Tumor Necrosis Factor For Crohn’s Disease Study

Crohn’s disease is a chronic inflammatory disorder characterized by patchy granulomatous inflammation of any part of the gastrointestinal tract.1 Patients have a spectrum of clinical features, with great variation in the course of the disease. Mesalamine is considered first-line therapy. The majority of patients have relapses requiring glucocorticoid treatment.2 Immunomodulatory agents, including azathioprine or mercaptopurine,3 methotrexate,4,5 and cyclosporine,6-9 may be used to treat severe, persistent disease that is refractory to treatment with corticosteroids, or symptoms that recur on tapering of the dose of corticosteroids.

In animal models, antibodies to tumor necrosis factor α (anti–TNF-α) prevent or reduce inflammation,10-14 suggesting that therapy with such antibodies may be useful for disorders in which chronic inflammation may be due to an increase in cytokines produced by the T helper 1 subclass of T cells. In vitro studies have shown that the production of TNF-α is increased in the mucosa of patients with Crohn’s disease15,16 and that the mucosal inflammatory process reflects a shift in the balance of cytokine production by T cells toward the T helper 1 subclass.17,18 Similar findings were reported in the synovia of patients with rheumatoid arthritis,19 and anti–TNF-α reduces clinical signs and symptoms of this disease.20,21 The role of TNF-α in the pathogenesis of Crohn’s disease and the successful use of anti–TNF-α in the treatment of rheumatoid arthritis stimulated an open-label trial of chimeric monoclonal antibody cA2 (infliximab, Centocor, Malvern, Pa.) for Crohn’s disease. In that preliminary trial, clinical remission occurred after one infusion of cA2 in eight of nine patients with Crohn’s disease.22 We report the results of a multicenter randomized, placebo-controlled, double-blind trial of cA2 for the treatment of active Crohn’s disease.
Methods
Patients

To be eligible for the study, patients had to have had Crohn’s disease for six months,1 with scores on the Crohn’s Disease Activity Index23 between 220 and 400. The Crohn’s Disease Activity Index incorporates eight variables related to the disease: the number of liquid or very soft stools, the severity of abdominal pain or cramping, general well-being, the presence of extraintestinal manifestations, abdominal mass, use of antidiarrheal drugs, hematocrit, and body weight. These items yield a composite score ranging from 0 to approximately 600. Higher scores indicate greater disease activity. Scores below 150 indicate remission, whereas scores above 450 indicate severe illness. Patients were eligible for the study if they had been receiving any of the following: mesalamine for eight or more weeks, with the dose remaining stable during the four weeks before screening; a maximum of 40 mg of corticosteroids per day for eight or more weeks, with the dose remaining stable during the two weeks before screening; and mercaptopurine or azathioprine for six or more months, with the dose remaining stable during the eight weeks before screening. Patients were excluded from the study if they had received treatment with cyclosporine, methotrexate, or experimental agents within three months before screening. Patients were also excluded if they met any of the following criteria: symptomatic stenosis or ileal strictures; proctocolectomy or total colectomy; stoma; a history of allergy to murine proteins; prior treatment with murine, chimeric, or humanized monoclonal antibodies; or treatment with parenteral corticosteroids or corticotropin within four weeks before screening.

Patients were enrolled at 18 centers in North America and Europe. The protocol was approved by the institutional review boards and ethics committees at all sites, and all patients gave written informed consent before enrolling in the trial. The study began on June 21, 1995, and concluded on March 12, 1996. A total of 203 patients were screened for the study, 95 of whom were excluded. The most common reasons for exclusion were a requirement for contraindicated medications, refusal to give informed consent, or disease activity that did not meet the study criteria.
Protocol

Subjects were screened one week before the administration of cA2 to establish base-line scores on the Crohn’s Disease Activity Index and the Inflammatory Bowel Disease Questionnaire,24 and base-line C-reactive protein concentrations. The Inflammatory Bowel Disease Questionnaire, a 32-item questionnaire, evaluates quality of life with respect to bowel function (e.g., loose stools and abdominal pain), systemic symptoms (fatigue and altered sleep pattern), social function (work attendance and the need to cancel social events), and emotional status (angry, depressed, or irritable). The score ranges from 32 to 224, with higher scores indicating a better quality of life. Patients in remission usually score between 170 and 190.24

