Infliximab for induction and maintenance therapy for ulcerative colitis

The new england journal of medicine Infliximab for Induction and Maintenance Paul Rutgeerts, M.D., Ph.D., William J. Sandborn, M.D., Brian G. Feagan, M.D., Walter Reinisch, M.D., Allan Olson, M.D., Jewel Johanns, Ph.D., Suzanne Travers, M.D., Daniel Rachmilewitz, M.D., Stephen B. Hanauer, M.D., Gary R. Lichtenstein, M.D., Willem J.S. de Villiers, M.D., Ph.D., Daniel Present, M.D., Bruce E. Sands, M.D., and Jean Frédéric Colombel, M.D.
b a c k g r o u n d
Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor a, berg, Leuven, Belgium (P.R.); Mayo Clinic, is an established treatment for Crohn’s disease but not ulcerative colitis.
Rochester, Minn. (W.J.S.); Robarts ResearchInstitute, University of Western Ontario,London, Ont., Canada (B.G.F.); Univer- sitätsklinik für Innere Medizin IV, Allge- Two randomized, double-blind, placebo-controlled studies — the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively) — evaluated the efficacy of inflix- Centocor, Malvern, Pa. (A.O., J.J., S.T.);Shaare Zedak Medical Center, Jerusalem, imab for induction and maintenance therapy in adults with ulcerative colitis. In each Israel (D.R.); University of Chicago, Chica- study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilo- Philadelphia (G.R.L.); University of Ken-tucky, Lexington (W.J.S.V.); Mount Sinai gram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks chusetts General Hospital, Boston (B.E.S.); and Hôpital Huriez–Centre d’Investiga-tion Clinique INSERM Centre Hospitalieret Universitaire de Lille, Lille, France (J.F.C.).
Address reprint requests for the Active Ul- In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of cerative Colitis Trial 1 (ACT 1) to Dr. Rut-geerts at the Universitaire Ziekenhuizen those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, Belgium, or at [email protected].
ac.be. Address reprint requests for the Ac- with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or tive Ulcerative Colitis Trial 2 (ACT 2) to Dr.
an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who re- Sandborn at the Mayo Clinic, 200 First St.
ceived 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical re- SW, Rochester, MN 55905, or at sandborn.
[email protected].
sponse at week 8, as compared with 29 percent of those who received placebo (P<0.001for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P≤0.002 for all comparisons).
In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical re- sponse at week 54 (45 percent and 44 percent, respectively) than did those who received Copyright 2005 Massachusetts Medical Society. placebo (20 percent, P<0.001 for both comparisons).
c o n c l u s i o n s
Patients with moderate-to-severe active ulcerative colitis treated with infliximab atweeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinicalresponse at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.govnumbers, NCT00036439 and NCT00096655.) Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. i n f l i x i m a b f o r u l c e r a t i v e c o l i t i s sis of ulcerative colitis. Patients with positive tu- ized by mucosal ulceration, rectal bleed- berculin skin tests with the use of purified pro- uing, diarrhea, and abdominal pain. Phar- tein derivative were ineligible. Also, standard chest macologic management of ulcerative colitis has radiographs were obtained during screening. En-relied mainly on 5-aminosalicylates, corticosteroids, doscopy (flexible sigmoidoscopy unless surveillanceand immunosuppressants, including purine anti- colonoscopy was clinically indicated) with biopsymetabolites and cyclosporine.1,2 Corticosteroid de- was performed during screening to confirm the di-pendence is a clinically important problem3; fur- agnosis of ulcerative colitis by both the physicianthermore, the probability of colectomy within the performing the endoscopy and the pathologist re-first five years after diagnosis ranges from 9 per- viewing the biopsy specimen. Patients who receivedcent in patients with distal colitis to 35 percent in a diagnosis of indeterminate colitis, Crohn’s dis-patients with total colitis, most commonly because ease, or clinical findings suggestive of Crohn’s dis-of failed medical therapy.4 The cumulative risk of ease (i.e., fistula or granulomas on biopsy) were ex-recurrent inflammatory bowel disease in the form cluded. Eligible patients had active ulcerative colitisof pouchitis ranges from 15.5 percent 1 year after with a Mayo score24 of 6 to 12 points (scores canthe procedure to 45.5 percent 10 years after the range from 0 to 12, with higher scores indicatingprocedure.5 Accordingly, new treatments for ulcer- more severe disease activity) (Table 1) and moder-ative colitis are needed.
