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GSK2983559 First Time in Human Study

Primary Purpose

Inflammatory Bowel Diseases

Status

Terminated

Phase

Phase 1

Locations

United Kingdom

Study Type

Interventional

Intervention

GSK2983559

Placebo

About this trial

This is an interventional treatment trial for Inflammatory Bowel Diseases focused on measuring Inflammatory Bowel disease, Pro-drug, Double-blinded, Crossover

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Male and female subjects between 18 and 65 years of age inclusive, at the time of signing the informed consent.
Volunteers who are overtly healthy as determined by medical evaluation including medical and psychiatric history, physical examination, neurological examination, clinical laboratory tests and cardiac monitoring.
3Body weight >= 50 kg (kilogram) and body mass index (BMI) within the range 19-32 kilogram per meter square (kg/m^2) .
A male subject must agree to use a highly effective contraception during the treatment period and for at least 5 half-lives plus an additional 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 is not a woman of childbearing potential (WOCBP)
Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Participants must agree to avoid prolonged Ultraviolet (UV) exposure to natural sunlight without required Ultraviolet A (UVA)/ Ultraviolet B (UVB) protection or tanning beds for the duration of the study.

Exclusion Criteria:

History or presence of/significant history 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 or current evidence of febrile seizures, epilepsy, convulsions, significant head injury, or other significant neurologic conditions.
History of clinically significant psychiatric disorders as judged by the investigator.
Any history of suicidal behavior within the past 6 months or any history of attempted suicide in a subject's lifetime.
ALT >1.5x upper limit of normal (ULN).
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN 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 Gastrointestinal (GI) surgery (with exception of appendectomy)
Average QTc > 450 millisecond (msec)
Intended use of over-the-counter or prescription medication including herbal medications within 7 days prior to dosing
Live or attenuated vaccine(s) within 30 days of randomization, or plans to receive such vaccines during the study or plans to receive a vaccine within 30 days + 5 half-lives of the last dose of study medication.
Regular alcohol consumption within 6 months prior to the study defined as: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
Current use or history of regular tobacco- or nicotine-containing products within 6 months prior to screening. Subject must have urinary cotinine levels indicative of non-smoking status at screening visit.
Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
Current enrollment or past participation within the last 30 days before signing of consent in this or any other clinical study involving an investigational study treatment or any other type of medical research.
Subjects with impaired renal function defined as Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) calculation <= 60 milliliter per minute per 1.73 meter square (mL/min/1.73 m^2) estimated by the CKD-EPI equation.
An elevated C-reactive protein (CRP) outside of the normal reference range.
Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. As potential for and magnitude of immunosuppression with this compound is unknown, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded. Subjects positive for HBsAg and/or positive for anti-HBc antibody (regardless of anti-HBs antibody status) are excluded.
A positive pre-study drug/alcohol screen.
A positive test for HIV antibody.
A positive diagnostic TB test at screening defined as a positive QuantiFERON-TB Gold test or T-spot test. In cases where the QuantiFERON or T-spot test is indeterminate, the subject may have the test repeated once, but they will not be eligible for the study unless the second test is negative. In cases where the QuantiFERON or T-spot test is positive, but a locally-read follow up chest x-ray, shows no evidence of current or previous pulmonary tuberculosis, the subject may be eligible for the study at the discretion of the Investigator and GSK Medical Monitor.
Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates participation in the study.
Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56-day period.
Part A (Food Effect) Cohort: Subject must have no dietary restrictions (e.g., lactose intolerance) or inability to eat a high fat meal.

Sites / Locations

GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Part A: Cohort 1

Part A: Cohort 2 fasting

Part A: Cohort 2 fed

Part B

Arm Description

Cohort 1 will be 5-way crossover with 5 treatment periods. Subjects will be randomized in the ratio 4:1 to receive either single dose of GSK2983559 or placebo.

Cohort 2 will be 4-way crossover design with one additional period of open-label. Subjects will be randomized in the ratio 3:1 to receive either single dose of GSK2983559 or placebo in fasted conditions

In Cohort 2, treatment period 5 will be open-label period. This open-label period is to determine food effect and subjects will receive GSK2983559 under fed conditions.

Part B is repeat ascending dose sequential period. There will four cohorts (3-6) of 10 healthy subjects. In each cohort subjects will be randomized to receive GSK2983559 or placebo in ratio 4:1. Subjects will receive GSK2983559 or placebo QD and twice daily dose will be decided based upon the pharmacokinetic, safety and tolerability observed in Part A.

Outcomes

Primary Outcome Measures

Part A: Number of Participants With Non Serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)

An adverse event was 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. SAE was defined as any untoward medical occurrence that, at any dose may result in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement.

Part B: Number of Participants With Non-SAEs and SAEs

Part A: Number of Participants With Worst Case Hematology Parameters of Potential Clinical Importance (PCI)

Hematology parameters included hematocrit, hemoglobin, lymphocytes, platelet counts, total neutrophils and white blood cells (WBCs) count. PCI ranges were: hematocrit (high: >0.54 proportion of red blood cells in blood and low: change from baseline<0.0075); hemoglobin (high: >180 grams per liter [g/L] and low: change from baseline<25 g/L); lymphocytes (low: <0.8 Giga cells/L); platelet count (low: <100 Giga cells/L and high: >550 Giga cells/L); neutrophil count (low: <1.5 Giga cells/L); white blood cell count (low: <3 Giga cells/L and high: >20 Giga cells/L). Participants were counted in the worst-case category that their value changed to (low, within range or no change, or high) unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category. Only those hematology parameters with PCI values have been presented.

