses (One Day) of GSK2982772 in Japanese Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Autoimmune Diseases
Keywords: Sentinel-dosing
GSK2982772
Japnese
Dose-ascending
Crossover
Healthy
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2018-07-18
Enrollment: 13
Sex: MALE
Minimum age (years): 20
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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.
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* Subject must be 20 to 64 years of age inclusive, at the time of signing the informed consent.
* Healthy as determined by the Investigators based on a medical evaluation including medical history, physical examination, neurological examination, laboratory tests, and ECG. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigators in consultation with the GSK Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* 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.

Exclusion Criteria:

* 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.
* Past or intended use of over-the-counter or prescription medication including herbal medications within 14 days prior to dosing; live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the study.
* History of donation of blood or blood products \>= 400 mL within 3 months or \>= 200 mL within 1 month prior to screening.
* Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
* The subject has participated in a other clinical study or other medical research within 4 months prior to the first dosing day in the current study.
* Subject is positive Serological test for syphilis Rapid Plasma Reagin \[RPR\] and Treponema pallidum \[TP\]), Tuberculosis, human immunodeficiency virus (HIV) Antigen/Antibody, Hepatitis B surface antigen (HbsAg), Hepatitis C virus (HCV) antibody, or Human T-cell leukemia virus type 1 (HTLV-1) antibody at screening.
* Positive pre-study drug screen.
* Regular use of known drugs of abuse.
* Regular alcohol consumption within 6 months prior to the study defined as: for an average weekly intake of \> 14 units for males. One unit is equivalent to 350 mL of beer, 150 mL of wine or 45 mL of 80 proof distilled spirits.
* 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 investigators or GSK Medical Monitor, contraindicates participation in the study.

Primary outcomes:
measure: Number of Participants Reporting Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From the day of first dose to 39 days
measure: Change From Baseline in Clinical Chemistry Parameters
timeFrame: Baseline (Day -1) and at 72 hours at each treatment period
measure: Change From Baseline in Clinical Chemistry Parameters: Albumin and Protein
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: 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)
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Clinical Chemistry Parameter: Amylase
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine and Urate (Uric Acid)
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Clinical Chemistry Parameter: C-reactive Protein (CRP) of TID Doses for One Day of GSK2982772
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Hematology Parameter: Hemoglobin
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Hemoglobin (MCH)
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Hematology Parameter: Erythrocyte Mean Corpuscular Volume (MCV)
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Hematology Parameter: Erythrocytes
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Hematology Parameter: Reticulocytes/Erythrocytes
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Hematology Parameters: Platelets and Leukocytes of TID Doses for One Day of GSK2982772
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Hematology Parameters of TID Doses for One Day of GSK2982772
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Urine Potential of Hydrogen (pH)
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Change From Baseline in Urine Specific Gravity
timeFrame: Baseline (Day -1) and at 72 hours at each Treatment Period
measure: Number of Participants With Abnormal Urinalysis Results by Dipstick Method
timeFrame: At 72 hours of each Treatment Period
measure: Change From Baseline in Electrocardiogram (ECG) Finding: Mean Heart Rate
timeFrame: Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each Treatment Period
measure: Change From Baseline in ECG Findings of TID Doses for One Day of GSK2982772
timeFrame: Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each Treatment Period
measure: Number of Participants With Abnormal Not Clinically Significant Cardiac Telemetry
timeFrame: Up to 24 hours at each Treatment Period
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each treatment period
measure: Change From Baseline in Pulse Rate of TID Doses for One Day of GSK2982772
timeFrame: Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each Treatment Period
measure: Change From Baseline in Body Temperature of TID Doses for One Day of GSK2982772
timeFrame: Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each Treatment Period
measure: Number of Participants With Abnormal Neurological Examinations of TID Doses for One Day of GSK2982772
timeFrame: Baseline (Day -1) and at 2, 7, 14, 24, 48 and 72 hours at each Treatment Period
Secondary outcomes:
measure: 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
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) and Observed Trough Drug Plasma Concentrations Following Each TID Doses for One Day of GSK2982772
timeFrame: 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
measure: Terminal Half Life (t1/2) After the Third TID Dose for One Day of GSK2982772
timeFrame: 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
measure: Time to Maximum Observed Plasma Drug Concentration (Tmax) of Each TID Doses for One Day of GSK2982772
timeFrame: 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
Other outcomes:
Locations:
city: Fukuoka
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.