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An Adaptive Phase II Study to Evaluate the Efficacy, Pharmacodynamics, Safety and Tolerability of GSK2586184

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ClinicalTrials.gov Identifier: NCT01777256
Recruitment Status : Terminated (This study met a protocol defined futility criterion and will be terminated following completion of the Follow Up Visit on the last subject randomised.)
First Posted : January 28, 2013
Last Update Posted : April 26, 2017
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE January 24, 2013
First Posted Date  ICMJE January 28, 2013
Last Update Posted Date April 26, 2017
Study Start Date  ICMJE March 1, 2013
Actual Primary Completion Date March 1, 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 25, 2017)
  • Percentage Inhibition from Baseline of interferon (IFN) Transcriptional Biomarkers at Week 2 [ Time Frame: Baseline(Day1) and Week 2 ]
    Mean reduction (40%) from Baseline of the IFN transcriptional signature biomarker was monitored at Week 2. Percentage (Per) inhibition (=[(Day x-Baseline)/Baseline]*-100), was the Per reduction from Baseline (Day1) and evaluated in any pre-designated panels of genes i.e. Addenbrookes 1, Addenbrookes 2, JAK439, PD, Panel Stripping, Flare and Transcription. Analysis was performed using a repeated measures model with covariates of treatment, baseline, Day, Day by baseline and Day by treatment interactions. Only those Par available at the specified time points were analysed (n=X,X,X,X,X). Different Par may have been analysed at different time points, so the overall number of Par analysed reflects everyone in the Intent To Treat (ITT) Population i.e. Par randomised to treatment, received >=1 dose of study medication and had >=1 valid post dose assessment
  • Change from Baseline of SELENA SLEDAI score at indicated time points up to Week 16 [ Time Frame: Baseline(Day1), Weeks 2, 4, 6, 8, 10, 12 and 16 ]
    The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is a validated index for assessing SLE disease activity. It is a weighted index in which signs and symptoms, laboratory tests, and physician's assessment for each of 9 organ systems are given a weighted score and summed, if present at the time of the visit or in the preceding 10 days. Modified version of SLEDAI is Safety of Estrogen in Lupus National Assessment (SELENA) SLEDAI where the maximum theoretical score for the SELENA SLEDAI was 105 with 0 indicating inactive disease. Baseline value is defined as Day 1 (pre-dose) SELENA SLEDAI score.
  • Change from Baseline in systolic blood pressure and diastolic blood pressure at the indicated time points up to Week 16 [ Time Frame: Baseline(Day1), Weeks 2, 4, 6, 8, 10, 12 and 16 ]
    Change from Baseline in systolic blood pressure (BP) and diastolic BP is summarized for each post-Baseline assessment up to Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in heart rate at the indicated time points up to Week 16 [ Time Frame: Baseline (Day 1), Weeks 2, 4, 6, 8, 10, 12 and 16 ]
    Change from Baseline in sitting and supine heart rate is summarized for each post-Baseline assessment up to Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last pre-treatment value observed.
  • Change from Baseline in temperature at the indicated time points up to Week 16 [ Time Frame: Baseline (Day 1), Weeks 2, 4, 6, 8, 10, 12 and 16 ]
    Change from Baseline in temperature is summarized for each post-Baseline assessment up to Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in albumin, globulin and protein at the indicated time points up to Week 16 [ Time Frame: Baseline (Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the albumin, globulin and protein values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from baseline in alkaline phosphatase, alanine amino transferase, aspartate amino transferase, creatine kinase, gamma glutamyl transferase and lactate dehydrogenase at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), creatine kinase (CK), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in anion gap, calcium, cholesterol, chloride, carbon dioxide, glucose, HDL cholesterol, potassium, LDL cholesterol, magnesium, phosphate, soidium, triglycerides, urea, VLDL cholesterol at the indicated time points up to Week 16 [ Time Frame: Baseline (Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the anion gap, calcium, ionised calcium, cholesterol, chloride, carbon dioxide, glucose, high density lipoprotein (HDL) cholesterol (fasted and not fasted), potassium, low density lipoprotein (LDL) cholesterol (fasted and not fasted), magnesium, phosphate, sodium, triglycerides (fasted and not fasted), urea and very low density lipoprotein (VLDL) cholesterol values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in bilirubin, creatinine, iron binding capacity, iron and urate at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the bilirubin, direct and indirect bilirubin, creatinine, total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), iron and uric acid values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in albumin/globulin, BUN/creatinine and transferrin saturation at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from baseline in the albumin/globulin, blood urea nitrogen (BUN)/creatinine and transferrin saturation values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in creatinine clearance at the indicated time points up to Week 16 [ Time Frame: Baseline (Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the Creatinine Clearance values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, neutrophils, neutrophils segmented (SG), platelets and leukocytes at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the basophils, eosinophils, lymphocytes, monocytes, neutrophils, neutrophils segmented (SG), platelets and leukocytes values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/leukocytes, neutrophils/leukocytes, neutrophils SG/leukocytes and erythrocyte distribution width (EDW) at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/leukocytes, neutrophils/leukocytes, neutrophils segmented (SG)/leukocytes and erythrocyte distribution width (EDW) values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in erythrocytes and reticulocytes at the indicated time points up to Week 16 [ Time Frame: Baseline (Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the erythrocyte and reticulocyte values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in hemoglobin and erythrocyte mean corpuscular hemoglobin concentration (EMCHC) at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the hemoglobin and erythrocyte mean corpuscular hemoglobin concentration (EMCHC) values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in erythrocyte mean corpuscular hemoglobin (EMCH) at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the hemoglobin and erythrocyte mean corpuscular hemoglobin (EMCH) values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in erythrocyte mean corpuscular volume (EMCV) and mean platelet volume (MPV) at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the erythrocyte mean corpuscular volume (EMCV) and mean platelet volume (MPV) values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in hematocrit and reticulocytes/erythrocytes at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the hematocrit and reticulocytes/erythrocytes values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Number of participants with urinalysis data at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Number of participants with negative and positives (trace, +, ++ and +++) data for urine glucose (UGLU), urine ketones (UKET) and urine occult blood (UOB) are summarized for each post-Baseline assessment until Week 16. Urinalysis was performed by dipstick method. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in urine protein at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the urine protein values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Change from Baseline in urine protein/creatinine at the indicated time points up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16 ]
    Change from Baseline in the urine protein/creatinine values are summarized for each post-Baseline assessment until Week 16. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Number of participants with any adverse events (AEs) and any serious adverse events (SAEs) up to Week 16 [ Time Frame: Up to Week 16 ]
    An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign(including an abnormal laboratory finding), symptom, or disease(new or exacerbated) temporally associated with the use of a medicinal product. An 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, a congenital anomaly/birth defect, important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.
  • Number of participants with severity Grade 1, 2, 3, 4 and 5 adverse events (AEs) [ Time Frame: Up to 16 Weeks ]
    The Common Terminology Criteria for Adverse Events (CTCAE, Version 4) has categorised AEs in five grades. Grade refers to the severity of the AE. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE.
Original Primary Outcome Measures  ICMJE
 (submitted: January 24, 2013)
  • Interferon biomarkers over time [ Time Frame: Up to 16 weeks ]
