A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor for Crohn's Disease
Stephan R. Targan, M.D., Stephen B. Hanauer, M.D., Sander J.H. van Deventer, M.D., Ph.D., Lloyd Mayer, M.D., Daniel H. Present, M.D., Tanja Braakman, M.D., Kimberly L. DeWoody, M.S., Thomas F. Schaible, Ph.D., Paul J. Rutgeerts, M.D., Ph.D., for The Crohn's Disease cA2 Study Group
Background Studies in animals and an open-label trial have suggesteda role for antibodies to tumor necrosis factor , specificallychimeric monoclonal antibody cA2, in the treatment of Crohn'sdisease.
Methods We conducted a 12-week multicenter, double-blind, placebo-controlledtrial of cA2 in 108 patients with moderate-to-severe Crohn'sdisease that was resistant to treatment. All had scores on theCrohn's Disease Activity Index between 220 and 400 (scores canrange from 0 to about 600, with higher scores indicating moresevere illness). Patients were randomly assigned to receivea single two-hour intravenous infusion of either placebo orcA2 in a dose of 5 mg per kilogram of body weight, 10 mg perkilogram, or 20 mg per kilogram. Clinical response, the primaryend point, was defined as a reduction of 70 or more points inthe score on the Crohn's Disease Activity Index at four weeksthat was not accompanied by a change in any concomitant medications.
Results At four weeks, 81 percent of the patients given 5 mgof cA2 per kilogram (22 of 27 patients), 50 percent of thosegiven 10 mg of cA2 per kilogram (14 of 28), and 64 percent ofthose given 20 mg of cA2 per kilogram (18 of 28) had had a clinicalresponse, as compared with 17 percent of patients in the placebogroup (4 of 24) (P<0.001 for the comparison of the cA2 groupas a whole with placebo). Thirty-three percent of the patientsgiven cA2 went into remission (defined as a score below 150on the Crohn's Disease Activity Index), as compared with 4 percentof the patients given placebo (P = 0.005). At 12 weeks, 41 percentof the cA2-treated patients (34 of 83) had had a clinical response,as compared with 12 percent of the patients in the placebo group(3 of 25) (P = 0.008). The rates of adverse effects were similarin the groups.
Conclusions A single infusion of cA2 was an effective short-termtreatment in many patients with moderate-to-severe, treatment-resistantCrohn's disease.
Crohn's disease is a chronic inflammatory disorder characterizedby patchy granulomatous inflammation of any part of the gastrointestinaltract.1 Patients have a spectrum of clinical features, withgreat variation in the course of the disease. Mesalamine isconsidered first-line therapy. The majority of patients haverelapses requiring glucocorticoid treatment.2 Immunomodulatoryagents, including azathioprine or mercaptopurine,3 methotrexate,4,5and cyclosporine,6,7,8,9 may be used to treat severe, persistentdisease 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 (anti–TNF-)prevent or reduce inflammation,10,11,12,13,14 suggesting thattherapy with such antibodies may be useful for disorders inwhich chronic inflammation may be due to an increase in cytokinesproduced by the T helper 1 subclass of T cells. In vitro studieshave shown that the production of TNF- is increased in the mucosaof patients with Crohn's disease15,16 and that the mucosal inflammatoryprocess reflects a shift in the balance of cytokine productionby T cells toward the T helper 1 subclass.17,18 Similar findingswere reported in the synovia of patients with rheumatoid arthritis,19and anti–TNF- reduces clinical signs and symptoms of thisdisease.20,21 The role of TNF- in the pathogenesis of Crohn'sdisease and the successful use of anti–TNF- in the treatmentof rheumatoid arthritis stimulated an open-label trial of chimericmonoclonal antibody cA2 (infliximab, Centocor, Malvern, Pa.)for Crohn's disease. In that preliminary trial, clinical remissionoccurred after one infusion of cA2 in eight of nine patientswith Crohn's disease.22 We report the results of a multicenterrandomized, placebo-controlled, double-blind trial of cA2 forthe treatment of active Crohn's disease.
