This is the first study with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase inhibitor, in subjects with active plaque-type psoriasis (PsO). The primary objective will be to investigate the safety and tolerability of repeat oral doses of GSK2982772 60 milligram (mg) twice daily (BID) for 84 days in Cohort 1 and 60 mg thrice daily (TID) for 84 days in Cohort 2. In addition, a number of experimental and clinical endpoints will be employed to obtain information on the pharmacokinetics, pharmacodynamics, and efficacy in subjects with active PsO. There will be two Cohorts of subjects. In Cohort 1 after a screening period of up to 30 days, approximately 30 subjects will be randomized to receive either GSK2982772 60 mg BID or placebo for 84 days (12 Weeks), followed by a follow-up period (28 days). In Cohort 2 after a screening period of up to 30 days, approximately 24 subjects will be randomized to receive either GSK2982772 60 mg TID or placebo for 84 days (12 Weeks), followed by a follow-up period (28 days). The total duration of participation is approximately 20 Weeks from screening to the last study visit.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
65
GSK2982772 will be supplied as a white to almost white, round, film coated 30 mg oral tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.
Matching placebo will be supplied as a white to almost white, round film coated tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.
GSK Investigational Site
Markham, Ontario, Canada
GSK Investigational Site
Peterborough, Ontario, Canada
GSK Investigational Site
Waterloo, Ontario, Canada
GSK Investigational Site
Montreal, Quebec, Canada
Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is associated with liver injury and impaired liver function or any other situations as per medical or scientific judgment. Safety Population comprised of all participants who received at least one dose of study treatment.
Time frame: Up to Day 116
Number of Participants With Worst-case Post-Baseline Clinical Chemistry Results by Potential Clinical Importance (PCI) Criteria
Blood samples were collected for analysis of clinical chemistry parameters. Clinical concern ranges were \>=2x Upper Limit of Normal (ULN) units per liter (U/L) for alanine aminotransferase (ALT), \<30 millimoles per liter (mmol/L) for albumin, \>=2x ULN U/L for alkaline phosphatase, \>=2x ULN U/L for aspartate aminotransferase (AST), \<2 or \>2.75 mmol/L for Calcium, \>44.2 mmol/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 \>=1.5xULN micromoles per liter for total bilirubin. Participants were counted in worst case category that their value changes to (Low, Normal or High), unless there is no change in their category. Participants whose value category was unchanged (example given \[e.g.\], High to High), or whose value became normal, were recorded in "To Normal or No Change" category. Participants were counted twice if they had values that changed 'To Low' and 'To High', Baseline is defined as the latest pre-dose assessment.
Time frame: Up to Day 116
Number of Participants With Worst-case Post-Baseline Hematology Results by PCI Criteria
Blood samples were collected for analysis of hematology parameters. Clinical concern ranges were \>0.54 calculated as proportion of red blood cells in blood for Hematocrit, \>180 grams per liter for Hemoglobin, \<0.8 x10\^9 cells per liter for Lymphocytes, \<1.5 x10\^9 cells per liter for Neutrophil count, \<100 or \>550 x10\^9 cells per liter for Platelet count and \<3 or \>20 x10\^9 cells per liter White Blood Cell count. Participants were counted in the worst case category that their value changes to (Low, Normal 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 normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if they had values that changed 'To Low' and 'To High'. Baseline is defined as the latest pre-dose assessment.
Time frame: Up to Day 116
Change From Baseline in Urine Potential of Hydrogen (pH)
Urine samples were collected for measurement of urine pH at indicated time points. pH is a measure of hydrogen ion concentration and used to determine the acidity or alkalinity of urine. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value.
Time frame: Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 43, Day 85 and Follow-up (Day 116)
Change From Baseline in Urine Specific Gravity
Urine samples were collected to analyze specific gravity of urine. Specific gravity, is a measure of urine concentration and is measured using a chemical test. Specific gravity measurements provide a comparison of the amount of substances dissolved in urine as compared to pure water. If there were no solutes present, the specific gravity of urine would be 1.000 the same as pure water. Specific gravity between 1.002 and 1.035 could be considered as normal. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value.
Time frame: Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 43, Day 85 and Follow-up (Day 116)
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Blood pressure was measured at indicated time points in supine or semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value.
Time frame: Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, Day 85 and Follow-up (Day 116)
Change From Baseline in Heart Rate
Heart rate was measured at indicated time points in supine or semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value.
Time frame: Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, Day 85 and Follow-up (Day 116)
Change From Baseline in Respiratory Rate
Respiratory rate was measured at indicated time points in supine or semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value.
Time frame: Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, Day 85 and Follow-up (Day 116)
Change From Baseline in Body Temperature
Body temperature was measured at indicated time points in supine or semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value.
Time frame: Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, Day 85 and Follow-up (Day 116)
Number of Participants With Any Time Post-Baseline Results for Electrocardiogram Findings
Single 12-lead electrocardiograms were obtained at indicated time points during the study using an electrocardiogram machine that automatically calculates the heart rate and measures PR, QRS, QT, QT interval corrected for heart rate (QTc) using Bazett's formula (QTcB) intervals and QTc using Fridericia's formula (QTcF). The abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). Baseline is defined as the latest pre-dose assessment. 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. The number of participants with normal and abnormal electrocardiogram findings at any time post-Baseline visit has been presented.
Time frame: Up to Day 116
Plasma Concentrations of GSK2982772 at Days 43 and 85
Blood samples were collected for pharmacokinetic analysis of GSK2982772 following 60 mg BID and 60 mg TID dose at indicated time points. The pharmacokinetic analysis was performed using non-compartmental methods. The analysis was based on Pharmacokinetic Population which comprised of participants in the 'Safety' Population for whom a pharmacokinetic sample was obtained and analyzed.
Time frame: Day 43 (Pre-dose) and Day 85
Post-dose Plasma Concentrations of GSK2982772 on Days 1 and 43
Blood samples were collected for pharmacokinetic analysis of GSK2982772 following 60 mg BID and 60 mg TID dose at indicated time points. The pharmacokinetic analysis was performed using non-compartmental methods.
Time frame: 1, 2, 4 and 6 Hours Post-dose on Days 1 and 43
Adjusted Mean Percentage Change in Histopathological Scoring of Psoriatic Lesional Biopsy Following Administration of GSK2982772
A target lesion for biopsy was identified on the trunk or extremities at indicated time points. The manual cell counting performed on stained tissue section was referred as histopathological scoring of psoriatic lesions. Histologic assessment included measurement of Cluster of differentiation 11 (CD11+), CD161+, CD3+ and Elastase. Baseline is defined as the latest pre-dose assessment. Percentage change from Baseline was determined from the back-calculation of the log ratio to Baseline. Data for all the listed biomarkers from skin biopsy has been presented for two skin types; dermis and epidermis at Day 43. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all biomarker analyses. NA indicates that data was not available as geometric coefficient of variation could not be calculated for single participant.
Time frame: Baseline (Pre-dose on Day 1) and Day 43
Adjusted Mean Percentage Change in Histopathological Scoring of Psoriatic Lesional Biopsy: Epidermis Thickness
A target lesion for biopsy was identified on the trunk or extremities at indicated time points. The manual cell counting performed on stained tissue section was referred as histopathological scoring of psoriatic lesions. Histologic assessment included measurement of epidermis thickness. Baseline is defined as the latest pre-dose assessment. Percentage change from Baseline was determined from the back-calculation of the log ratio to Baseline. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all biomarker analyses.
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Time frame: Baseline (Pre-dose on Day 1) and Day 43
Number of Participants With Changes in Keratin 16 (K16) Histopathological Scoring in Psoriatic Lesional Biopsies
A target lesion for biopsy was identified on the trunk or extremities at indicated time points. The manual cell counting performed on stained tissue section was referred as histopathological scoring of psoriatic lesions. Histologic assessment included measurement of K16 as keratin expression. Baseline is defined as the latest pre-dose assessment. Results for K16 were categorized as, negative to positive, no change and positive to negative at Day 43. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all biomarker analyses.
Time frame: Baseline (Pre-dose on Day 1) and Day 43
Messenger Ribonucleic Acid (mRNA) Expression of Inflammatory Gene Transcripts in Psoriatic Lesional Biopsies Following Administration of GSK2982772
A target lesion for biopsy was identified on the trunk or extremities at indicated time points. mRNA expression of inflammatory markers and tissue healing were assessed. Data has been presented for inflammatory gene transcripts including interferon gamma, interleukin 10, interleukin 17A, interleukin 21, interleukin 22, interleukin 23 subunit alpha, interleukin 4 and tumor necrosis factor. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all biomarker analyses.
Time frame: Day 1 and Day 43
Percentage Change From Baseline Psoriatic Lesion Severity Sum (PLSS) Scores in the Index Lesion Following Administration of GSK2982772
Two plaques were selected, one for clinical assessment (index plaque) and one for biopsy. Each lesion was evaluated for 3 components: erythema, induration, and scaling. Each component was given a score using a scale ranging from 0 (no symptom) to 4 (very marked) with increasing score reflecting increased lesion severity. The PLSS is the sum of the erythema, scaling and plaque thickness scores. The total PLSS score ranged from 0 (no symptom) to 12 (very marked). Each lesion must have a PLSS score of \>=5. Baseline is defined as the latest pre-dose assessment. Percentage change from Baseline was determined from the back-calculation of the log ratio to Baseline. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all efficacy analyses.
Time frame: Baseline (Pre-dose on Day 1) and Days 15, 29, 43, 57, 71, 85
Actual PLSS Scores in the Index Psoriatic Lesion Following Administration of GSK2982772
Two plaques were selected one for clinical assessment (index plaque) and one for biopsy. Each lesion was evaluated for 3 components: erythema, induration, and scaling. Each component was given a score using a scale ranging from 0 (no symptom) to 4 (very marked) with increasing score reflecting increased lesion severity. The PLSS is the sum of the erythema, scaling and plaque thickness scores. The total PLSS score ranged from 0 (no symptom) to 12 (very marked). Each lesion must have a PLSS score of \>=5. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all efficacy analyses.
Time frame: Days 1, 15, 29, 43, 57, 71 and 85