    The relationship between dose of GSK2586184 and pharmacodynamic effect on expression of selected mRNA transcripts
  • SELENA SLEDAI score over time [ Time Frame: Up to 16 weeks ]
    The Safety of Estrogen in Lupus National Assessment (SELENA) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is a validated index for assessing SLE disease activity.
  • Change from baseline for vital signs [ Time Frame: Baseline and up to 16 weeks ]
    Vital sign measurements will include heart rate, sitting blood pressure, and temperature.
  • Change from baseline in clinical chemistry and hematology parameters [ Time Frame: Baseline and up to 16 weeks ]
    Clinical laboratory tests will include hematology, clinical chemistry and urinalysis
  • Number of subjects with adverse events and severity of adverse events [ Time Frame: Up to 16 weeks ]
    Adverse events (AEs) will be collected from the start of Investigation Product and until the follow-up visit.
Change History Complete list of historical versions of study NCT01777256 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2017)
  • SRI Response Rate at Week 4, 8, 12 and 16 [ Time Frame: Week 4, 8, 12 and 16 ]
    The relationship between dose of GSK2586184 and clinical response was assessed by the SLE Responder Index (SRI). The percentage of participants achieving a response on the composite endpoint are summarized. Response is defined as:>= 4 point reduction from the Baseline in the SELENA SLEDAI score and no worsening (increase of <0.30 points from the Baseline) in Physicians Global Assessment (PGA),and no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with the Baseline. Baseline value is defined as the last Pre-treatment value observed.
  • Change from baseline in SLEDAI-2K score and the S2K RI-50 score over time (up to Week 12) [ Time Frame: Baseline(Day 1) to Week 12 ]
    The relationship between dose of GSK2586184 and clinical response was assessed by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and SLEDAI-2K Responder Index 50 (S2K RI-50) scores. SLEDAI-2K is a revised version of the SLEDAI in which the persistent active disease in the items rash, alopecia, mucosal ulcers and proteinuria would be scored as opposed to new occurrences as are measured in the SLEDAI. S2K RI-50 detects a minimum 50% improvement in disease manifestations among lupus participants. It covers 9 organ systems, utilising the same 24 descriptors and reflects disease activity over the previous 30 days. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed. Due to early termination of the study, data for this endpoint was not summarized.
  • Mean GSK2586184 plasma concentrations on Weeks 2, 4, 6, 8, 10 and 12 [ Time Frame: Weeks 2, 4, 6, 8, 10 and 12 ]
    Plasma pharmacokinetic (PK) pre-dose (PRD) samples were collected for all participants at Weeks 2, 4, 8, 10 and 12 prior to the morning dose. At Week 2, additional blood sample were collected at 1hour (hr) and 4 hr post-dose (POD) and at Week 6, additional blood sample were collected, from 6 hr to 10 hr POD. PK Population comprised of all participants randomised to treatment, who have taken at least one dose. Only participants for whom plasma PK samples were obtained were assessed (represented by n=X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the Pharmacokinetic(PK) Population.
  • Area under the concentration-time curve over the dosing interval (AUC[0-tau]) up to Week 12 [ Time Frame: Weeks 2, 4, 6, 8, 10 and 12 ]
    Plasma PK PRD samples were collected for all participants at Weeks 2, 4, 8, 10 and 12 prior to the morning dose. At Week 2, additional blood sample were collected at 1hr and 4 hr POD and at Week 6, additional blood sample were collected, from 6 hr to 10 hr POD. AUC(0-tau).is calculated from a population pharmacokinetic model using Non Linear Mixed Effect Model (NONMEM) after log-transformation of PK data. Only participants for whom plasma PK samples were obtained and assessed.
  • Apparent clearance (CL/F) up to Week 12 [ Time Frame: Weeks 2, 4, 6, 8, 10 and 12 ]
    Plasma PK PRD samples were collected for all participants at Weeks 2, 4, 8, 10 and 12 prior to the morning dose. At Week 2, additional blood sample were collected at 1hr and 4 hr POD and at Week 6, additional blood sample were collected, from 6 hr to 10 hr POD. CL/F is calculated, as dose divided by AUC(0-tau), from a population pharmacokinetic model using Non Linear Mixed Effect Model (NONMEM) after log-transformation of PK data. Only participants for whom plasma PK samples were obtained and assessed.
  • Volume of distribution (Vss) up to Week 12 [ Time Frame: Weeks 2, 4, 6, 8, 10 and 12 ]