Part B: Number of Participants With Worst Case Hematology Parameters of PCI

Hematology parameters included hematocrit, hemoglobin, lymphocytes, platelet counts, total neutrophils and WBC count. PCI ranges were: hematocrit (high: >0.54 proportion of red blood cells in blood and low: change from baseline<0.0075); hemoglobin (high: >180 grams per liter [g/L] and low: change from baseline<25 g/L); lymphocytes (low: <0.8 Giga cells/L); platelet count (low: <100 Giga cells/L and high: >550 Giga cells/L); neutrophil count (low: <1.5 Giga cells/L); white blood cell count (low: <3 Giga cells/L and high: >20 Giga cells/L). Participants were counted in the worst-case category that their value changed to (low, within range or no change, or high) unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category. Participants with worst case hematology parameters of PCI were planned to be collected.

Part A: Number of Participants With Worst Case Clinical Chemistry Parameters of PCI

Clinical chemistry parameters included alanine amino transferase (ALT), albumin, alkaline phosphatase (ALP), aspartate amino transferase (AST), calcium, creatinine, glucose, potassium, sodium and total bilirubin (T.bil). PCI ranges were: ALT, AST, ALP (high): >=2*Upper limit of Normal(ULN) units per liter(U/L), albumin(low): 30 g/L, calcium: <2(low) or >2.75 millimoles per liter (mmol/L)(high), creatinine (high): increase from Baseline >44.2 micromoles per liter(µmol/L), glucose: <3(low) or >9 mmol/L(high), potassium: <3(low) or >5.5 mmol/L(high), sodium: <130(low) or >150 mmol/L(high) and T.bil(high): >=1.5*ULN (µmol/L). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category.

Part B: Number of Participants With Worst Case Clinical Chemistry Parameters of PCI

Clinical chemistry parameters included ALT, albumin, alkaline phosphatase, AST, calcium, creatinine, glucose, potassium, sodium and total bilirubin. PCI ranges were ALT(high): >=2*ULN U/L, albumin(low): 30 g/L, alkaline phosphatase(high): >=2*ULN U/L, AST(high): >=2*ULN U/L, calcium: <2(low) or >2.75 mmol/L (high), creatinine (high): increase from Baseline >44.25 µmol/L, glucose: <3(low) or >9 mmol/L(high), potassium: <3(low) or >5.5 mmol/L(high), sodium: <130(low) or >150 mmol/L(high) and total bilirubin(high): >=1.5*ULN (µmol/L). Participants with worst case clinical chemistry parameters of PCI were planned to be collected.

Part A: Number of Participants With Worst Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method

Urine samples were collected to assess glucose, ketones, occult blood and protein by dipstick method. The dipstick test gave results in a semi-quantitative manner, and results for urinalysis parameters glucose, ketones, occult blood and protein were categorized as 'any increase from Baseline', which imply any increase in their concentrations in the urine sample. Baseline was defined as latest predose (Day 1) assessment with a non-missing value.

Part B: Number of Participants With Worst Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method

Urine analysis included assessment of glucose, ketones, occult blood and protein by dipstick method. The dipstick test gives results in a semi-quantitative manner. Baseline was defined as latest predose (Day 1) assessment with a non-missing value. Participants with worst case any increase in urinalysis results post-Baseline relative to Baseline were planned to be collected.

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

12-lead ECGs were obtained using an ECG machine. Only those participants who had any abnormal ECG findings are presented. Abnormal ECG findings were categorized as clinically significant (CS) and not clinically significant (NCS) abnormal ECG findings. 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.

Part B: Number of Participants With Abnormal ECG Findings

12-lead ECGs were planned to be obtained using an ECG machine. Abnormal ECG findings were categorized as CS and NCS abnormal ECG findings. CS 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. Participants with any abnormal ECG findings were planned to be evaluated.

Part A: Number of Participants With Worst Case Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) Values of PCI

DBP and SBP were measured in semi-supine position after 5 minutes rest. PCI ranges included DBP: <45 millimeters of mercury (mmHg) (lower) and >100 mmHg (higher) and SBP: <85 mmHg (lower) and >160 mmHg (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category.

Part B: Number of Participants With Worst Case DBP and SBP Values of PCI

DBP and SBP were measured in semi-supine position after 5 minutes rest. PCI ranges included DBP: <45 mmHg (lower) and >100 mmHg (higher) and SBP: <85 mmHg (lower) and >160 mmHg (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category. Participants with worst case DBP and SBP values of PCI were planned to be evaluated.

Part A: Number of Participants With Worst Case Respiration Rate Values of PCI

Respiration rate was measured in semi-supine position after 5 minutes rest. PCI ranges included <=8 breaths per minute (lower) and >=20 breaths per minute (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category.

Part B: Number of Participants With Worst Case Respiration Rate Values of PCI

Part A: Number of Participants With Worst Case Heart Rate Values of PCI

Heart rate was measured in semi-supine position after 5 minutes rest. PCI ranges included <40 beats per minute (lower) and >110 beats per minute (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category.