ate-to-severe active disease on sigmoidoscopy (Mayo Tumor necrosis factor a (TNF-a) is a key proin- endoscopic subscore of at least 2) despite concur- flammatory cytokine in patients with Crohn’s dis- rent treatment with corticosteroids alone or in com-ease but is also found in increased concentrations bination with azathioprine or mercaptopurine inin the blood, colonic tissue, and stools of patientswith ulcerative colitis.6-8 However, the role of TNF-a in the pathogenesis of ulcerative colitis has been Table 1. Mayo Scoring System for Assessment of Ulcerative Colitis Activity.*
Infliximab, a chimeric IgG1 monoclonal anti- 0 = Normal no. of stools for this patient1 = 1 to 2 stools more than normal body, binds with high affinity to TNF-a, neutraliz- ing its biologic activity.14 Infliximab therapy is ef- fective for the induction and maintenance of clinical remission; closure of enterocutaneous, perianal, and rectovaginal fistulas; maintenance of fistula 1 = Streaks of blood with stool less than half the time closure; and corticosteroid sparing in patients with 2 = Obvious blood with stool most of the time Crohn’s disease.15-18 However, the few small stud- ies of infliximab in patients with active ulcerative colitis have yielded conflicting results.19-23 We therefore conducted 54-week and 30-week studies 1 = Mild disease (erythema, decreased vascular pattern, mild friability) of infliximab in patients with moderate-to-severe 2 = Moderate disease (marked erythema, lack of vascular pattern, friability, ulcerative colitis: the Active Ulcerative Colitis Trials 3 = Severe disease (spontaneous bleeding, ulceration) 1 and 2 (ACT 1 and 2, respectively).
1 = Mild disease2 = Moderate disease3 = Severe disease p a t i e n t s
These multicenter, randomized, double-blind, pla-cebo-controlled studies were conducted globally * The Mayo score ranges from 0 to 12, with higher scores indicating more se- between March 2002 and March 2005 among 364 vere disease. Data are from Schroeder et al.24 patients at 62 sites in the ACT 1 trial and 364 pa- † Each patient serves as his or her own control to establish the degree of abnor- tients at 55 sites in the ACT 2 trial. The institutional ‡ The daily bleeding score represents the most severe bleeding of the day.
review board or ethics committee at each site ap- § The physician’s global assessment acknowledges the three other criteria, the proved the protocols. All patients gave written in- patient’s daily recollection of abdominal discomfort and general sense of well-being, and other observations, such as physical findings and the patient’s per- All eligible patients had an established diagno- Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine ACT 1 or despite concurrent treatment with corti- patients in both studies and at week 54 for patientscosteroids alone or in combination with azathio- in ACT 1. A partial Mayo score (Mayo score withoutprine or mercaptopurine and medications contain- endoscopy) was determined at all visits. ing 5-aminosalicylates in ACT 2. Concurrent therapy Clinical response was defined as a decrease from was not required at enrollment for patients in ACT 1 baseline in the total Mayo score of at least 3 pointsand ACT 2 who had had no response to corticoste- and at least 30 percent, with an accompanying de-roids within the preceding 18 months or who could crease in the subscore for rectal bleeding of at leastnot tolerate corticosteroids, patients in either study 1 point or an absolute subscore for rectal bleedingwho had had no response to azathioprine or mer- of 0 or 1. Clinical remission was defined as a totalcaptopurine within the preceding 5 years or who Mayo score of 2 points or lower, with no individu-could not tolerate these drugs, and patients in ACT al subscore exceeding 1 point. Mucosal healing2 who had had no response to medications con- was defined as an absolute subscore for endosco-taining 5-aminosalicylates within the preceding py of 0 or 1.
18 months or who could not tolerate such drugs.