    Plasma PK PRD samples were collected for all participants at Weeks 2, 4, 8, 10 and 12 prior to the morning dose. At Week 2, additional blood sample were collected at 1hr and 4 hr POD and at Week 6, additional blood sample were collected, from 6 hr to 10 hr POD. Apparent volume of distribution is calculated as dose divided by (AUC[0-tau] lambda z) where lambda z is the terminal phase rate constant. Vss is calculated from a population pharmacokinetic model using Non Linear Mixed Effect Model (NONMEM) after log-transformation of PK data. Only participants for whom plasma PK samples were obtained and assessed
  • Mean change from Baseline in the SF-36 Domain Scores up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 12 and 16 ]
    The Short Form (36) Health Survey (SF-36v2 ) is a participant-reported survey of participant health and measures general health-related quality of life. There are 36 items grouped into nine health domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, Mental Health, Reported health transition (RHT). SF-36v2 gives a score for each of these domains based on the questions as assessed by participants. The lower the score the more disability and the higher the score the less disability. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Mean change from Baseline in the Brief Fatigue Inventory (BFI) Domain Score up to Week 16 [ Time Frame: Baseline (Day 1), Weeks 2, 4, 6, 8, 10, 12 and 16 ]
    The BFI was developed to quickly measure severity of fatigue in participants as well as its impact on their ability to function over the previous 24 hrs. It consists of nine items that look at fatigue in the past that are rated on a 0 -10 numeric rating scale where 0 is no fatigue or does not interfere and 10 is bad fatigue or completely interferes with activity. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
  • Mean change from Baseline in the Brief Pain Inventory (BPI) Domain Score up to Week 16 [ Time Frame: Baseline(Day 1), Weeks 2, 4, 6, 8, 10, 12 and 16 ]
    The BPI is a questionnaire used to assess the severity of pain and the impact of pain on daily functioning in the following areas: general activity, mood, walking ability, normal work, including outside the home and housework, relations with other people, enjoyment of life and sleep. Two sub scores are derived from questionnaire: the worst pain score and the interference score. To derive a valid worst pain score, a minimum of 3 (out of 6) non missing values were required versus 4 (out of 7) for the interference score. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2013)
  • SRI Response Rate over time [ Time Frame: Up to 16 weeks ]
    The relationship between dose of GSK2586184 and clinical response will be assessed by the SLE Responder Index (SRI). Response is defined as:>= 4 point reduction from baseline in the SELENA SLEDAI score and no worsening (increase of <0.30 points from baseline) in Physicians Global Assessment (PGA),and no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with baseline.
  • Change from baseline in SLEDAI-2K score and the S2K RI-50 score [ Time Frame: Baseline and Up to 12 weeks ]
    The relationship between dose of GSK2586184 and clinical response will be assessed by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and SLEDAI-2K Responder Index 50 (S2K RI-50) scores.
  • Individual and summary PK parameters [ Time Frame: Weeks 2, 4, 8, 10 and 12 ]
    Pharmacokinetic (PK) parameters for GSK2586184 will be measured to evaluate PK of repeat doses of GSK2586184.
  • Mean change from baseline in Short Form-36 Health Survey (SF-36) score (8 domains) at Week 12 [ Time Frame: Baseline and Week 12 ]
    The effect of GSK2586184 on health economics and general patient quality of life will be assessed by the SF-36 health survey.
  • Mean change from baseline in Brief Fatigue Inventory (BFI) score [ Time Frame: Baseline up to 12 weeks ]
    BFI is a fatigue assessment tool that asks patients to rate their current level of fatigue, usual fatigue and, worst level of fatigue in the last 24 hours, and how fatigue has interfered with general activity, mood, walking, work, relationships, and enjoyment of life.
  • Mean change from baseline in Brief Pain Inventory (BPI) (short form) score [ Time Frame: Baseline up to 12 weeks ]
    BPI allows subjects to rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Adaptive Phase II Study to Evaluate the Efficacy, Pharmacodynamics, Safety and Tolerability of GSK2586184
Official Title  ICMJE An Adaptive Phase II Study to Evaluate the Efficacy, Pharmacodynamics, Safety and Tolerability of GSK2586184 in Patients With Mild to Moderate Systemic Lupus Erythematosus
Brief Summary

