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

GlaxoSmithKline62 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Autoimmune Diseases

Interventions

GSK2982772 capsuleDRUG

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 capsuleDRUG

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

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Subject must be 18 to 65 years of age inclusive, at the time of signing the informed consent. * Healthy as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, neurological examination, laboratory tests and cardiac monitoring. 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 Investigator in consultation with the Medical Monitor (if required) agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * 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. Exclusion Criteria: * 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. PART B Specific exclusion criteria: * 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.

Locations (1)

GSK Investigational Site

Cambridge, United Kingdom

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Up to Week 9

Number of Participants With Worst Case Urinalysis Results: Part B

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Up to Day 4

Number of Participants With Abnormal ECG Findings: Part B

Time frame: Up to Week 4

Secondary Outcomes

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

Blood samples were collected at indicated timepoints for pharmacokinetic analysis of GSK2982772. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

Time frame: 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

Blood samples were collected at indicated timepoints for pharmacokinetic analysis of GSK2982772. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

Time frame: 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

Blood samples were collected at indicated timepoints for pharmacokinetic analysis of GSK2982772. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

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

Blood samples were collected at indicated timepoints for pharmacokinetic analysis of GSK2982772. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

Time frame: 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

Blood samples were collected at indicated timepoints for pharmacokinetic analysis of GSK2982772. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

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

Data from ClinicalTrials.gov

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AUC (14-24) Following TID Dosing of GSK2982772 : Part A

Blood samples were collected at indicated timepoints for pharmacokinetic analysis of GSK2982772. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

Time frame: 14 hours, 14 hours 20 and 40 minutes, 15 hours ,15 hours 30 minutes, 16, 19, 22 and 24 hours on Day 1

AUC (0-12) Following BID Dosing of GSK2982772 in Part A

Blood samples were collected at indicated timepoints for pharmacokinetic analysis of GSK2982772. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 20 and 40 minutes, 1 and 1 hour 30 minutes, 2, 3, 4, 6, 8, 10 hours,12 hours on Day 1

AUC (12-24) Following BID Dosing of GSK2982772 in Part A

Blood samples were collected at indicated timepoints for pharmacokinetic analysis of GSK2982772. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

Time frame: 12 hours, 12 hours 20 and 40 minutes, 13 and 13 hours 30 minutes, 14, 15, 16, 19, 22 and 24 hours on Day 1

AUC(0-7) Following TID Dosing of GSK2982772 in Part B