Part B: Number of Participants With Worst Case Heart Rate Values of PCI

Part A: Number of Participants With Worst Case Body Temperature Values of PCI

Body temperature was measured in semi-supine position after 5 minutes rest. PCI ranges included <=35.5 degrees Celsius (lower) and >=37.8 degrees Celsius (higher). Participants were counted in the worst case category that their value changes to (low, or within range or no change, or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became within range, were recorded in the 'To within Range or No Change' category.

Part B: Number of Participants With Worst Case Body Temperature Values of PCI

Part A: Number of Participants With Abnormal Findings in Physical Examination

Physical examinations included assessment of the skin, cardiovascular, respiratory, and gastrointestinal systems. This analysis was not planned and data was not collected and not captured in the database.

Part B: Number of Participants With Abnormal Findings in Physical Examination

Physical examinations included assessment of the skin, cardiovascular, respiratory, and gastrointestinal systems. Data was not collected and not captured in the database.

Part A: Change From Baseline in Activated Partial Thromboplastin Time and Prothrombin Time at Indicated Time Points

Blood samples were collected to evaluate activated partial thromboplastin time (APTT) and prothrombin time (PT) at indicated time points. Baseline was defined as latest pre-dose (Day 1) assessment with a non-missing value. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Part B: Change From Baseline in Activated Partial Thromboplastin Time and Prothrombin Time at Indicated Time Points

Blood samples were planned to be collected to evaluate PTT and PT at indicated time points. Baseline was defined as latest pre-dose (Day 1) assessment with a non-missing value. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Part A: Change From Baseline in International Normalized Ratio at Indicated Time Points

Blood samples were collected to evaluate international normalized ratio at indicated time points. Baseline was defined as latest pre-dose (Day 1) assessment with a non-missing value. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Part B: Change From Baseline in International Normalized Ratio at Indicated Time Points

Blood samples were planned to be collected to evaluate international normalized ratio at indicated time points. Baseline was defined as latest pre-dose (Day 1) assessment with a non-missing value. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Secondary Outcome Measures

Part A (Cohort 1): Area Under Plasma Concentration-time Curve (AUC) From Zero Hours to Time of Last Quantifiable Concentration (AUC[0-t]) for GSK2983559

Blood samples were collected to measure AUC(0-t) at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Part A (Cohort 2): AUC(0-t) for GSK2983559

Blood samples were collected to measure AUC(0-t) at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Part A (Cohort 1): AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559)

Blood samples were collected to measure AUC(0-t) at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559)

Part A (Cohort 1): AUC From Time Zero to Infinity (AUC[0-inf]) for GSK2983559

Blood samples were collected to measure AUC(0-inf) at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Part A (Cohort 2): AUC(0-inf) for GSK2983559

Blood samples were collected to measure AUC(0-inf) at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Part A (Cohort 1): AUC(0-inf) for GSK2668176 (Active Moiety of GSK2983559)

Blood samples were collected to measure AUC(0-inf) at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): AUC(0-inf) for GSK2668176 (Active Moiety of GSK2983559)

Part A (Cohort 1): Maximum Plasma Concentration (Cmax) for GSK2983559

Blood samples were collected to measure Cmax at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Part A (Cohort 2): Cmax for GSK2983559

Blood samples were collected to measure Cmax at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Part A (Cohort 1): Cmax for GSK2668176 (Active Moiety of GSK2983559)

Blood samples were collected to measure Cmax at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): Cmax for GSK2668176 (Active Moiety of GSK2983559)

Part A (Cohort 1): Terminal Elimination Half-life (T1/2) for GSK2983559

Blood samples were collected to measure T1/2 at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Part A (Cohort 2): T1/2 for GSK2983559

Blood samples were collected to measure T1/2 at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Part A (Cohort 1): T1/2 for GSK2668176 (Active Moiety of GSK2983559)

Blood samples were collected to measure T1/2 at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): T1/2 for GSK2668176 (Active Moiety of GSK2983559)

Part A (Cohort 1): Time to Cmax (Tmax) for GSK2983559

Blood samples were collected to measure Tmax at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Part A (Cohort 2): Tmax for GSK2983559

Blood samples were collected to measure Tmax at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Part A (Cohort 1): Tmax for GSK2668176 (Active Moiety of GSK2983559)

Blood samples were collected to measure Tmax at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): Tmax for GSK2668176 (Active Moiety of GSK2983559)

Part B: AUC(0-t) for GSK2983559 Following Single Dose on Day 1

Blood samples were planned to be collected to measure AUC(0-t) at indicated time-points.

Part B: AUC(0-t) for GSK2983559 on Day 14

Blood samples were planned to be collected to measure AUC(0-t) at indicated time-points.

Part B: AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559) Following Single Dose on Day 1

Blood samples were planned to be collected to measure AUC(0-t) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part B: AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559) on Day 14

Blood samples were planned to be collected to measure AUC(0-t) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part B: AUC From 0 Hours to the Time of Next Dosing AUC(0-tau) for GSK2983559 Following Single Dose on Day 1

Blood samples were planned to be collected to measure AUC(0-tau) at indicated time-points.

Part B: AUC(0-tau) for GSK2983559 on Day 14

Blood samples were planned to be collected to measure AUC(0-tau) at indicated time-points.