This is an adaptive, dose ranging, Phase II study to investigate the relationship between repeat doses of GSK2586184 and the pharmacodynamic effect and clinical efficacy in patients with active systemic lupus erythematosus (SLE). This study will also investigate the safety and tolerability of repeat doses of GSK2586184. During the study, up to 3 Interim Analyses will be conducted. These are to monitor the pharmacodynamic effect and safety following 2 weeks of therapy (Interim Analysis 1); and the clinical efficacy and safety of GSK2586184 following 12 weeks of therapy (Interim Analyses 2 and 3). Subjects who meet the entry criteria (approximately 150 to 250) will be randomized in a 1:1:1:1:1 ratio to receive GSK2586184 at doses of 50 milligram (mg) twice daily (b.i.d), 100 mg b.i.d, 200 mg b.i.d, 400 mg b.i.d or Placebo b.i.d. GSK2586184 tablets available in 50 and 200 mg dose strength will be administered orally up to 12 weeks.

Subjects who complete the study will participate in the study for approximately 21 weeks.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Systemic Lupus Erythematosus
Intervention  ICMJE
  • Drug: GSK2586184 50 mg
    GSK2586184 tablet will be administered orally as twice daily dose of 50 mg (1 x 50 mg tablet) up to 12 weeks.
  • Drug: GSK2586184 100 mg
    GSK2586184 tablet will be administered orally as twice daily dose of (2 X 50 mg tablet) up to 12 weeks.
  • Drug: GSK2586184 200 mg
    GSK2586184 tablet will be administered orally as twice daily dose of 200 mg (1 x 200 mg) up to 12 weeks.
  • Drug: GSK2586184 400 mg
    GSK2586184 tablet will be administered orally as twice daily dose of (2 X 200 mg) up to 12 weeks.
  • Drug: Placebo
    Matching placebo tablet will be administered orally twice daily up to 12 weeks.
Study Arms  ICMJE
  • Experimental: GSK2586184 50 mg Arm
    Subjects in the GSK2586184 50 mg Arm will receive twice daily dose of GSK2586184 50 mg 1 x 50 mg tablet + 1x placebo tablet) orally up to 12 weeks. Study medication should be taken with food, immediately following a meal
    Interventions:
    • Drug: GSK2586184 50 mg
    • Drug: Placebo
  • Experimental: GSK2586184 100 mg Arm
    Subjects in the GSK2586184 100 mg Arm will receive twice daily dose of GSK2586184 100 mg (2 x 50 mg tablets) orally up to 12 weeks. Study medication should be taken with food, immediately following a meal.
    Intervention: Drug: GSK2586184 100 mg
  • Experimental: GSK2586184 200 mg Arm
    Subjects in the GSK2586184 200 mg Arm will receive twice daily dose of GSK2586184 200 mg (1 x 200 mg tablet + 1x placebo tablet) orally up to 12 weeks. Study medication should be taken with food, immediately following a meal.
    Interventions:
    • Drug: GSK2586184 200 mg
    • Drug: Placebo
  • Experimental: GSK2586184 400 mg Arm
    Subjects in the GSK2586184 400 mg Arm will receive twice daily dose of GSK2586184 400 mg (2 x 200 mg tablets) orally up to 12 weeks. Study medication should be taken with food, immediately following a meal.
    Intervention: Drug: GSK2586184 400 mg
  • Placebo Comparator: Placebo
    Subjects in the placebo arm will receive twice daily dose of 2 matching placebo tablets orally up to 12 weeks; taken with food, immediately following a meal.
    Intervention: Drug: Placebo
Publications * Kahl L, Patel J, Layton M, Binks M, Hicks K, Leon G, Hachulla E, Machado D, Staumont-Sallé D, Dickson M, Condreay L, Schifano L, Zamuner S, van Vollenhoven RF; JAK115919 Study Team. Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus. Lupus. 2016 Nov;25(13):1420-1430. doi: 10.1177/0961203316640910. Epub 2016 Jul 11.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: March 27, 2014)
51
Original Estimated Enrollment  ICMJE
 (submitted: January 24, 2013)
250
Actual Study Completion Date  ICMJE March 31, 2014
Actual Primary Completion Date March 1, 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age & Gender: Male or female between 18 and 75 years of age inclusive
  • SLE classification: a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) classification criteria
  • Severity of disease: clinically active SLE disease defined as a SELENA SLEDAI score ≥8 at screening
  • Auto antibodies: serologically active having unequivocally positive anti-nuclear antibody (ANA) or anti-double stranded DNA (anti-dsDNA) antibody test results from 2 independent time points
  • Treatment for SLE: patient stable on either no treatment or a stable dose of: corticosteroids (<=15 mg/day prednisolone or equivalent) and /or hydroxychloroquine (<=400 mg daily dose) Subjects receiving azathioprine (<=2 mg/kg/day or <=150 mg/day, whichever is greater) or mycophenolate mofetil (<=1.5 g/day), or methotrexate (MTX) (<=20 mg/week), either alone or in addition to steroids and / or hydroxychloroquine
  • Prevention of Pregnancy:

