Efficacy, Safety and Pharmacokinetics of BIRB 796 BS Tablets in Patients With Active Rheumatoid Arthritis

Study Overview
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Brief Summary
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Study to determine the efficacy (including American College of Rheumatology (ACR) 20 response rate), safety, and pharmacokinetics of BIRB 796 BS as monotherapy in patients with moderate to severe rheumatoid arthritis who have failed at least one disease modifying antirheumatic drug (DMARD)

Official Title
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A 12 Week Double-blind, Randomized, Placebo-controlled Trial to Investigate Efficacy, Safety and Pharmacokinetics of BIRB 796 BS Tablets at Doses of 50 and 70 mg Administered Twice a Day in Patients With Active Rheumatoid Arthritis Who Have Failed at Least One DMARD

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: BIRB 796 BS, low dose
* Drug: BIRB 796 BS, high dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female from 18 to 75 years of age Diagnosis of rheumatoid arthritis (RA) established according to ACR criteria and date of diagnosis > 6 months Patient belonging to functional class I, II, or III Failure of at least one DMARD due to lack of efficacy or tolerability 2 out of the 3 following RA activity criteria: If this criterion is not met at visit 1, the whole set of RA activity criteria can be repeated at visit 2 (Repeated screening) documentation of ≥ 9 swollen joints in a 66 joint count documentation of ≥ 9 tender joints in a 68 joint count C-reactive protein (CRP) ≥ 1.5 mg/dl or erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr (or equivalent of ≥ 24mm/hr according to Panchenkov method) Written informed consent in accordance with Good Clinical Practice (GCP) and local legislation given prior to any study procedures, including washout of prohibited medications Only for centres participating in the pharmacokinetic (PK) substudy: Written informed consent in accordance with GCP and local legislation for participation in the PK substudy. Refusal to participate in the PK substudy is not an exclusion criterion for participation in the trial Exclusion Criteria: Inflammatory rheumatic disease other than RA Treatment failure to a tumor necrosis factor (TNF)-blocking agent. Treatment failure is defined as not achieving at least an ACR 20 response (e.g. in a clinical trial) or - in clinical practice - having the TNF-blocking agent discontinued due to ineffectiveness History of vasculitis (characterised by e.g. nail bed hemorrhages or infarcts, vasculitic purpura, ulcers or gangrene, multisensory neuropathy, vasculitic retinopathy or scleritis of eyes). Isolated rheumatoid nodules of the skin are not a criterion for exclusion Serologic evidence of active hepatitis B and/or C Known HIV-infection History of prior tuberculosis infection or suspicion of active infection at screening based on results of chest x-ray not older than 6 months History of cardiovascular, renal, neurologic, psychiatric, liver, gastrointestinal, immunologic or endocrine dysfunction if they are clinically significant. A clinically significant disease is defined as one which in the opinion of the investigator may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient's ability to participate in the study Recent history of heart failure (i.e. three years or less) or myocardial infarction (i.e. one year or less) or patients with any cardiac arrhythmia requiring drug therapy History of malignant disease in the last 5 years or suspicion of active malignant disease except successfully treated squamous or basal cell carcinoma of the skin Screening ECG results outside of the reference range of clinical relevance including, but not limited to QTcB > 480 msec, PR interval > 240 msec, QRS interval > 110 msec according to central ECG evaluation Clinically significant abnormal baseline hematology, blood chemistry or urinalysis if the abnormality defines a disease listed as an exclusion criterion or any of the following specific laboratory abnormalities: If this criterion is not met at visit 1, the laboratory assessments can be selectively repeated at visit 2 (Repeated screening) alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin greater than upper limit of normal (ULN) alkaline phosphatase, creatinine or white blood cell count greater than 1.5 x ULN History of drug or alcohol abuse within the past two years or active drug or alcohol