Part B: AUC(0-tau) for GSK2668176 (Active Moiety of GSK2983559) Following Single Dose on Day 1

Blood samples were planned to be collected to measure AUC(0-tau) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part B: AUC(0-tau) for GSK2668176 (Active Moiety of GSK2983559) on Day 14

Blood samples were planned to be collected to measure AUC(0-tau) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part B: Cmax for GSK2983559 Following Single Dose on Day 1

Blood samples were planned to be collected to measure Cmax at indicated time-points.

Part B: Cmax for GSK2983559 on Day 14

Blood samples were planned to be collected to measure Cmax at indicated time-points.

Part B: Cmax for GSK2668176 (Active Moiety of GSK2983559) Following Single Dose on Day 1

Blood samples were planned to be collected to measure Cmax at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part B: Cmax for GSK2668176 (Active Moiety of GSK2983559) on Day 14

Blood samples were planned to be collected to measure Cmax at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part B: Tmax for GSK2983559 Following Single Dose on Day 1

Blood samples were planned to be collected to measure Tmax at indicated time-points.

Part B: Tmax for GSK2983559 on Day 14

Blood samples were planned to be collected to measure Tmax at indicated time-points.

Part B: Tmax for GSK2668176 (Active Moiety of GSK2983559) Following Single Dose on Day 1

Blood samples were planned to be collected to measure Tmax at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part B: Tmax for GSK2668176 (Active Moiety of GSK2983559) on Day 14

Blood samples were planned to be collected to measure Tmax at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part B: T1/2 for GSK2983559 Following Single Dose on Day 1

Blood samples were planned to be collected to measure T1/2 at indicated time-points.

Part B: T1/2 for GSK2983559 on Day 14

Blood samples were planned to be collected to measure T1/2 at indicated time-points.

Part B: T1/2 for GSK2668176 (Active Moiety of GSK2983559) Following Single Dose on Day 1

Blood samples were planned to be collected to measure T1/2 at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part B: T1/2 for GSK2668176 (Active Moiety of GSK2983559) on Day 14

Blood samples were planned to be collected to measure T1/2 at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part B: Accumulation Ratio of GSK2983559

Blood samples were planned to be collected to measure accumulation ratio at indicated time-points. Accumulation ratio was to be calculated as ratio of AUC(0-tau) at Day 14 to AUC(0-tau) at Day 1.

Part B: Accumulation Ratio of GSK2668176 (Active Moiety of GSK2983559)

Blood samples were planned to be collected to measure accumulation ratio at indicated time-points. Accumulation ratio was to be calculated as ratio of AUC(0-tau) at Day 14 to AUC(0-tau) at Day 1. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): AUC (0-t) for GSK2983559 in Fasted Condition (Period 4)

Blood samples were planned to be collected to measure AUC(0-t) in fasted condition (Period 4) at indicated time-points.

Part A (Cohort 2): AUC(0-t) for GSK2983559 in Fed Condition (Period 5)

Blood samples were planned to be collected to measure AUC(0-t) in fed condition (Period 5) at indicated time-points.

Part A (Cohort 2): AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559) in Fasted Condition (Period 4)

Blood samples were planned to be collected to measure AUC(0-t) in fasted condition (Period 4) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559) in Fed Condition (Period 5)

Blood samples were planned to be collected to measure AUC(0-t) in fed condition (Period 5) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): AUC(0-inf) for GSK2983559 in Fasted Condition (Period 4)

Blood samples were planned to be collected to measure AUC(0-inf) in fasted condition (Period 4) at indicated time-points.

Part A (Cohort 2): AUC(0-inf) for GSK2983559 in Fed Condition (Period 5)

Blood samples were planned to be collected to measure AUC(0-inf) in fed condition (Period 5) at indicated time-points.

Part A (Cohort 2): AUC(0-inf) for GSK2668176 (Active Moiety of GSK2983559) in Fasted Condition (Period 4)

Blood samples were planned to be collected to measure AUC(0-inf) in fasted condition (Period 4) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): AUC(0-inf) for GSK2668176 (Active Moiety of GSK2983559) in Fed Condition (Period 5)

Blood samples were planned to be collected to measure AUC(0-inf) in fed condition (Period 5) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): Cmax for GSK2983559 in Fasted Condition (Period 4)

Blood samples were planned to be collected to measure Cmax in fasted condition (Period 4) at indicated time-points.

Part A (Cohort 2): Cmax for GSK2983559 in Fed Condition (Period 5)

Blood samples were planned to be collected to measure Cmax in fed condition (Period 5) at indicated time-points.

Part A (Cohort 2): Cmax for GSK2668176 (Active Moiety of GSK2983559) in Fasted Condition (Period 4)

Blood samples were planned to be collected to measure Cmax in fasted condition (Period 4) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): Cmax for GSK2668176 (Active Moiety of GSK2983559) in Fed Condition (Period 5)

Blood samples were planned to be collected to measure Cmax in fed condition (Period 5) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): Tmax for GSK2983559 in Fasted Condition (Period 4)

Blood samples were planned to be collected to measure Tmax in fasted condition (Period 4) at indicated time-points.

Part A (Cohort 2): Tmax for GSK2983559 in Fed Condition (Period 5)

Blood samples were planned to be collected to measure Tmax in fed condition (Period 5) at indicated time-points.