Clinical response, clinical remission, and mu- Rectally administered corticosteroids or medica- cosal healing were assessed at weeks 8 and 30 intions containing 5-aminosalicylates were not per- both studies and at week 54 in ACT 1. Patients whomitted within two weeks before screening. Patients had a clinical response or who were in clinical re-previously exposed to infliximab or any other anti- mission at each time were considered to have a sus-TNF agent were excluded.
tained clinical response or to be in sustained clini-cal remission, respectively. s t u d y d e s i g n
In both studies, adverse events and concomi- Eligible patients were randomly assigned in a 1:1:1 tant medications were recorded at each visit. Se-ratio to receive intravenous infusions of infliximab rum specimens for the identification of antibodies(Remicade, Centocor) at a dose of 5 mg or 10 mg against infliximab and antinuclear antibodies wereper kilogram of body weight or placebo at weeks 0, collected at weeks 0 and 30 in both studies and at2, and 6 and then every eight weeks through week week 54 in ACT 1, with the use of previously de-22 in ACT 2 or week 46 in ACT 1. Patients were fol- scribed methods.25 Samples positive for antinucle-lowed through week 30 in ACT 2 and week 54 in ar antibodies were tested for antibodies againstACT 1.
Each study used central randomization with a dynamic treatment allocation stratified according statistical analysis
to the investigational site and whether patients had The primary end point was a clinical response at
ulcerative colitis that was refractory to corticoste- week 8. Secondary end points were a clinical re-
roid therapy. Patients were considered to have ul- sponse or clinical remission with discontinuation
cerative colitis that was refractory to corticoste- of corticosteroids at week 30 in both studies and at
roids if their symptoms of ulcerative colitis had not week 54 in ACT 1, a clinical remission and mucosal
improved after they received the equivalent of at healing at weeks 8 and 30 in both studies and at
least 40 mg of prednisone daily, administered oral- week 54 in ACT 1, and a clinical response at week
ly for at least two weeks or intravenously for at least 8 in patients with a history of disease refractory to
one week.
corticosteroids. Patients who took prohibited medi- Doses of concomitant medications remained cation because of lack of efficacy or loss of response constant except for corticosteroids, which were ta- to the study medication, who discontinued the studypered by 5 mg weekly after week 8 until a dose of medication because of lack of efficacy, or who un-20 mg per day was reached. Thereafter, the dose was derwent a colectomy or ostomy were not consid-reduced by 2.5 mg weekly until discontinuation.
ered to have had a clinical response, to be in clinicalremission, or to have had mucosal healing from f o l l o w - u p a n d s a f e t y a n d e f f i c a c y
the time of the event onward, regardless of their e v a l u a t i o n s
Mayo score. In addition, patients with insufficient Patients in both studies were evaluated at weeks 0, data for the assessment of a response were not con-2, 6, 8, 14, 22, and 30. Patients in ACT 1 were also sidered to have had a clinical response, to be inevaluated at weeks 38, 46, and 54. The Mayo score clinical remission, or to have had mucosal heal-(Table 1) was determined at weeks 0, 8, and 30 for ing at that visit.
Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. i n f l i x i m a b f o r u l c e r a t i v e c o l i t i s Demographic and baseline characteristics were end points (i.e., clinical response, clinical remis- compared with the use of the chi-square test or sion, mucosal healing, and clinical remission withFisher’s exact test for categorical variables and with discontinuation of corticosteroids) among treat-the use of analysis of variance for van der Waerden ment groups. All efficacy analyses used intention-normal scores for continuous variables. A two-sid- to-treat methods. Safety comparisons were per-ed Cochran–Mantel–Haenszel chi-square test, at a formed with the use of Fisher’s exact test and weresignificance level of 0.05, stratified according to based on the combination of the two groups receiv-corticosteroid-refractory status and the location of ing infliximab as compared with the placebo group.
the study center, was used to compare dichotomous Assuming a response rate of 30 percent in the pla- Table 2. Baseline Characteristics of the Patients in ACT 1 and ACT 2.*
Characteristic
* Plus–minus values are means ±SD.
† P values for all categorical variables except race and smoking status are based on a two-sided chi-square test. P values for race and smoking status are based on Fisher’s exact test. P values for continuous variables are based on analysis of variance for the van der Waerden normal scores. Race was assigned by the local investigator.
‡ The Mayo scores range from 0 to 12, with higher scores indicating more severe disease.
§ Elevated baseline C-reactive protein values were those of 0.6 mg per deciliter or more.
Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine 122 Patients received 10 mg of infliximab 120 Patients received 10 mg of infliximab Figure 1. Enrollment and Treatment.
In ACT 1, 121 patients with moderate-to-severe ulcerative colitis were randomly assigned to receive intravenous placebo, 121 to receive 5 mg of infliximab per kilogram, and 122 to receive 10 mg of infliximab per kilogram at weeks 0, 2, 6, 14, 22, 30, 38, and 46. The efficacy and safety populations through week 54 consist of all 364 patients who underwent randomization, all of whom received at least one dose of study med-ication. In ACT 2, 123 patients with moderate-to-severe ulcerative colitis were randomly assigned to receive intravenous placebo, 121 to re-ceive 5 mg of infliximab per kilogram, and 120 to receive 10 mg of infliximab per kilogram at weeks 0, 2, 6, 14, and 22. The efficacy and safety populations consist of all 364 patients who underwent randomization, all of whom received at least one dose of study medication.
Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. i n f l i x i m a b f o r u l c e r a t i v e c o l i t i s cebo group and a two-sided probability of 0.05, weestimated that 120 patients would be needed in each group to give the study a statistical power of 95 percent to detect an improvement in the re- These studies were designed and conducted by the steering committees for ACT 1 and ACT 2 and by Centocor. The members of the steering commit- tee and Centocor jointly analyzed and interpreted the data and contributed to the manuscript. The ac-ademic authors had full access to the data and vouch for the veracity and completeness of the data Patients with a Response at Wk 8 (%)
c h a r a c t e r i s t i c s o f t h e p a t i e n t s
In ACT 1, 364 patients underwent randomization: 121 were assigned to receive placebo, 121 to receive 5 mg of infliximab, and 122 to receive 10 mg of in-fliximab. The baseline characteristics of the patients were similar (Table 2), although the mean duration of disease among patients who received 10 mg of infliximab was longer than among those who re- ceived 5 mg or placebo. Treatment was discontin- ued prematurely by 74 patients in the placebo group (61.2 percent), 45 patients in the group receiving5 mg of infliximab (37.2 percent), and 49 patients in the group receiving 10 mg of infliximab (40.2 per- Patients in Remission at Wk 8 (%)
In ACT 2, 364 patients underwent randomiza- tion: 123 were assigned to receive placebo, 121 to receive 5 mg of infliximab, and 120 to receive 10 mg of infliximab. The baseline characteristics of the patients were similar (Table 2). More than twice asmany patients in the placebo group as in the other two groups prematurely discontinued the study in- e f f i c a c y
In ACT 1 at week 8, 69.4 percent of patients in the group receiving 5 mg of infliximab (84 of 121) and 61.5 percent of patients in the group receiving 10mg of infliximab (75 of 122) had had a clinical re- Patients with Mucosal Healing at Wk 8 (%)
sponse, as compared with 37.2 percent of patients in the placebo group (45 of 121, P<0.001 for bothcomparisons) (Fig. 2A). In ACT 2 at week 8, 64.5 Figure 2. Proportion of Patients with a Clinical Response (Panel A), in Clinical
percent of patients in the group receiving 5 mg of Remission (Panel B), and with Mucosal Healing (Panel C) at Week 8 in ACT 1
infliximab (78 of 121) and 69.2 percent of patients and ACT 2.
in the group receiving 10 mg of infliximab (83 of Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 3. Summary of Primary and Secondary Efficacy Results from ACT 1 and ACT 2.*
Variable
roid therapy at week 8 — no./total no. (%) 120) had had a clinical response, as compared with clinical response or remission were significantly29.3 percent of patients in the placebo group (36 higher in the infliximab groups than in the placeboof 123, P<0.001 for both comparisons) (Fig. 2A).
groups (Fig. 3). The partial Mayo scores in both stud- In both studies, the proportions of patients who ies provide evidence of clinical improvement as ear- had a clinical response or remission at weeks 8 and ly as week 2 (Table 3).
