Oral CF101 and Methotrexate Treatment in Rheumatoid Arthritis Patients

Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of the Safety and Efficacy of Daily CF101 Administered Orally, When Added to Weekly Methotrexate, in Patients With Active Rheumatoid Arthritis

This trial will test the hypothesis that the addition of CF101, a novel anti-inflammatory agent, will improve the clinical condition of patients with rheumatoid arthritis who still have active joint inflammation despite taking methotrexate for at least 6 months.

This will be a multi-center, randomized, double-blind, parallel-group, placebo-controlled, dose-finding study in which patients with active RA despite receiving methotrexate for at least 6 months (at unchanged doses for >=2 months) will be randomized to the addition of either CF101 0.1 mg, CF101 1 mg, CF101 4 mg, or placebo given orally q12h for 12 weeks. Screening examinations will occur within 1 month prior to dosing. Washout of other disease-modifying antirheumatic drugs (DMARDs) (with the exception of hydroxychloroquine), including biological agents, will occur prior to dosing; if washout is necessary, patients must re-qualify for inclusion following the washout. Doses of nonsteroidal anti-inflammatory drugs (NSAIDS) and corticosteroids must be stable for >=1 month prior to dosing and remain so during protocol participation. Disease activity will be assessed using swollen and tender joint counts, duration of morning stiffness, physician and patient global assessments (by visual analog scale, VAS), patient reported pain (by VAS), a Health Assessment Questionnaire (HAQ) Disability Index (DI), Westergren erythrocyte sedimentation rate (ESR, Screening, Weeks 0 and12), and C-reactive protein (CRP) levels. Assessments will take place at Screening, Baseline (Week 0), and at Weeks 2, 4, 8, 12, and 14.

Inclusion Criteria:

• Males and females ages 18-75 years
• Meet the criteria of the American Rheumatism Association for RA (Arnett FC et al. Arthritis Rheum 1988;31:315-324, Appendix 1)
• Not bed- or wheelchair-bound
• Active RA, as indicated by the presence of (a) >=6 swollen joints (28 joint count); AND (b) >=6 tender joints (28 joint count); AND at least one of the following: (c) Westergren ESR of >=28 mm/hour; OR (d) CRP level above the upper limit of normal for the central reference laboratory; OR (e) morning stiffness for >=45 minutes
• Treatment with weekly oral or parenteral methotrexate for >=6 months prior to baseline
• Methotrexate route of administration has been unchanged for >=2 months prior to baseline
• Dose of methotrexate has been stable at 15-25 mg/week for >=2 months, and is expected to remain stable throughout the study; the stable dose of methotrexate may alternatively be 10-12.5 mg/week if documented toxicity has precluded a higher dose
• If taking hydroxychloroquine, administration duration has been >=3 months and dose has been stable for >=2 months prior to baseline
• If taking a nonsteroidal anti-inflammatory agent (NSAID), dose has been stable for at least 1 month prior to baseline, and will remain unchanged during protocol participation
• If taking an oral corticosteroid, dose is <=10 mg/day prednisone or equivalent, has been stable for at least 1 month prior to the washout period, and will remain stable through the washout and entire treatment and follow-up period
• Absence of clinically significant findings, such as interstitial pneumonitis or active pulmonary infection, on chest X-ray taken within 6 months prior to screening

Exclusion Criteria:

• Receipt of any of the following for at least a 1 month washout period prior to dosing: sulfasalazine, oral or injectable gold, azathioprine, minocycline, penicillamine, anakinra
• Receipt of etanercept for at least a 6 week period prior to dosing
• Receipt of cyclosporine, infliximab or adalimumab for at least a 2 month period prior to dosing
• Receipt of leflunomide for at least a 2 month period prior to screening, unless patient has undergone cholestyramine washout at least 1 month prior to dosing
• Receipt of cyclophosphamide for at least a 6 month period prior to dosing
• Receipt of rituximab at any previous time
• Receipt of CF101 in a previous trial
• Use of oral corticosteroids >10 mg of prednisone, or equivalent, per day
• Change in NSAID dose level for 1 month prior to dosing
• Change in oral corticosteroid dose level during the 1 month prior to, or during, the washout period
• Change in hydroxychloroquine dose level during the 2 months prior to, or during, the washout period
• Receipt of parenteral or intra-articular corticosteroids during the 1 month prior to, or during, the washout period
• Presence or history of uncontrolled asthma
• Presence or history of uncontrolled arterial hypertension or symptomatic hypotension
• Significant cardiac arrhythmia or conduction block, congestive heart failure, or any other evidence of clinically significant heart disease; other clinically significant findings on screening electrocardiogram (ECG)
• Hemoglobin level <9.0 gm/L
• Platelet count <125,000/mm3
• White blood cell count <3000/mm3
• Serum creatinine level outside the laboratory's normal limits
• Liver aminotransferase levels greater than 1.2 times the laboratory's upper limit of normal
• Known or suspected immunodeficiency or human immunodeficiency virus positivity
• Pregnancy, lactation, or inadequate contraception as judged by the Investigator