A female Subject is eligible to participate if she is not pregnant or nursing; is of non-childbearing potential. Females of child-bearing potential must agree to use one highly effective contraception method in addition to barrier protection OR two forms of highly effective contraception.

  • Informed consent: Capable of giving written informed consent

Exclusion Criteria:

  • Kidney Disease: meeting any of the following criteria:

Proteinuria > 0.5g/24 hour OR equivalent spot urine protein to creatinine ratio of 0.5mg/mg; Serum creatinine > 1.5 X upper limit of normal (ULN); active nephritis requiring acute therapy not permitted by protocol; required peritoneal dialysis or hemodialysis or high dose corticosteroid (> 100 mg/day prednisone or equivalent) within 90 days prior to first dose; active renal disease shown on renal biopsy in the three months prior to screening.

  • CNS Disease: active central nervous system (CNS) lupus (including seizures, psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis or CNS vasculitis) requiring therapeutic intervention within 60 days prior to first dose.
  • Alcohol Abuse: Evidence or, in the opinion of the investigator, suspicion of alcohol consumption exceeding national guidelines and / or symptoms of alcohol dependency.
  • Substance abuse: evidence of current recreational drug abuse or dependence.
  • Hepatitis B: A positive pre-study Hepatitis B surface antigen or anti-Hepatitis B core antibody test at screening
  • Hepatitis C: A positive Hepatitis C antibody at screening.
  • HIV: A positive test for HIV antibody
  • Previous Investigational Product Exposure:

The subject has participated in a clinical trial and has received an investigational product within 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) prior to the first dosing day in the current study; OR exposure to more than four new chemical entities within 12 months prior to the first dosing day.

  • Previous and current medication: Use of prescription or non-prescription drugs, including: agents known to interact with GSK2586184, erythopoetic stimulation factors; vitamins, herbal and dietary supplements
  • Prior biological therapies: treatment with a biological therapy within the last 12 months
  • Transplantation: Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
  • Uncontrolled Other Diseases: Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases not due to SLE which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk.
  • Surgery and Other Conditions: Have a planned surgical procedure or a history of any other medical disease laboratory abnormality, or condition that, in the opinion of the investigator, makes the subject unsuitable for the study.
  • Cancer: Have a history of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.-
  • Infections: have required management of acute or chronic infections as follows: currently on any suppressive therapy for a chronic infection (such as pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria); OR hospitalisation for treatment of infection OR use of parenteral (IV or intramuscular) antibiotics (antibacterials, antivirals, anti-fungals, or anti parasitic agents) within 60 days prior to first dose.
  • Mycobacterium Tuberculosis: Known latent or active infection with Mycobacterium Tuberculosis. Screening procedures consistent with local guidelines should be implemented.
  • Haematology: neutrophil count <=1.5 X 10^9/L, Hb <=10g/dL, lymphocyte count <=350/mm^3 or 0.35 x 10^9/L and platelet count <=100 X 10^9/L
  • Serum immunoglobulin (Ig) levels: IgG and/or IgM <= the lower limit of normal (LLN)
  • Liver function tests: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >=2x upper limit of normal (ULN); alkaline phosphatase and bilirubin >1.5xULN (isolated bilirubin >1.5ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Other laboratory abnormalities: Any Grade 3 or 4 haematology or clinical chemistry laboratory abnormality
  • Drug sensitivity: History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
  • Blood donation: Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Chile,   Czechia,   Estonia,   France,   Germany,   Greece,   Hong Kong,   Hungary,   Korea, Republic of,   Peru,   Poland,   Romania,   South Africa,   Spain,   Sweden
Removed Location Countries Brazil,   Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT01777256
Other Study ID Numbers  ICMJE 115919
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP