Clinical trial NCT01777256: An Adaptive Phase II Study to Evaluate the Efficacy, Pharmacodynamics, Safety and Tolerability of GSK2586184
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Keywords: systemic lupus erythematosus
adaptive design
clinical safety and efficacy
pharmacodynamics
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-01-28
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Percentage Inhibition from Baseline of interferon (IFN) Transcriptional Biomarkers at Week 2
timeFrame: Baseline(Day1) and Week 2
measure: Change from Baseline of SELENA SLEDAI score at indicated time points up to Week 16
timeFrame: Baseline(Day1), Weeks 2, 4, 6, 8, 10, 12 and 16
measure: Change from Baseline in systolic blood pressure and diastolic blood pressure at the indicated time points up to Week 16
timeFrame: Baseline(Day1), Weeks 2, 4, 6, 8, 10, 12 and 16
measure: Change from Baseline in heart rate at the indicated time points up to Week 16
timeFrame: Baseline (Day 1), Weeks 2, 4, 6, 8, 10, 12 and 16
measure: Change from Baseline in temperature at the indicated time points up to Week 16
timeFrame: Baseline (Day 1), Weeks 2, 4, 6, 8, 10, 12 and 16
measure: Change from Baseline in albumin, globulin and protein at the indicated time points up to Week 16
timeFrame: Baseline (Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: 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
timeFrame: Baseline(Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: 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
timeFrame: Baseline (Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in bilirubin, creatinine, iron binding capacity, iron and urate at the indicated time points up to Week 16
timeFrame: Baseline(Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in albumin/globulin, BUN/creatinine and transferrin saturation at the indicated time points up to Week 16
timeFrame: Baseline(Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in creatinine clearance at the indicated time points up to Week 16
timeFrame: Baseline (Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, neutrophils, neutrophils segmented (SG), platelets and leukocytes at the indicated time points up to Week 16
timeFrame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: 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
timeFrame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in erythrocytes and reticulocytes at the indicated time points up to Week 16
timeFrame: Baseline (Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in hemoglobin and erythrocyte mean corpuscular hemoglobin concentration (EMCHC) at the indicated time points up to Week 16
timeFrame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in erythrocyte mean corpuscular hemoglobin (EMCH) at the indicated time points up to Week 16
timeFrame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in erythrocyte mean corpuscular volume (EMCV) and mean platelet volume (MPV) at the indicated time points up to Week 16
timeFrame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in hematocrit and reticulocytes/erythrocytes at the indicated time points up to Week 16
timeFrame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Number of participants with urinalysis data at the indicated time points up to Week 16
timeFrame: Baseline(Day 1), Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in urine protein at the indicated time points up to Week 16
timeFrame: Baseline(Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Change from Baseline in urine protein/creatinine at the indicated time points up to Week 16
timeFrame: Baseline(Day 1), Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16
measure: Number of participants with any adverse events (AEs) and any serious adverse events (SAEs) up to Week 16
timeFrame: Up to Week 16
measure: Number of participants with severity Grade 1, 2, 3, 4 and 5 adverse events (AEs)
timeFrame: Up to 16 Weeks
Secondary outcomes:
measure: SRI Response Rate at Week 4, 8, 12 and 16
timeFrame: Week 4, 8, 12 and 16
measure: Change from baseline in SLEDAI-2K score and the S2K RI-50 score over time (up to Week 12)
timeFrame: Baseline(Day 1) to Week 12
measure: Mean GSK2586184 plasma concentrations on Weeks 2, 4, 6, 8, 10 and 12
timeFrame: Weeks 2, 4, 6, 8, 10 and 12
measure: Area under the concentration-time curve over the dosing interval (AUC[0-tau]) up to Week 12
timeFrame: Weeks 2, 4, 6, 8, 10 and 12
measure: Apparent clearance (CL/F) up to Week 12
timeFrame: Weeks 2, 4, 6, 8, 10 and 12
measure: Volume of distribution (Vss) up to Week 12
timeFrame: Weeks 2, 4, 6, 8, 10 and 12
measure: Mean change from Baseline in the SF-36 Domain Scores up to Week 16
timeFrame: Baseline(Day 1), Weeks 12 and 16
measure: Mean change from Baseline in the Brief Fatigue Inventory (BFI) Domain Score up to Week 16
timeFrame: Baseline (Day 1), Weeks 2, 4, 6, 8, 10, 12 and 16
measure: Mean change from Baseline in the Brief Pain Inventory (BPI) Domain Score up to Week 16
timeFrame: Baseline(Day 1), Weeks 2, 4, 6, 8, 10, 12 and 16
Other outcomes:
Locations:
city: Ciudad de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: GSK Investigational Site
state: Santa Fe
city: San Juan
country: Argentina
facility: GSK Investigational Site
city: Santiago
country: Chile
facility: GSK Investigational Site
state: Región Metro De Santiago
city: Olomouc
country: Czechia
facility: GSK Investigational Site
city: Praha 2
country: Czechia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Brest Cedex
country: France
facility: GSK Investigational Site
city: Lille Cedex
country: France
facility: GSK Investigational Site
city: Limoges Cedex
country: France
facility: GSK Investigational Site
city: Paris Cedex 13
country: France
facility: GSK Investigational Site
city: Pessac cedex
country: France
facility: GSK Investigational Site
city: Herne
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Kiel
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Jena
country: Germany
facility: GSK Investigational Site
state: Thueringen
city: Athens
country: Greece
facility: GSK Investigational Site
city: Heraklion-Crete
country: Greece
facility: GSK Investigational Site
city: Larissa
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Hong Kong
country: Hong Kong
facility: GSK Investigational Site
city: Shatin
country: Hong Kong
facility: GSK Investigational Site
city: Tuen Mun
country: Hong Kong
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Debrecen
country: Hungary
facility: GSK Investigational Site
city: Zalaegerszeg
country: Hungary
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: La Victoria
country: Peru
facility: GSK Investigational Site
state: Lima
city: San Borja
country: Peru
facility: GSK Investigational Site
state: Lima
city: Surco
country: Peru
facility: GSK Investigational Site
state: Lima
city: Lima
country: Peru
facility: GSK Investigational Site
city: Bialystok
country: Poland
facility: GSK Investigational Site
city: Gdynia
country: Poland
facility: GSK Investigational Site
city: Lublin
country: Poland
facility: GSK Investigational Site
city: Poznan
country: Poland
facility: GSK Investigational Site
city: Poznan
country: Poland
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Cluj-Napoca
country: Romania
facility: GSK Investigational Site
city: Cape Town
country: South Africa
facility: GSK Investigational Site
city: Parow
country: South Africa
facility: GSK Investigational Site
city: Pinelands, Cape Town
country: South Africa
facility: GSK Investigational Site
city: Stellenbosch
country: South Africa
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Santiago De Compostela
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Göteborg
country: Sweden
facility: GSK Investigational Site
city: Linköping
country: Sweden
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Kahl L, Patel J, Layton M, Binks M, Hicks K, Leon G, Hachulla E, Machado D, Staumont-Salle 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.