Patients were randomly assigned to receive a single dose of either placebo or 5 mg of cA2 per kilogram of body weight, 10 mg of cA2 per kilogram, or 20 mg of cA2 per kilogram in an intravenous infusion, administered over a two-hour period. The cA2 monoclonal antibody is a chimeric mouse–human IgG1 that binds to both soluble25 and transmembrane26 human TNF-α with high affinity and specificity. It neutralizes the functional activity of TNF in a variety of bioassays by blocking the binding of the factor to the p55 and p75 receptors.27 The placebo preparation contained 0.1 percent human serum albumin instead of cA2 and was identical in appearance to the cA2 solution. Patients were enrolled from June 21, 1995, to October 31, 1995. Randomization was performed centrally by an independent organization (PPD Pharmaco, Austin, Tex.). The cA2 and placebo solutions were prepared by a pharmacist at each site who was aware of the treatment assignments. The investigators, all other study personnel, and the patients were blinded to the treatment assignments.

The primary end point was defined before the initiation of the trial as a reduction of 70 points or more in the score on the Crohn’s Disease Activity Index at the four-week evaluation that was not accompanied by a change in any concomitant medications. Patients who did not have a clinical response at that time were enrolled in a parallel, open-label study and received a single infusion of 10 mg of cA2 per kilogram and were followed for 12 additional weeks. Patients who were receiving mesalamine, corticosteroids, azathioprine, or mercaptopurine before the study continued to receive a stable dose during the trial period. The dose of corticosteroids could be tapered beginning eight weeks after the initiation of the study. Treatment with these drugs or with methotrexate or cyclosporine could not be initiated during the trial. After all patients had completed 12 weeks of the trial and the data were finalized, the treatment assignments were revealed.
Immunologic Investigations

Serum samples were obtained at base line and at 12 weeks for the evaluation of antinuclear antibodies and human anti-cA2. Antinuclear antibodies were detected by immunofluorescence on Hep-2 cells. Serum samples positive by immunofluorescence for antinuclear antibodies were tested for antibodies to double-stranded DNA by an enzyme-linked immunosorbent assay (North American centers) or by Crithidia immunofluorescence (European centers). Human anti-cA2 was measured by a double-antigen enzyme-linked immunosorbent assay.
Statistical Analysis

An adaptive stratified design was used to assign patients to a treatment group, with investigational site and corticosteroid use as the strata. We calculated that approximately 25 patients were needed in each treatment group to detect a difference in the number of patients who responded with 80 percent power (α = 0.05), assuming a response rate of 30 percent in the placebo group, 80 percent in the cA2 group with the greatest response, and 55 percent in the remaining cA2 groups. The original study protocol did not specify the use of intention-to-treat analysis. Two patients were assigned to a treatment but did not receive it: one declined to participate and one did not meet eligibility criteria. No further data were collected on these two patients, and they are not included in the analysis. Otherwise, all patients were analyzed according to the treatment to which they were assigned. When we assessed the response or remission rates in all evaluation periods after the initial blinded infusion, patients who received an open-label infusion or those with a change in concomitantly administered medications were considered to have had no response.

Categorical variables (clinical response and remission) were compared with use of the Mantel–Haenszel chi-square test for general association stratified according to investigational site.28 Analyses comparing each of the cA2 treatment groups with placebo were performed only when the treatment effect was considered significant (P<0.05). The changes from base line in continuous variables (Crohn’s Disease Activity Index score, Inflammatory Bowel Disease Questionnaire score, and C-reactive protein concentration) were compared with use of analysis of variance, with the van der Waerden normal scores blocked according to center.29 If the treatment effect was significant, the cA2 treatment groups were compared with the placebo group with linear contrasts. All P values are two-sided.

This information is from: The New England Journal of Medicine referenced here.

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