abuse, present alcohol intake more than three drinks per day Female of childbearing potential (not 6 months post- menopausal or surgically sterilized) not using an approved form of birth control (hormonal contraceptives, oral or injectable/implantable, intra-uterine device (IUD)) Inability to comply with the protocol Previous enrolment in this trial or previous exposure to BIRB 796 BS in another trial Hypersensitivity to trial drug To be assessed at visit 3 (Baseline): Pregnancy (to be excluded by serum and urine beta human chorion-gonadotropin (βHCG)-test in women of childbearing potential) or breast feeding Active vasculitis Active infection or serious infectious diseases resulting in hospitalisation or requiring systemic anti-infective therapy within the last 4 weeks DMARD treatment within the last 4 weeks Last dose given within the specified time period for one of the following compounds or drugs: Infliximab (Remicade®): 3 months Adalimumab (D2E7): 3 months Leflunomide: 3 months. If cholestyramine has been given for 10 days : 4 weeks Investigational agent: 5- fold of the respective plasma half life or 4 weeks, whichever is longer Treatment with systemic corticosteroids in a dose higher than 10 mg/day prednisone equivalent Change in treatment with nonsteroidal antiinflammatory drugs (NSAIDs) or systemic corticosteroids within the last 4 weeks Synovectomy, joint surgery, radio-/chemo synoviorthesis, adrenocorticotropic hormone (ACTH) or any steroid injections (intraarticular, intravenous or intramuscular) within the last 4 weeks Participation in another clinical trial within the last 4 weeks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIRB 796 BS, low dose<br> | Drug: BIRB 796 BS, low dose<br> <br> Drug: Placebo<br> <br> |
| Experimental: BIRB 796 BS, high dose<br> | Drug: BIRB 796 BS, high dose<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of responders according to the American College of Rheumatology (ACR) 20 criteria |  | after 12 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute differences to baseline in tender joint count (TJC, 68 joint count) |  | up to 12 weeks | 
| Absolute differences to baseline swollen joint count (SJC, 66 joint count) |  | up to 12 weeks | 
| Absolute differences to baseline in patients assessment of pain on a visual analogue scale (VAS) |  | up to 12 weeks | 
| Absolute differences to baseline in patients global assessment of disease activity (PADA) on a VAS |  | up to 12 weeks | 
| Absolute differences to baseline in physicians global assessment of disease activity on a VAS |  | up to 12 weeks | 
| Absolute differences to baseline in patient's assessment of physical function measured by a standardised Health Assessment Questionnaire (HAQ) |  | up to 12 weeks | 
| Absolute differences to baseline in concentration of C-reactive protein (CRP) |  | up to 12 weeks | 
| Absolute differences to baseline in erythrocyte sedimentation rate (ESR) |  | up to 12 weeks | 
| Number of responders to ACR 50 |  | after 12 weeks of treatment | 
| Number of responders to ACR 70 |  | after 12 weeks of treatment | 
| Number of responders to European League against Rheumatism (EULAR) response criteria |  | after 12 weeks of treatment | 
| Number of drop-outs due to lack of efficacy, according to final assessment of investigator |  | after 12 weeks of treatment | 
| Number of patients with adverse Events (AE) |  | up to 12 weeks after first drug administration | 
| Number of patients with clinically relevant changes in laboratory tests |  | up to 12 weeks after first drug administration | 
| Number of patients with clinically relevant changes in electrocardiogram (ECG) |  | up to 12 weeks after first drug administration | 
| Number of patients with clinically relevant changes in vital signs |  | up to 12 weeks after first drug administration | 
| Number of withdrawals due to AEs |  | up to 12 weeks after first drug administration | 
| Cmax,ss (Maximum measured concentration of the analyte in plasma at steady state) |  | up to 24 hours after last drug administration | 
| AUC0-t,ss (area under the drug plasma concentration-time curve over a dosing interval (t) at steady state |  | up to 24 hours after last drug administration | 
| Cpre (predose concentration of the analyte in Plasma) |  | up to 24 hours after last drug administration | 
| Cmin,ss (Minimum measured concentration of the analyte in plasma at steady state) |  | up to 24 hours after last drug administration |