Methods
Patients
To be eligible for the study, patients had to have had Crohn'sdisease for six months,1 with scores on the Crohn's DiseaseActivity Index23 between 220 and 400. The Crohn's Disease ActivityIndex incorporates eight variables related to the disease: thenumber of liquid or very soft stools, the severity of abdominalpain or cramping, general well-being, the presence of extraintestinalmanifestations, abdominal mass, use of antidiarrheal drugs,hematocrit, and body weight. These items yield a composite scoreranging from 0 to approximately 600. Higher scores indicategreater disease activity. Scores below 150 indicate remission,whereas scores above 450 indicate severe illness. Patients wereeligible for the study if they had been receiving any of thefollowing: mesalamine for eight or more weeks, with the doseremaining stable during the four weeks before screening; a maximumof 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, withthe dose remaining stable during the eight weeks before screening.Patients were excluded from the study if they had received treatmentwith cyclosporine, methotrexate, or experimental agents withinthree months before screening. Patients were also excluded ifthey met any of the following criteria: symptomatic stenosisor ileal strictures; proctocolectomy or total colectomy; stoma;a history of allergy to murine proteins; prior treatment withmurine, chimeric, or humanized monoclonal antibodies; or treatmentwith parenteral corticosteroids or corticotropin within fourweeks before screening.
Patients were enrolled at 18 centers in North America and Europe.The protocol was approved by the institutional review boardsand ethics committees at all sites, and all patients gave writteninformed consent before enrolling in the trial. The study beganon June 21, 1995, and concluded on March 12, 1996. A total of203 patients were screened for the study, 95 of whom were excluded.The most common reasons for exclusion were a requirement forcontraindicated 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 ofcA2 to establish base-line scores on the Crohn's Disease ActivityIndex and the Inflammatory Bowel Disease Questionnaire,24 andbase-line C-reactive protein concentrations. The InflammatoryBowel Disease Questionnaire, a 32-item questionnaire, evaluatesquality of life with respect to bowel function (e.g., loosestools and abdominal pain), systemic symptoms (fatigue and alteredsleep pattern), social function (work attendance and the needto cancel social events), and emotional status (angry, depressed,or irritable). The score ranges from 32 to 224, with higherscores indicating a better quality of life. Patients in remissionusually score between 170 and 190.24
Patients were randomly assigned to receive a single dose ofeither placebo or 5 mg of cA2 per kilogram of body weight, 10mg of cA2 per kilogram, or 20 mg of cA2 per kilogram in an intravenousinfusion, administered over a two-hour period. The cA2 monoclonalantibody is a chimeric mouse–human IgG1 that binds toboth soluble25 and transmembrane26 human TNF- with high affinityand specificity. It neutralizes the functional activity of TNFin a variety of bioassays by blocking the binding of the factorto the p55 and p75 receptors.27 The placebo preparation contained0.1 percent human serum albumin instead of cA2 and was identicalin appearance to the cA2 solution. Patients were enrolled fromJune 21, 1995, to October 31, 1995. Randomization was performedcentrally by an independent organization (PPD Pharmaco, Austin,Tex.). The cA2 and placebo solutions were prepared by a pharmacistat each site who was aware of the treatment assignments. Theinvestigators, all other study personnel, and the patients wereblinded to the treatment assignments.
The primary end point was defined before the initiation of thetrial as a reduction of 70 points or more in the score on theCrohn's Disease Activity Index at the four-week evaluation thatwas not accompanied by a change in any concomitant medications.Patients who did not have a clinical response at that time wereenrolled in a parallel, open-label study and received a singleinfusion of 10 mg of cA2 per kilogram and were followed for12 additional weeks. Patients who were receiving mesalamine,corticosteroids, azathioprine, or mercaptopurine before thestudy continued to receive a stable dose during the trial period.The dose of corticosteroids could be tapered beginning eightweeks after the initiation of the study. Treatment with thesedrugs or with methotrexate or cyclosporine could not be initiatedduring the trial. After all patients had completed 12 weeksof the trial and the data were finalized, the treatment assignmentswere revealed.
Immunologic Investigations
Serum samples were obtained at base line and at 12 weeks forthe evaluation of antinuclear antibodies and human anti-cA2.Antinuclear antibodies were detected by immunofluorescence onHep-2 cells. Serum samples positive by immunofluorescence forantinuclear antibodies were tested for antibodies to double-strandedDNA by an enzyme-linked immunosorbent assay (North Americancenters) or by Crithidia immunofluorescence (European centers).Human anti-cA2 was measured by a double-antigen enzyme-linkedimmunosorbent assay.
Statistical Analysis
An adaptive stratified design was used to assign patients toa treatment group, with investigational site and corticosteroiduse as the strata. We calculated that approximately 25 patientswere needed in each treatment group to detect a difference inthe number of patients who responded with 80 percent power (= 0.05), assuming a response rate of 30 percent in the placebogroup, 80 percent in the cA2 group with the greatest response,and 55 percent in the remaining cA2 groups. The original studyprotocol did not specify the use of intention-to-treat analysis.Two patients were assigned to a treatment but did not receiveit: one declined to participate and one did not meet eligibilitycriteria. No further data were collected on these two patients,and they are not included in the analysis. Otherwise, all patientswere analyzed according to the treatment to which they wereassigned. When we assessed the response or remission rates inall evaluation periods after the initial blinded infusion, patientswho received an open-label infusion or those with a change inconcomitantly administered medications were considered to havehad no response.
Categorical variables (clinical response and remission) werecompared with use of the Mantel–Haenszel chi-square testfor general association stratified according to investigationalsite.28 Analyses comparing each of the cA2 treatment groupswith placebo were performed only when the treatment effect wasconsidered significant (P<0.05). The changes from base linein continuous variables (Crohn's Disease Activity Index score,Inflammatory Bowel Disease Questionnaire score, and C-reactiveprotein concentration) were compared with use of analysis ofvariance, with the van der Waerden normal scores blocked accordingto center.29 If the treatment effect was significant, the cA2treatment groups were compared with the placebo group with linearcontrasts. All P values are two-sided.
Results
Base-Line Characteristics of the Study Patients
A total of 108 patients were studied, with 25 to 28 patientsin each group. There were no significant differences in age,weight, race (all patients were white), sex, duration of disease,scores on the Crohn's Disease Activity Index and InflammatoryBowel Disease Questionnaire, or C-reactive protein concentrationsat base line among the groups, although patients in the placebogroup had a lower mean concentration of C-reactive protein (Table 1).Significantly more patients had ileal disease alone in theplacebo group than in the other three groups (P = 0.02), butthere were no significant differences in the number who hadundergone previous segmental resections among the groups. Similarnumbers of patients in each group had been treated with oralcorticosteroids, mercaptopurine, azathioprine, and oral mesalamineat base line. All treatment groups had a mean score on the Crohn'sDisease Activity Index of approximately 300, despite concurrenttreatment with drugs other than cA2; thus, the patients hadmoderate-to-severe, treatment-resistant Crohn's disease.
Table 1. Base-Line Characteristics of the 108 Patients.
Clinical Response and Remission
Week 2
Figure 1A demonstrates that clinical response was achieved early:61 percent of cA2-treated patients had a clinical response byweek 2, as compared with 17 percent of patients in the placebogroup (P< 0.001). At two weeks, 27 percent of cA2-treatedpatients were in clinical remission (defined as a score of lessthan 150 on the Crohn's Disease Activity Index), as comparedto 4 percent of the patients in the placebo group (P = 0.06)(Figure 1B).
Figure 1. Rates of Clinical Response and Remission after a Single Infusion of cA2 or Placebo.
Clinical remission was defined as a score of less than 150 on the Crohn's Disease Activity Index and a score of 170 to 190 on the Inflammatory Bowel Disease Questionnaire. The asterisks (P<0.001), daggers (P<0.01), and double dagger (P<0.05) indicate a significant difference from placebo.
Week 4
Four weeks after the infusion, the primary end point of a reductionof 70 or more points in the score on the Crohn's Disease ActivityIndex was reached in 81 percent of those given 5 mg of cA2 perkilogram (22 of 27 patients), 50 percent of those given 10 mgof cA2 per kilogram (14 of 28 patients), and 64 percent of thosegiven 20 mg of cA2 per kilogram (18 of 28 patients), as comparedwith 17 percent of those given placebo (4 of 24 patients) (Figure 1A).The overall response of the cA2 groups was 65 percent (P<0.001for the comparison with placebo). No dose–response relationwas seen during this period. At four weeks, 33 percent of thecA2-treated group were in remission, as compared with 4 percentof the placebo group (P = 0.005). Thus approximately half ofthe patients who had a clinical response at either two or fourweeks also entered remission. Consistent treatment effects wereobserved when the analyses for both response and remission atweek 4 were stratified according to the location of diseaseor concurrent drug regimens (data not shown).