30, and at week 54 in the ACT 1 trial, were higher Mucosal healing at weeks 8 and 30 in each study by a factor of 1.7 to more than 2 in the infliximab and at week 54 in ACT 1 occurred in significantlygroups than in the placebo groups (Fig. 2A and 2B). more patients in the infliximab groups than in theThe rates of clinical response were similar between placebo groups (P≤0.009 for all comparisons) (Ta-the subpopulations of patients who were cortico- ble 3 and Fig. 2C).
steroid-refractory and those who were not corti- At baseline, 61.0 percent of patients (222 of 364) were receiving corticosteroids in ACT 1, as were The proportions of patients with a sustained 51.1 percent in ACT 2 (186 of 364). The baseline Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. i n f l i x i m a b f o r u l c e r a t i v e c o l i t i s Table 3. (Continued.)
Variable
20.0 (10.0–30.0) 20.0 (10.0–25.0) 20.0 (10.0–25.0) 20.0 (15.0–30.0) 20.0 (10.0–30.0) 20.0 (15.0–26.7) 20.0 (10.0–30.0) 20.0 (10.0–25.0) 20.0 (10.0–25.0) 20.0 (15.0–30.0) 20.0 (10.0–30.0) 20.0 (10.0–25.0) ued use of corticosteroids— no./total no. (%) * Dashes denote not applicable.
† Mayo scores range from 0 to 12, with higher scores indicating more severe disease. A partial Mayo score is the Mayo score without the endo- median daily corticosteroid dose was 20 mg per day trations). Among 188 patients in ACT 2 who hadin both studies. The proportions of patients who serum samples available for the assessment of an-were in clinical remission and had discontinued cor- tibodies against infliximab, 12 (6.4 percent) hadticosteroids at week 30 in both studies and at week positive tests for antibodies, 34 (18.1 percent)54 in ACT 1 were higher in the infliximab groups had negative tests, and 142 (75.5 percent) had in-than in the placebo groups. Similarly, the decreases conclusive tests.
in the median daily corticosteroid doses were great- In ACT 1, a clinical response at week 54 occurred er among patients in the infliximab groups than in 3 of 14 patients with positive tests for antibodiesamong those in the placebo group (Table 3).
(21.4 percent), as compared with 3 of 36 patientswith negative tests (8.3 percent) and 103 of 179 pa- a n t i b o d i e s a g a i n s t i n f l i x i m a b
tients with inconclusive tests (57.5 percent). In At week 54, among 229 patients in ACT 1 who had ACT 2, a clinical response at week 30 occurred in
serum samples available for the assessment of an- 11 of 19 patients with positive tests for antibodies
tibodies against infliximab, 14 (6.1 percent) had (57.9 percent), as compared with 45 of 79 patients
positive tests for antibodies at some point after the with negative tests (57.0 percent) and 71 of 92 pa-
first infusion of infliximab (Table 4), 36 (15.7 per- tients with inconclusive tests (77.2 percent).
cent) had negative tests (undetectable serum inflix-
imab concentrations), and 179 (78.2 percent) had safety
inconclusive tests (negative for antibodies in the In the 54-week ACT 1, patients were treated for
presence of detectable serum infliximab concen- a mean of 24.2 weeks in the placebo group, 34.8
Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Patients with a Sustained Response (%)
Response at Wk 8 and 30
Response at Wk 8, 30, and 54
Response at Wk 8 and 30
Patients in Sustained Remission (%)
Remission at Wk 8 and 30
Remission at Wk 8, 30, and 54
Remission at Wk 8 and 30
Figure 3. Proportion of Patients with a Sustained Clinical Response (Panel A) and in Sustained Clinical Remission (Panel
B) in ACT 1 and ACT 2.
weeks in the group receiving 5 mg of infliximab, were 19.5 percent, 10.7 percent, and 9.2 percent.
and 33.3 weeks in the group receiving 10 mg of in- In both studies, serious adverse events were mostfliximab. In the 30-week ACT 2, patients received commonly related to the gastrointestinal system.
treatment for 14.4 weeks in the placebo group, In ACT 1, similar numbers of patients in each 19.3 weeks in the group receiving 5 mg of inflix- group discontinued treatment because of an ad-imab, and 18.6 weeks in the group receiving 10 mg verse event; in ACT 2, more patients in the placeboof infliximab (Table 4).
