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

• Register: ClinicalTrials.gov
• Last refreshed on: 16 December 2017
• Main ID: NCT01777256
• Date of registration: 24/01/2013
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: An Adaptive Phase II Study to Evaluate the Efficacy, Pharmacodynamics, Safety and Tolerability of GSK2586184
• Scientific 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
• Date of first enrolment: March 1, 2013
• Target sample size: 51
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT01777256
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 2

Countries of recruitment

Argentina, Brazil, Chile, Czech Republic, Czechia, Estonia, France, Germany, Greece, Hong Kong, Hungary, Korea, Republic of, Peru, Poland, Romania, South Africa, Spain, Sweden

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion 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.



Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Systemic Lupus Erythematosus

Intervention(s)

Drug: GSK2586184 100 mg

Drug: GSK2586184 200 mg

Drug: Placebo

Drug: GSK2586184 400 mg

Drug: GSK2586184 50 mg

Primary Outcome(s)

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]

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]

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 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 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 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 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]

Number of participants with any adverse events (AEs) and any serious adverse events (SAEs) up to Week 16 [Time Frame: Up to Week 16]

Number of participants with severity Grade 1, 2, 3, 4 and 5 adverse events (AEs) [Time Frame: Up to 16 Weeks]

Percentage Inhibition from Baseline of interferon (IFN) Transcriptional Biomarkers at Week 2 [Time Frame: Baseline(Day1) and Week 2]

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 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 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 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 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 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 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 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 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 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 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 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 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]

Secondary Outcome(s)

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]

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]

Apparent clearance (CL/F) up to Week 12 [Time Frame: Weeks 2, 4, 6, 8, 10 and 12]

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]

Mean change from Baseline in the SF-36 Domain Scores up to Week 16 [Time Frame: Baseline(Day 1), Weeks 12 and 16]

Volume of distribution (Vss) up to Week 12 [Time Frame: Weeks 2, 4, 6, 8, 10 and 12]

SRI Response Rate at Week 4, 8, 12 and 16 [Time Frame: Week 4, 8, 12 and 16]

Mean GSK2586184 plasma concentrations on Weeks 2, 4, 6, 8, 10 and 12 [Time Frame: Weeks 2, 4, 6, 8, 10 and 12]

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]

Secondary ID(s)

115919

Source(s) of Monetary Support

Please refer to primary and secondary sponsors