Changes in Clinical and Inflammatory Measures during the First Four Weeks
The mean change in the scores on the Crohn's Disease ActivityIndex in the cA2-treated group as a whole was significant atweeks 2 and 4 of the trial, as compared with the changes inscores in the placebo group (P<0.001) (Table 2). The meandecrease in the score on the Crohn's Disease Activity Indexin the cA2 group as a whole was 110 at four weeks, as comparedwith 13 in the placebo group. Most of this decrease had occurredby week 2, with a mean decrease of 103 in the cA2 group and16 in the placebo group.
Table 2. Measures of Clinical Response and Inflammation at Base Line and Weeks 2 and 4.
The Inflammatory Bowel Disease Questionnaire was given at baseline and four weeks. There was a mean increase of 46, 30, and32 in the groups treated with cA2 at 5, 10, and 20 mg of cA2per kilogram, respectively, yielding a mean increase of 36 inthe cA2 group as a whole, as compared with a mean increase of5 in the placebo group (P = 0.001) (Table 2).
Concentrations of C-reactive protein were measured at base lineand weeks 2 and 4. At four weeks, the mean decrease in C-reactiveprotein was 16.3, 11.1, and 15.0 mg per liter in the groupstreated with 5, 10, and 20 mg of cA2 per kilogram, respectively,yielding a mean decrease of 14.3 mg per liter in the group asa whole, as compared with a mean increase of 2.0 mg per literin the placebo group (P<0.001). The maximal reduction inC-reactive protein occurred within the first two weeks. At twoweeks, the mean decrease in C-reactive protein in the cA2 groupsas a whole was 16.0 mg per liter, as compared with a mean increaseof 3.9 mg per liter in the placebo group (P<0.001).
Week 12
The differences in the rates of clinical response between thecA2-treated groups and the placebo group remained significantthrough the 12 weeks of follow-up: it was 48 percent in thegroup given 5 mg of cA2 per kilogram (13 of 27 patients), 29percent in the group given 10 mg of cA2 per kilogram (8 of 28patients), and 46 percent in the group given 20 mg of cA2 perkilogram (13 of 28 patients), for an overall rate of responseof 41 percent (34 of 83 patients), as compared with a rate of12 percent in the placebo group (3 of 25 patients) (P = 0.008).The difference in the percentage of patients who were in remissionwas not significant at 12 weeks: 30 percent of the group given5 mg of cA2 per kilogram (8 of 27 patients), 18 percent of thegroup given 10 mg of cA2 per kilogram (5 of 28 patients), and25 percent of the group given 20 mg of cA2 per kilogram (7 of28 patients), for an overall rate of remission achieved of 24percent (20 of 83 patients), as compared with a rate of 8 percentin the placebo group (2 of 25 patients) (P = 0.31).
Characterization of the Response to Treatment
The magnitude and duration of response were characterized throughthe 12-week follow-up period in the 54 patients who respondedto a single infusion of cA2. The improvement in the scores onthe Crohn's Disease Activity Index (clinical remission was definedas a score below 150) and Inflammatory Bowel Disease Questionnaire(remission was defined as a score between 170 and 190) in patientswith a response was maintained. The mean (±SD) scoreon the Crohn's Disease Activity Index was 318±52 at baseline, 144±67 at week 4, 151±86 at week 8, and182±91 at week 12, and the mean score on the InflammatoryBowel Disease Questionnaire was 121±26 at base line,175±26 at week 4, 165±36 at week 8, and 162±35at week 12. Concentrations of C-reactive protein (normal, <8mg per liter) began to rise at 12 weeks, potentially indicatinga relapse of disease (from 25.8±2.7 mg per liter at baseline to 7.5±1.5 mg per liter at week 4, 11.0±2.1mg per liter at week 8, and 14.1±2.2 mg per liter atweek 12).
Effects of Open-Label cA2 in Patients with No Response Four Weeks after the Initial Infusion of cA2
Patients who did not have a clinical response after the firstinfusion were given a second infusion of open-label cA2 in adose of 10 mg per kilogram and followed for an additional 12weeks. Among 19 patients who initially received placebo, theresponse rate was 58 percent and the remission rate was 47 percentfour weeks after the second infusion — rates that weresimilar to those in the initial, blinded study (Figure 1). Bycontrast, among the 29 patients who had no response to the initialcA2 infusion, the rates of response and remission after thesecond infusion were 34 percent (P = 0.14 for the comparisonwith the patients who received placebo initially) and 17 percent(P = 0.05), respectively, confirming that this group was lessresponsive to cA2.
Adverse Effects
Adverse effects were recorded at the time of infusion and 2,4, 8, and 12 weeks after the infusion. In patients who receivedan open-label infusion 4 weeks after an infusion of placeboor cA2, adverse effects were monitored for an additional 12weeks. As shown in Table 3, the percentages of patients withadverse effects were similar in the placebo and cA2 groups.Of the 29 patients who received two cA2 infusions, 2 had a reaction(chest pain, dyspnea, or nausea) that led to the discontinuationof the infusion. These reactions resolved spontaneously withinminutes after the infusion was discontinued. In addition, complicationsrequiring hospitalization developed in two patients (abdominalabscess in one patient in the placebo group and salmonella colitisin one patient given an infusion of 20 mg of cA2 per kilogram).Both patients were treated successfully. A bowel obstructionoccurred in one patient given cA2, and a flare of Crohn's diseaseoccurred in another.
Serum samples were screened for antibodies to double-strandedDNA at base line and at 12 weeks in 98 patients who receivedcA2 (in either a blinded or an open-label infusion); all patientswere negative for these antibodies at base line, and 3 werepositive at 12 weeks. Serum samples from 101 patients treatedwith cA2 (in either a blinded or an open-label infusion) werealso tested for human anti-cA2; 6 patients tested positive.In two thirds of the patients, however, cA2 was still detectablein serum samples taken at 12 weeks, and this may have interferedwith the assay.
Discussion
Many of our patients with moderate-to-severe Crohn's diseasethat was resistant to treatment had a rapid response to cA2.Other treatments for such patients have not had beneficial effectsover the long term and may not be well tolerated.30,31,32,33Our short-term study suggests that anti–TNF- therapy withcA2 may represent a new treatment option for patients with moderate-to-severeCrohn's disease. Further studies will be necessary to determinethe long-term efficacy of a single infusion of cA2 as well asthe efficacy and safety of repeated treatments.
The mechanisms of the chronic mucosal inflammatory processesmanifesting as Crohn's disease are not clear. However, our resultsadd strength to the suggestion that TNF- may have a centralrole in the inflammatory process in at least two thirds of thepatients with Crohn's disease.22 Studies in rodent models haveprovided insight into the role of anti–TNF- in the pathogenesisof Crohn's disease. Studies involving the transfer of CD45RBhighcells to mice with severe combined immunodeficiency have shownthat these cells can induce a chronic, transmural inflammatoryprocess in the colon.34 Powrie et al. have demonstrated thatthis colitis can be reversed or ameliorated by the use of agents,including anti–TNF-, capable of down-regulating the productionof the T helper 1 subclass of T cells.10 These cells produceproinflammatory cytokines including interferon-, interleukin-2,and potentially, TNF. A mechanistic role for TNF- in intestinalinflammation has been suggested on the basis of these studies.
Other studies involving animal models have shown that cytokinesproduced by the T helper 1 subclass are expressed in the mucosaof people with Crohn's disease.17,18 Anti–TNF- may participatein the down-regulation of mucosal inflammation in this diseaseby inhibiting the T helper 1 population of active T cells. Extensivefollow-up studies are needed to determine how the eliminationof TNF affects mucosal inflammation after treatment with anti–TNF-.
In this study, a clinical response or remission occurred in65 percent of patients with severe Crohn's disease after a singleinfusion of cA2. Furthermore, results in the open-label retreatmentphase corroborated the finding that patients with no responseto the first infusion of cA2 were less likely to have a responseto a second infusion. Thus, this group of patients may differfrom those that responded. The similarities among the patients,including age, duration of disease, types of concomitant treatment,and disease activity at base line, suggest that any differencesare more likely to be detected subclinically. There was no apparentdose–response relation between a dose of 5 mg of cA2 perkilogram and a dose of 20 mg per kilogram with respect to eitherthe magnitude or the duration of the clinical response. In aprevious open-label trial of cA2 doses of 1 mg, 5 mg, 10 mg,and 20 mg per kilogram, the group receiving 1 mg of cA2 perkilogram had a more transient response than the groups giventhe higher doses.35 This transient response was similar to thatin a small trial of a different anti–TNF- antibody.36The results of these trials support the use of a dose of 5 mgof cA2 per kilogram in future trials.
In summary, we found that a single infusion of cA2 was an effectiveshort-term treatment for patients with moderate-to-severe Crohn'sdisease that was resistant to treatment.
Supported by Centocor, Inc., and by a grant (FD-R-001276) fromthe Food and Drug Administration Orphan Products DevelopmentDivision. Drs. Hanauer, van Deventer, Present, and Rutgeertshave received honorariums from Centocor for lectures.
Source Information
From the Cedars–Sinai Medical Center, Los Angeles (S.R.T.); the University of Chicago, Chicago (S.B.H.); Academisch Medisch Centrum, Amsterdam (S.J.H.D.); Mt. Sinai Medical Center, New York (L.M., D.H.P.); Centocor, Inc., Malvern, Pa. (T.B., K.L.D., T.F.S.); and Academisch Ziekenhuis Gasthuisberg, Leuven, Belgium (P.J.R.).
Address reprint requests to Dr. Targan at Cedars–Sinai Medical Center, Division of Gastroenterology and Inflammatory Bowel Disease Center D4063, 8700 Beverly Blvd., Los Angeles, CA 90048.
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Appendix
The Crohn's Disease cA2 Study Group consists of the followingcenters and investigators (the number of patients enrolled ateach center is given in parentheses): Massachusetts GeneralHospital,Boston (5 patients): D. Podolsky, B.E. Sands, M.T.Marcucci; Cedars–Sinai Medical Center,Los Angeles (20patients): S.R. Targan, E.A. Vasiliauskas, B. Voigt, J. Gaiennie;University of Chicago Hospitals and Clinics, Chicago (11 patients):S.B. Hanauer; University of Alabama School of Medicine, Birmingham(2 patients): C.O. Elson, R.P. McCabe, Jr.; Mount Sinai MedicalCenter, New York (8 patients): L. Mayer, D.H. Present, C. Stamaty;Washington University School of Medicine, St. Louis (2 patients):W.F. Stenson, J.J. O'Brien; Virginia Mason Medical Center, Seattle(5 patients): R. Kozarek, M. Gelfand; Hospital of the Universityof Pennsylvania, Philadelphia (4 patients): D. Bachwich, G.Lichtenstein, L. Hurd; McMaster University Medical Center, Hamilton,Ont., Canada (2 patients): E.J. Irvine, S. Collins; Lahey Clinic,Burlington, Mass. (3 patients): A.S. Warner, L.J. Costa; Universityof North Carolina, Chapel Hill (5 patients): K.L. Isaacs; Universityof Maryland Medical System, Baltimore (5 patients): S. James,B. Greenwald, M.L. Mullen; University of Kentucky, Lexington(5 patients): G.W. Varilek, B. Vivian; Academisch ZiekenhuisLeiden, Leiden, the Netherlands (4 patients): R.A. van Hogezand,M.J. Wagtmans; Institute for Clinical Immunology and Rheumatology,Erlangen, Germany (1 patient): H. Schönekäs, J.R.Kalden, J.M.L. Bauer; University of Amsterdam, Amsterdam (9patients): S.J.H. van Deventer, C.M.J. Kothe, O.J.B. de Smit;Leeds General Infirmary, Leeds, United Kingdom (4 patients):D.M. Chalmers, S. Chitturi, D. Todi; and Academisch ZiekenhuisGasthuisberg, Leuven, Belgium (13 patients): P.J. Rutgeerts,G.R.A.M. D'Haens, A.F.M. Verstraeten.
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