Phase III Randomized Study of Anti-Tumor Necrosis Factor Chimeric Monoclonal Antibody (cA2) for Patients With Enterocutaneous Fistulae as a Complication of Crohn's Disease

PROTOCOL OUTLINE: This is a randomized, double blind, placebo controlled, multicenter study. Patients are stratified according to investigational site and number of fistulae (single vs multiple).

Patients are randomized to one of three treatment arms: Arm I: Patients receive an infusion of chimeric monoclonal antibody (cA2) on weeks 0, 2, and 6. Arm II: Patients receive an infusion of cA2 on weeks 0 and 2, and an infusion of placebo on week 6. Arm III: Patients receive an infusion of placebo on day 1 of weeks 0, 2, and 6.

Patients are followed every month for 3 months, then every 6-12 months for up to 2 years.

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

Crohn's disease of at least 3 months duration confirmed by radiography or endoscopy

Single or multiple draining enterocutaneous (including perianal) fistulae of at least 3 months duration

All fistulae separate and distinctly identifiable

No local complications of Crohn's disease such as strictures or abscesses

--Prior/Concurrent Therapy--

Biologic therapy:

• No prior chimeric monoclonal antibody (cA2)
• At least 3 months since treatment with other therapeutic agent targeted at reducing tumor necrosis factor (e.g., pentoxifylline or thalidomide)
• At least 4 weeks since cyclosporine

Chemotherapy:

• Concurrent methotrexate permitted if treatment began at least 3 months prior to enrollment, dose has been stable for at least 4 weeks prior to enrollment and remains stable throughout study period
• Otherwise, no methotrexate within 4 weeks prior to enrollment

Concurrent 6-mercaptopurine or azathioprine permitted if treatment began at least 6 months prior to enrollment, dose has been stable for at least 8 weeks prior to enrollment, and remains stable throughout study period Otherwise, no 6-mercaptopurine or azathioprine within 4 weeks prior to enrollment

Endocrine therapy:

• Concurrent corticosteroids (e.g., oral prednisone) permitted if dose has been stable for at least 3 weeks prior to enrollment, does not exceed 40 mg/kg, and remains stable throughout study period (dosage may be tapered after 6 weeks for some patients)
• Otherwise, no corticosteroids within 4 weeks prior to enrollment

Other:

• Concurrent antibiotics or aminosalicylates for Crohn's disease permitted if dose has been stable for at least 4 weeks prior to enrollment and remains stable throughout study period
• Otherwise, no antibiotics or aminosalicylates within 4 weeks prior to enrollment
• At least 3 months since investigational drugs

--Patient Characteristics--

Hematopoietic:

• WBC at least 3,500/mm3
• Neutrophil count at least 1,500/mm3
• Lymphocyte count at least 500/mm3
• Platelet count at least 100,000/mm3
• Hemoglobin at least 8.5 g/dL
• No severe, progressive, or uncontrolled hematologic disease

Hepatic:

• SGOT no greater than 3 times upper limit of normal (ULN)
• Alkaline phosphatase no greater than 3 times ULN
• No severe, progressive, or uncontrolled hepatic disease

Renal:

• Creatinine no greater than 1.7 mg/dL
• No severe, progressive, or uncontrolled renal disease

Cardiovascular: No severe, progressive, or uncontrolled cardiac disease

Pulmonary: No severe, progressive, or uncontrolled pulmonary disease

Neurologic: No severe, progressive, or uncontrolled neurologic or cerebral disease

Other:

• Negative pregnancy test required and no planned pregnancy within 7.5 months following first infusion
• Effective contraception required of fertile patients during and for 6 months after study
• No severe, progressive, or uncontrolled endocrine disease
• No serious infections (e.g., hepatitis, pneumonia, pyelonephritis) within prior 3 months
• No history of opportunistic infections (e.g., herpes zoster) within 2 months
• No allergy to murine proteins
• No active cytomegalovirus, Pneumocystis carinii, or drug resistant atypical mycobacterial infections
• No recent drug or alcohol abuse
• No HIV infection, ARC (AIDS-related complex) or AIDS
• Total parenteral nutrition or tube feeding not permitted
• No prior or concurrent malignancy within 5 years