group than in the two infliximab groups discon- In both studies, the proportions of patients with tinued treatment because of an adverse event (Ta- adverse events were similar in the placebo group ble 4). Among adverse events in ACT 1, prostaticand the two infliximab groups (Table 4). In ACT 1, adenocarcinoma developed in one patient with aserious adverse events occurred in 25.6 percent of two-year history of an elevated prostate-specific an-patients in the placebo group, 21.5 percent of pa- tigen concentration, and colonic dysplasia devel-tients receiving 5 mg of infliximab, and 23.8 per- oped in one patient; both had received 5 mg of in-cent of patients receiving 10 mg of infliximab. In fliximab. Basal-cell carcinoma developed in oneACT 2, the respective rates of serious adverse events patient treated with 10 mg of infliximab. In ACT 2, Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. i n f l i x i m a b f o r u l c e r a t i v e c o l i t i s basal-cell carcinoma developed in one patient placebo group, 14 patients (11.6 percent) in thewho received placebo, and rectal adenocarcinoma group receiving 5 mg of infliximab, and 14 patientsdeveloped in one patient treated with 5 mg of in- (11.7 percent) in the group receiving 10 mg of in-fliximab.
fliximab. A possible delayed hypersensitivity reac- Only three neurologic events occurred, all in pa- tion occurred in one patient (0.8 percent) in the tients treated with infliximab. In ACT 1, optic neu- group receiving 10 mg of infliximab.
ritis developed in one patient who received 5 mg of At week 54 in ACT 1, 35.7 percent of patients infliximab. After the completion of ACT 2, a multi- with positive tests for antibodies against infliximabfocal motor neuropathy with conduction block syn- (5 of 14) had infusion reactions, as compared withdrome developed in one patient who received 10 mg 9.8 percent of patients with negative or inconclu-of infliximab and optic neuritis developed in one sive tests (21 of 215). In ACT 2, at week 30, 50.0patient who received 5 mg of infliximab.
percent of patients with positive tests for antibod- In both studies, the development of antinuclear ies against infliximab (6 of 12) had infusion reac- antibodies and anti–double-stranded DNA antibod- tions, as compared with 9.7 percent of patients withies was more common among patients in the in- negative or inconclusive tests (17 of 176). No pa-fliximab groups than among those in the placebo tient in either study who had a positive test for anti-group (Table 4). Only one patient had a lupus-like bodies had a serious infusion reaction or an ana-reaction. This patient was enrolled in ACT 2 and re- phylactic reaction. Only one patient in the groupceived 5 mg of infliximab.
receiving 5 mg of infliximab in ACT 1 who had a The incidence of infections was similar among positive test for antibodies had a serious delayed the groups in both studies (Table 4). In ACT 1, seri- hypersensitivity reaction.
ous infections occurred in five patients (4.1 per-cent) in the placebo group, three patients (2.5 per- cent) in the group receiving 5 mg of infliximab, andeight patients (6.6 percent) in the group receiving Inducing and maintaining a clinical response and10 mg of infliximab. In ACT 2, serious infections clinical remission and minimizing the use of corti-occurred in one patient (0.8 percent) in the placebo costeroids are unmet goals in the treatment of pa-group, two patients (1.7 percent) in the group re- tients with ulcerative colitis, particularly those whoceiving 5 mg of infliximab, and three patients (2.5 have not had a response to corticosteroids, aza-percent) in the group receiving 10 mg of inflix- thioprine, or mercaptopurine.26 Our results showimab. In ACT 1, tuberculosis developed in one pa- that infliximab is effective in patients who have mod-tient treated with 10 mg of infliximab. Histoplas- erate-to-severe disease despite the use of conven-ma pneumonia developed in one patient in the tional therapy, in terms of a clinical response andgroup receiving 5 mg of infliximab during the ACT remission. As compared with patients who received2 extension, a study phase in which patients who placebo, patients who received infliximab were sig-completed the 30-week, double-blind phase — nificantly more likely to have a clinical response andand in the opinion of the investigators would bene- be in clinical remission at weeks 8 and 30 in bothfit from continued treatment — were enrolled and trials and in week 54 in ACT 1. Similarly, patientscontinued to receive the study medication to which who received infliximab were significantly morethey had been randomly assigned. The disease pro- likely to have mucosal healing at weeks 8 and 30 ingressed to acute respiratory distress syndrome, re- both trials and in week 54 in ACT 1. These findingssulting in the patient’s death.
