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

GlaxoSmithKline (GSK)

Status and phase: Terminated; Phase 2

Conditions: Systemic Lupus Erythematosus

Treatments: Drug: Placebo; Drug: GSK2586184 50 mg; Drug: GSK2586184 200 mg; Drug: GSK2586184 100 mg; Drug: GSK2586184 400 mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT01777256

115919

Details and patient eligibility

About

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.

Enrollment: 51 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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51 participants in 5 patient groups, including a placebo group

GSK2586184 50 mg Arm

Experimental group

Description:

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

Treatment:

Drug: Placebo

Drug: GSK2586184 50 mg

GSK2586184 100 mg Arm

Experimental group

Description:

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.

Treatment:

Drug: GSK2586184 100 mg

GSK2586184 200 mg Arm

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: GSK2586184 200 mg

GSK2586184 400 mg Arm

Experimental group

Description:

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.

Treatment:

Drug: GSK2586184 400 mg

Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo