Resumen

Este es un estudio adaptativo de búsqueda de dosis de Fase II para investigar la relación entre dosis repetidas de GSK2586184 y el efecto farmacodinámico y la eficacia clínica en pacientes con lupus eritematoso sistémico (LES) activo. El estudio también investigará la seguridad y tolerabilidad de dosis repetidas de GSK2586184. Durante el estudio se realizarán hasta 3 análisis intermedios: para monitorear el efecto farmacodinámico y la seguridad tras 2 semanas de tratamiento (Análisis Intermedio 1); y para evaluar la eficacia clínica y seguridad de GSK2586184 tras 12 semanas de tratamiento (Análisis Intermedios 2 y 3). Los sujetos que cumplan los criterios de entrada (aproximadamente 150 a 250) serán aleatorizados en una proporción 1:1:1:1:1 para recibir GSK2586184 a dosis de 50 miligramos (mg) dos veces al día (b.i.d.), 100 mg b.i.d., 200 mg b.i.d., 400 mg b.i.d. o placebo b.i.d. Los comprimidos de GSK2586184 disponibles en concentraciones de 50 y 200 mg se administrarán por vía oral durante hasta 12 semanas. Los sujetos que completen el estudio participarán en él durante aproximadamente 21 semanas.

Elegibilidad

Edad mínima: 18 YearsEdad máxima: 75 YearsSexo: ALL

Criterios de inclusión

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

Criterios de exclusión

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.

Intervenciones

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.

Estudio Adaptativo de Fase II para Evaluar la Eficacia, Farmacodinámica, Seguridad y Tolerabilidad de GSK2586184 en Pacientes con Lupus Eritematoso Sistémico Leve a Moderado

Resumen

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

GSK2586184 50 mg

GSK2586184 100 mg

GSK2586184 200 mg

GSK2586184 400 mg

Placebo

Ubicaciones

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

Patrocinadores