are of particular importance in light of the recent In ACT 1, infusion reactions occurred in 13 pa- suggestion that mucosal healing is the strongest tients (10.7 percent) in the placebo group, 12 pa- predictor of a reduced risk of cancer among pa-tients (9.9 percent) in the group receiving 5 mg of tients with ulcerative colitis.27,28infliximab, and 15 patients (12.3 percent) in the It is noteworthy that these studies were con- group receiving 10 mg of infliximab (Table 4). A ducted in patients who had active disease despitepossible delayed hypersensitivity reaction devel- treatment with conventional therapy. At baseline,oped in two patients (1.7 percent) in the placebo among all 728 patients, 72 percent were receivinggroup and two patients (1.7 percent) in the group 5-aminosalicylates, 56 percent were receiving cor-receiving 5 mg of infliximab. In ACT 2, infusion re- ticosteroids, and 46 percent were receiving immu-actions occurred in 10 patients (8.1 percent) in the nosuppressants. Of the patients who were receiv- Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine ACT 2 (through W
ACT 1 (through W
Summary of Safety and Immunogenicity Analyses for All Patients Who Underwent Randomization.*
Any adverse event — no. of patients (%) Adverse events occurring in ≥10% of any treatment group — no. of patients (%) Adverse events of particular interest — no. of patients (%) Adverse events leading to discontinuation of study drug — no. of patients (%) Serious adverse events — no. of patients (%) Infections requiring antimicrobial treatment — no. of patients (%) Serious infections — no. of patients (%) Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. i n f l i x i m a b f o r u l c e r a t i v e c o l i t i s sitive if the titer was at least 1:10 (according to a crithidia sitive if the titer was at least 1:40. Samples positive for an- me time after their first infusion or at least one sample ob- est results for anti–double-stranded DNA were po est results for antinuclear antibodies were considered po any adverse event occurring ≤2 hr after start orticosteroids without immunosuppressants Immunosuppressants without corticosteroids Neither corticosteroids nor immunosuppressants values are based on Fisher’s exact test for the comparison of the combined infliximab groups with the placebo group.
Possible delayed hypersensitivity reactions — no. of patients (%) Antinuclear antibodies — no. of patients/total no. (%)‡ Antibodies against double-stranded DNA — no. of patients/total no. (%)‡ Antibodies against infliximab during the study — no. of patients/ Pharmacologic management at baseline — no. of patients/total no. (%)¶ ND denotes not done, and dashes not applicable.
Denominators represent patients with negative findings at baseline. T tinuclear antibodies were tested for antibodies against double-stranded DNA . T assay) and at least 5.4 IU (according to F Denominators represent patients with appropriate serum samples (i.e., patients with either antibodies against infliximab at so Immunosuppressants include mercaptopurine and azathioprine.
Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine ing corticosteroids at baseline, approximately 22 tests for antibodies were more likely than thosepercent of patients treated with infliximab had dis- without antibodies to have infusion reactions; how-continued corticosteroids by week 30 among 269 ever, most of these infusion reactions were mild.
patients in both studies or by week 54 among 143 In contrast to previous experience, patients withpatients in ACT 1 while maintaining clinical remis- positive or inconclusive tests for antibodies weresion. Since corticosteroid therapy is associated more likely to have a clinical response at week 30with considerable morbidity,29 this corticosteroid- or 5425 than were patients with negative antibodysparing effect is likely to be clinically meaningful.
tests. Patients with negative tests had a lower rate of Our data do not show any major differences in clinical response at those times, perhaps owing to efficacy between the two doses of infliximab that undetectable serum infliximab concentrations. Thiswere studied. Thus, the preferred initial dose of in- effect was most prominent at week 54. Concomi-fliximab in patients with ulcerative colitis is 5 mg tant use of mercaptopurine or azathioprine mayper kilogram on the basis of a combination of safe- have protected against the development of anti-ty, efficacy, and pharmacoeconomic issues.
bodies against infliximab; however, these findings In both studies, the proportions of patients re- should be interpreted with caution because of the porting any adverse event were similar among the small number of patients with positive tests forthree groups. The numbers of serious infections, antibodies.