Part A (Cohort 2): Tmax for GSK2668176 (Active Moiety of GSK2983559) in Fasted Condition (Period 4)

Blood samples were planned to be collected to measure Tmax in fasted condition (Period 4) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): Tmax for GSK2668176 (Active Moiety of GSK2983559) in Fed Condition (Period 5)

Blood samples were planned to be collected to measure Tmax in fed condition (Period 5) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): T1/2 for GSK2983559 in Fasted Condition (Period 4)

Blood samples were planned to be collected to measure T1/2 in fasted condition (Period 4) at indicated time-points.

Part A (Cohort 2): T1/2 for GSK2983559 in Fed Condition (Period 5)

Blood samples were planned to be collected to measure T1/2 in fed condition (Period 5) at indicated time-points.

Part A (Cohort 2): T1/2 for GSK2668176 (Active Moiety of GSK2983559) in Fasted Condition (Period 4)

Blood samples were planned to be collected to measure T1/2 in fasted condition (Period 4) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Part A (Cohort 2): T1/2 for GSK2668176 (Active Moiety of GSK2983559) in Fed Condition (Period 5)

Blood samples were planned to be collected to measure T1/2 in fed condition (Period 5) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Full Information

NCT ID

NCT03358407

First Posted

November 27, 2017

Last Updated

November 13, 2020

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT03358407

Brief Title

GSK2983559 First Time in Human Study

Official Title

A Single-centre, Randomized, Double-blind (Sponsor Open), Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2983559, in Single (in Both Fed and Fasted States) and Repeat Oral Doses in Healthy Participants

Study Type

Interventional

2. Study Status

Record Verification Date

November 2020

Overall Recruitment Status

Terminated

Why Stopped

Terminated due to non clinical toxicology findings and reduced safety margins.

Study Start Date

January 11, 2018 (Actual)

Primary Completion Date

February 19, 2019 (Actual)

Study Completion Date

February 19, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

This study is the first administration of GSK2983559, a selective receptor interacting protein 2 (RIP2) kinase inhibitor, to humans. This will be randomized, double-blinded (sponsor open) and two part study (A and B). Part A of the study is single ascending dose crossover design with two separate cohorts (1 and 2). In Part A, 9 single dose levels will be explored. In Cohort 1, 10 healthy subjects will randomized to receive single oral doses of either GSK2983559 or placebo in a ratio of 4:1 in 5 way cross-over design with 5 treatment periods. In Cohort 2, 8 healthy subjects will be randomized to receive single oral doses of either GSK2983559 or placebo in a ratio of 3:1 in 4 way cross-overs design with 4 treatment periods. In Cohort 2 there will be an additional period (period 5-open label) for assessing GSK2983559 under fed conditions. There will be 48 hours wash-out period between each dose escalation period. Part B is repeat ascending dose sequential group design. It will contain 4 Cohorts of and dosing will be done sequential dosing. Subjects in Part B will receive once daily (QD) dose or twice daily dose (will be decided based upon the pharmacokinetic, safety and tolerability observed in Part A). There will 58 subjects involved in this study. Total duration of Part A will be approximately for 11 Weeks and Part B will be approximately for 15 Weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Inflammatory Bowel Diseases

Keywords

Inflammatory Bowel disease, Pro-drug, Double-blinded, Crossover

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

31 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part A: Cohort 1

Arm Type

Experimental

Arm Description

Cohort 1 will be 5-way crossover with 5 treatment periods. Subjects will be randomized in the ratio 4:1 to receive either single dose of GSK2983559 or placebo.

Arm Title

Part A: Cohort 2 fasting

Arm Type

Experimental

Arm Description

Arm Title

Part A: Cohort 2 fed

Arm Type

Experimental

Arm Description

In Cohort 2, treatment period 5 will be open-label period. This open-label period is to determine food effect and subjects will receive GSK2983559 under fed conditions.

Arm Title

Part B

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

GSK2983559

Intervention Description

GSK2983559 will be available as oral capsules with dose strength of 2-45 milligram (mg), 100 and 114 mg.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo oral capsules matching GSK2983559 will be available for subjects.

Primary Outcome Measure Information:

Title

Part A: Number of Participants With Non Serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)

Description

Time Frame

Up to 7 weeks

Title

Part B: Number of Participants With Non-SAEs and SAEs

Description

Time Frame

Up to 11 weeks

Title

Part A: Number of Participants With Worst Case Hematology Parameters of Potential Clinical Importance (PCI)

Description

Time Frame

Up to 7 weeks

Title

Part B: Number of Participants With Worst Case Hematology Parameters of PCI

Description

Time Frame

Up to 11 weeks

Title

Part A: Number of Participants With Worst Case Clinical Chemistry Parameters of PCI

Description

Time Frame

Up to 7 weeks

Title

Part B: Number of Participants With Worst Case Clinical Chemistry Parameters of PCI

Description

Time Frame

Up to 11 weeks

Title

Part A: Number of Participants With Worst Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method

Description

Time Frame

Up to 7 weeks

Title

Part B: Number of Participants With Worst Case Any Increase in Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method

