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

This study has been 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.)
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01777256
First received: January 24, 2013
Last updated: October 23, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Systemic Lupus Erythematosus
Drug: GSK2586184 50 mg
Drug: GSK2586184 100 mg
Drug: GSK2586184 200 mg
Drug: GSK2586184 400 mg
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: An Adaptive Phase II Study to Evaluate the Efficacy, Pharmacodynamics, Safety and Tolerability of GSK2586184 in Patients With Mild to Moderate Systemic Lupus Erythematosus

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Interferon biomarkers over time [ Time Frame: Up to 16 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Adverse events (AEs) will be collected from the start of Investigation Product and until the follow-up visit.


Secondary Outcome Measures:
  • SRI Response Rate over time [ Time Frame: Up to 16 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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


Enrollment: 51
Study Start Date: March 2013
Estimated Study Completion Date: November 2015
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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: Placebo
Matching placebo tablet will be administered orally twice daily up to 12 weeks.
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.
Drug: GSK2586184 100 mg
GSK2586184 tablet will be administered orally as twice daily dose of (2 X 50 mg tablet) up to 12 weeks.
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.
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: Placebo
Matching placebo tablet will be administered orally twice daily up to 12 weeks.
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.
Drug: GSK2586184 400 mg
GSK2586184 tablet will be administered orally as twice daily dose of (2 X 200 mg) up to 12 weeks.
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.
Drug: Placebo
Matching placebo tablet will be administered orally twice daily up to 12 weeks.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01777256

  Show 53 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01777256     History of Changes
Other Study ID Numbers: 115919
Study First Received: January 24, 2013
Last Updated: October 23, 2014
Health Authority: Hungary: National Institute of Pharmacy
Estonia: State Agency of Medicines
Argentina: National Administration of Medicines, Food and Medical Technology
Peru: National Institute of Health
Romania: National Agency for Drug and Medical Devices
Chile: Public Health Institute
South Africa: Medicines Control Council
Hong Kong: Department of Health
Sweden: Medical Products Agency
Korea: Korea Food and Drug Administration [KFDA]
Germany: Federal Institute for Drugs and Medical Devices
Czech Republic: State Institute for Drug Control
France: National Agency for the Safety of Medicine and Health Products
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Greece: National Organization for Medicines
Spain: Spanish Agency for Medicines and Health Products
Brazil: National Health Surveillance Agency

Keywords provided by GlaxoSmithKline:
pharmacodynamics
systemic lupus erythematosus
adaptive design
clinical safety and efficacy

Additional relevant MeSH terms:
Lupus Erythematosus, Systemic
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases

ClinicalTrials.gov processed this record on November 27, 2014