Description

Time Frame

Up to 11 weeks

Title

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

Description

Time Frame

1.5, 2, 2.5, 3, 4, 5, 8, 12, 24 and 48 hours post-dose

Title

Part B: Number of Participants With Abnormal ECG Findings

Description

Time Frame

Up to 11 weeks

Title

Part A: Number of Participants With Worst Case Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) Values of PCI

Description

Time Frame

Up to 7 weeks

Title

Part B: Number of Participants With Worst Case DBP and SBP Values of PCI

Description

Time Frame

Up to 11 weeks

Title

Part A: Number of Participants With Worst Case Respiration Rate Values of PCI

Description

Time Frame

Up to 7 weeks

Title

Part B: Number of Participants With Worst Case Respiration Rate Values of PCI

Description

Time Frame

Up to 11 weeks

Title

Part A: Number of Participants With Worst Case Heart Rate Values of PCI

Description

Time Frame

Up to 7 weeks

Title

Part B: Number of Participants With Worst Case Heart Rate Values of PCI

Description

Time Frame

Up to 11 weeks

Title

Part A: Number of Participants With Worst Case Body Temperature Values of PCI

Description

Time Frame

Up to 7 weeks

Title

Part B: Number of Participants With Worst Case Body Temperature Values of PCI

Description

Time Frame

Up to 11 weeks

Title

Part A: Number of Participants With Abnormal Findings in Physical Examination

Description

Time Frame

Up to 7 weeks

Title

Part B: Number of Participants With Abnormal Findings in Physical Examination

Description

Physical examinations included assessment of the skin, cardiovascular, respiratory, and gastrointestinal systems. Data was not collected and not captured in the database.

Time Frame

Up to 11 weeks

Title

Part A: Change From Baseline in Activated Partial Thromboplastin Time and Prothrombin Time at Indicated Time Points

Description

Time Frame

Baseline (Day 1, Pre-dose), 24 and 48 hours post-dose

Title

Part B: Change From Baseline in Activated Partial Thromboplastin Time and Prothrombin Time at Indicated Time Points

Description

Time Frame

Baseline and Up to 11 weeks

Title

Part A: Change From Baseline in International Normalized Ratio at Indicated Time Points

Description

Time Frame

Baseline (Day 1, Pre-dose), 24 and 48 hours

Title

Part B: Change From Baseline in International Normalized Ratio at Indicated Time Points

Description

Time Frame

Baseline and Up to 11 weeks

Secondary Outcome Measure Information:

Title

Part A (Cohort 1): Area Under Plasma Concentration-time Curve (AUC) From Zero Hours to Time of Last Quantifiable Concentration (AUC[0-t]) for GSK2983559

Description

Blood samples were collected to measure AUC(0-t) at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 2): AUC(0-t) for GSK2983559

Description

Blood samples were collected to measure AUC(0-t) at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 1): AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 2): AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 1): AUC From Time Zero to Infinity (AUC[0-inf]) for GSK2983559

Description

Blood samples were collected to measure AUC(0-inf) at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 2): AUC(0-inf) for GSK2983559

Description

Blood samples were collected to measure AUC(0-inf) at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 1): AUC(0-inf) for GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 2): AUC(0-inf) for GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 1): Maximum Plasma Concentration (Cmax) for GSK2983559

Description

Blood samples were collected to measure Cmax at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 2): Cmax for GSK2983559

Description

Blood samples were collected to measure Cmax at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 1): Cmax for GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 2): Cmax for GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 1): Terminal Elimination Half-life (T1/2) for GSK2983559

Description

Blood samples were collected to measure T1/2 at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 2): T1/2 for GSK2983559

Description

Blood samples were collected to measure T1/2 at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 1): T1/2 for GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 2): T1/2 for GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 1): Time to Cmax (Tmax) for GSK2983559

Description

Blood samples were collected to measure Tmax at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 2): Tmax for GSK2983559

Description

Blood samples were collected to measure Tmax at indicated time-points. Pharmacokinetic parameters were measured using standard non-compartmental methods.

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 1): Tmax for GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part A (Cohort 2): Tmax for GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Pre-dose and at 15 and 30 minutes; 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: AUC(0-t) for GSK2983559 Following Single Dose on Day 1

Description

Blood samples were planned to be collected to measure AUC(0-t) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in each period

Title

Part B: AUC(0-t) for GSK2983559 on Day 14

Description

Blood samples were planned to be collected to measure AUC(0-t) at indicated time-points.

Time Frame

Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559) Following Single Dose on Day 1

Description

Blood samples were planned to be collected to measure AUC(0-t) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in each period

Title

Part B: AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559) on Day 14

Description

Blood samples were planned to be collected to measure AUC(0-t) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: AUC From 0 Hours to the Time of Next Dosing AUC(0-tau) for GSK2983559 Following Single Dose on Day 1

Description

Blood samples were planned to be collected to measure AUC(0-tau) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in each period

Title

Part B: AUC(0-tau) for GSK2983559 on Day 14

Description

Blood samples were planned to be collected to measure AUC(0-tau) at indicated time-points.

Time Frame

Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: AUC(0-tau) for GSK2668176 (Active Moiety of GSK2983559) Following Single Dose on Day 1

Description

Blood samples were planned to be collected to measure AUC(0-tau) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in each period

Title

Part B: AUC(0-tau) for GSK2668176 (Active Moiety of GSK2983559) on Day 14

Description

Blood samples were planned to be collected to measure AUC(0-tau) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: Cmax for GSK2983559 Following Single Dose on Day 1

Description

Blood samples were planned to be collected to measure Cmax at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in each period

Title

Part B: Cmax for GSK2983559 on Day 14

Description

Blood samples were planned to be collected to measure Cmax at indicated time-points.

Time Frame

Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: Cmax for GSK2668176 (Active Moiety of GSK2983559) Following Single Dose on Day 1

Description

Blood samples were planned to be collected to measure Cmax at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in each period

Title

Part B: Cmax for GSK2668176 (Active Moiety of GSK2983559) on Day 14

Description

Blood samples were planned to be collected to measure Cmax at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: Tmax for GSK2983559 Following Single Dose on Day 1

Description

Blood samples were planned to be collected to measure Tmax at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in each period

Title

Part B: Tmax for GSK2983559 on Day 14

Description

Blood samples were planned to be collected to measure Tmax at indicated time-points.

Time Frame

Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: Tmax for GSK2668176 (Active Moiety of GSK2983559) Following Single Dose on Day 1

Description

Blood samples were planned to be collected to measure Tmax at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in each period

Title

Part B: Tmax for GSK2668176 (Active Moiety of GSK2983559) on Day 14

Description

Blood samples were planned to be collected to measure Tmax at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: T1/2 for GSK2983559 Following Single Dose on Day 1

Description

Blood samples were planned to be collected to measure T1/2 at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in each period

Title

Part B: T1/2 for GSK2983559 on Day 14

Description

Blood samples were planned to be collected to measure T1/2 at indicated time-points.

Time Frame

Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: T1/2 for GSK2668176 (Active Moiety of GSK2983559) Following Single Dose on Day 1

Description

Blood samples were planned to be collected to measure T1/2 at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in each period

Title

Part B: T1/2 for GSK2668176 (Active Moiety of GSK2983559) on Day 14

Description

Blood samples were planned to be collected to measure T1/2 at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: Accumulation Ratio of GSK2983559

Description

Blood samples were planned to be collected to measure accumulation ratio at indicated time-points. Accumulation ratio was to be calculated as ratio of AUC(0-tau) at Day 14 to AUC(0-tau) at Day 1.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose; Day 14: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 48 hours post-dose in each period

Title

Part B: Accumulation Ratio of GSK2668176 (Active Moiety of GSK2983559)

Description

Time Frame

Title

Part A (Cohort 2): AUC (0-t) for GSK2983559 in Fasted Condition (Period 4)

Description

Blood samples were planned to be collected to measure AUC(0-t) in fasted condition (Period 4) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 4

Title

Part A (Cohort 2): AUC(0-t) for GSK2983559 in Fed Condition (Period 5)

Description

Blood samples were planned to be collected to measure AUC(0-t) in fed condition (Period 5) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 5

Title

Part A (Cohort 2): AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559) in Fasted Condition (Period 4)

Description

Blood samples were planned to be collected to measure AUC(0-t) in fasted condition (Period 4) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 4

Title

Part A (Cohort 2): AUC(0-t) for GSK2668176 (Active Moiety of GSK2983559) in Fed Condition (Period 5)

Description

Blood samples were planned to be collected to measure AUC(0-t) in fed condition (Period 5) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 5

Title

Part A (Cohort 2): AUC(0-inf) for GSK2983559 in Fasted Condition (Period 4)

Description

Blood samples were planned to be collected to measure AUC(0-inf) in fasted condition (Period 4) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 4

Title

Part A (Cohort 2): AUC(0-inf) for GSK2983559 in Fed Condition (Period 5)

Description

Blood samples were planned to be collected to measure AUC(0-inf) in fed condition (Period 5) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 5

Title

Part A (Cohort 2): AUC(0-inf) for GSK2668176 (Active Moiety of GSK2983559) in Fasted Condition (Period 4)

Description

Blood samples were planned to be collected to measure AUC(0-inf) in fasted condition (Period 4) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 4

Title

Part A (Cohort 2): AUC(0-inf) for GSK2668176 (Active Moiety of GSK2983559) in Fed Condition (Period 5)

Description

Blood samples were planned to be collected to measure AUC(0-inf) in fed condition (Period 5) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 5

Title

Part A (Cohort 2): Cmax for GSK2983559 in Fasted Condition (Period 4)

Description

Blood samples were planned to be collected to measure Cmax in fasted condition (Period 4) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 4

Title

Part A (Cohort 2): Cmax for GSK2983559 in Fed Condition (Period 5)

Description

Blood samples were planned to be collected to measure Cmax in fed condition (Period 5) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 5

Title

Part A (Cohort 2): Cmax for GSK2668176 (Active Moiety of GSK2983559) in Fasted Condition (Period 4)

Description

Blood samples were planned to be collected to measure Cmax in fasted condition (Period 4) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 4

Title

Part A (Cohort 2): Cmax for GSK2668176 (Active Moiety of GSK2983559) in Fed Condition (Period 5)

Description

Blood samples were planned to be collected to measure Cmax in fed condition (Period 5) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 5

Title

Part A (Cohort 2): Tmax for GSK2983559 in Fasted Condition (Period 4)

Description

Blood samples were planned to be collected to measure Tmax in fasted condition (Period 4) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 4

Title

Part A (Cohort 2): Tmax for GSK2983559 in Fed Condition (Period 5)

Description

Blood samples were planned to be collected to measure Tmax in fed condition (Period 5) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 5

Title

Part A (Cohort 2): Tmax for GSK2668176 (Active Moiety of GSK2983559) in Fasted Condition (Period 4)

Description

Blood samples were planned to be collected to measure Tmax in fasted condition (Period 4) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 4

Title

Part A (Cohort 2): Tmax for GSK2668176 (Active Moiety of GSK2983559) in Fed Condition (Period 5)

Description

Blood samples were planned to be collected to measure Tmax in fed condition (Period 5) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 5

Title

Part A (Cohort 2): T1/2 for GSK2983559 in Fasted Condition (Period 4)

Description

Blood samples were planned to be collected to measure T1/2 in fasted condition (Period 4) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 4

Title

Part A (Cohort 2): T1/2 for GSK2983559 in Fed Condition (Period 5)

Description

Blood samples were planned to be collected to measure T1/2 in fed condition (Period 5) at indicated time-points.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 5

Title

Part A (Cohort 2): T1/2 for GSK2668176 (Active Moiety of GSK2983559) in Fasted Condition (Period 4)

Description

Blood samples were planned to be collected to measure T1/2 in fasted condition (Period 4) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 4

Title

Part A (Cohort 2): T1/2 for GSK2668176 (Active Moiety of GSK2983559) in Fed Condition (Period 5)

Description

Blood samples were planned to be collected to measure T1/2 in fed condition (Period 5) at indicated time-points. GSK2668176 is the active moiety of pro-drug GSK2983559.

Time Frame

Day 1: Pre-dose, 15 minutes, 30 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24 hours post-dose in Period 5

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male and female subjects between 18 and 65 years of age inclusive, at the time of signing the informed consent. Volunteers who are overtly healthy as determined by medical evaluation including medical and psychiatric history, physical examination, neurological examination, clinical laboratory tests and cardiac monitoring. 3Body weight >= 50 kg (kilogram) and body mass index (BMI) within the range 19-32 kilogram per meter square (kg/m^2) . A male subject must agree to use a highly effective contraception during the treatment period and for at least 5 half-lives plus an additional 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 is not a woman of childbearing potential (WOCBP) Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Participants must agree to avoid prolonged Ultraviolet (UV) exposure to natural sunlight without required Ultraviolet A (UVA)/ Ultraviolet B (UVB) protection or tanning beds for the duration of the study. Exclusion Criteria: History or presence of/significant history 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 or current evidence of febrile seizures, epilepsy, convulsions, significant head injury, or other significant neurologic conditions. History of clinically significant psychiatric disorders as judged by the investigator. Any history of suicidal behavior within the past 6 months or any history of attempted suicide in a subject's lifetime. ALT >1.5x upper limit of normal (ULN). Bilirubin >1.5xULN (isolated bilirubin >1.5xULN 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 Gastrointestinal (GI) surgery (with exception of appendectomy) Average QTc > 450 millisecond (msec) Intended use of over-the-counter or prescription medication including herbal medications within 7 days prior to dosing Live or attenuated vaccine(s) within 30 days of randomization, or plans to receive such vaccines during the study or plans to receive a vaccine within 30 days + 5 half-lives of the last dose of study medication. Regular alcohol consumption within 6 months prior to the study defined as: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. Current use or history of regular tobacco- or nicotine-containing products within 6 months prior to screening. Subject must have urinary cotinine levels indicative of non-smoking status at screening visit. Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day. Current enrollment or past participation within the last 30 days before signing of consent in this or any other clinical study involving an investigational study treatment or any other type of medical research. Subjects with impaired renal function defined as Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) calculation <= 60 milliliter per minute per 1.73 meter square (mL/min/1.73 m^2) estimated by the CKD-EPI equation. An elevated C-reactive protein (CRP) outside of the normal reference range. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. As potential for and magnitude of immunosuppression with this compound is unknown, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded. Subjects positive for HBsAg and/or positive for anti-HBc antibody (regardless of anti-HBs antibody status) are excluded. A positive pre-study drug/alcohol screen. A positive test for HIV antibody. A positive diagnostic TB test at screening defined as a positive QuantiFERON-TB Gold test or T-spot test. In cases where the QuantiFERON or T-spot test is indeterminate, the subject may have the test repeated once, but they will not be eligible for the study unless the second test is negative. In cases where the QuantiFERON or T-spot test is positive, but a locally-read follow up chest x-ray, shows no evidence of current or previous pulmonary tuberculosis, the subject may be eligible for the study at the discretion of the Investigator and GSK Medical Monitor. Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates participation in the study. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56-day period. Part A (Food Effect) Cohort: Subject must have no dietary restrictions (e.g., lactose intolerance) or inability to eat a high fat meal.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Cambridge

State/Province

Cambridgeshire

ZIP/Postal Code

CB2 2GG

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

IPD for this study is available via the Clinical Study Data Request site.

IPD Sharing Time Frame

IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)

IPD Sharing Access Criteria

Access is provided after a research proposal is submitted and has received approval from the 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 can be granted, when justified, for up to another 12 months.

IPD Sharing URL

https://www.clinicalstudydatarequest.com/Posting.aspx?ID=20726

Learn more about this trial

GSK2983559 First Time in Human Study

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