lupus-like reactions, and neurologic diseases were Our results also provide insight into the patho- slightly higher among patients treated with inflix- genesis of ulcerative colitis. Ulcerative colitis isimab than among patients who received placebo. believed to result from an immune response ofThe case of tuberculosis and the fatal case of histo- type 2 helper T cells in the colonic mucosa, where-plasmosis in patients receiving infliximab under- as Crohn’s disease is considered an immune dis-score the need for physicians and patients to re- ease of type 1 helper T cells, which would suggestmain vigilant for signs and symptoms of infection. that TNF-a is not an important mediator in ulcer-Studies such as ACT 1 and ACT 2 were designed to ative colitis. Our findings show that TNF-a plays aevaluate efficacy and lack sufficient statistical pow- role in the disease process and that targeting thiser to detect differences among treatment groups in cytokine is an effective therapy for ulcerative coli-the occurrence of rare side effects. The safety find- tis. Whether the mechanism of action of infliximabings in these studies were similar to the data re- in ulcerative colitis also includes the induction ofported in clinical studies of infliximab in patients apoptosis of inflammatory cells expressing mem-with Crohn’s disease,15,16,30-32 in cohort stud- brane-bound TNF-a, as in Crohn’s disease,39 re-ies,33,34 and in post-marketing surveillance.35 The risks of infliximab use must be weighed In conclusion, an induction regimen of three against the risks of colectomy with the creation of doses of infliximab followed by maintenance infu-an ileoanal pouch, which include pouchitis in ap- sions every eight weeks in patients with moderate-proximately 50 percent of patients,5 pouch failure to-severe active ulcerative colitis was superior to pla-in approximately 10 percent of patients,36 an 80 cebo in achieving clinical response and remission,percent reduction in female fecundity,37 and the in- mucosal healing, and corticosteroid-sparing effectsconvenience of nocturnal fecal incontinence in ap- during 30 to 54 weeks of therapy.
proximately 24 percent of patients.38 Supported by a research grant from Centocor, Malvern, Pa., and The rate of development of antibodies against Schering Plough, Kenilworth, N.J.
Drs. Rutgeerts, Sandborn, Feagan, Hanauer, Lichtenstein, and infliximab after the three-dose induction regimen Colombel report having served as consultants for Centocor. Drs.
and after the maintenance dose every eight weeks Rutgeerts, Sandborn, Feagan, Hanauer, and Lichtenstein reportin the patients with ulcerative colitis in our studies having participated in continuing medical education events sup- ported by unrestricted educational grants from Centocor. Drs. Ol- is similar to that reported for patients with Crohn’s son, Johanns, and Travers are employees of Centocor.
disease.15,16,25,31 As was true of patients with We are indebted to Mr. James Barrett at Centocor for editorial Crohn’s disease who were treated with infliximab, support.
patients with ulcerative colitis who had positive a p p e n d i x
The following principal investigators, listed alphabetically, participated in ACT 1 and ACT 2: L. Abreu, Clinica Puerta de Hierro, Madrid; F.
Anderson, Liver and Intestinal Research Centre, Vancouver, B.C., Canada; J.P. Baker, St. Michael’s Hospital, Toronto; P. Bampton, FlindersMedical Centre, Bedford Park, S.A., Australia; M. Barclay, Christchurch Hospital, Christchurch, New Zealand; C. Barish, Wake Research Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. i n f l i x i m a b f o r u l c e r a t i v e c o l i t i s Associates, Raleigh, N.C.; C. Beglinger, Kantonsspital Basel, Basel, Switzerland; C.N. Bernstein, Health Sciences Centre, Winnipeg, Man.,Canada; M.A. Bigard, Hôpital Brabois Adulte, Vandoeuvre les Nancy, France; D. Binion, Medical College of Wisconsin, Milwaukee; W. Bray,Digestive Health Specialists, Winston-Salem, N.C.; A. Brzezinski, Cleveland Clinic Foundation, Cleveland; J.R. Cangemi, Mayo Clinic–Jack-sonville, Jacksonville, Fla.; R.M. Chasen, Maryland Digestive Disease Research, Laurel; W. Chey, Rochester Institute for Digestive Diseases& Sciences, Rochester, N.Y.; A. Cohen, Jewish General Hospital, Montreal; J. Collins, Oregon Health Sciences University, Portland; F. Com-inelli, University of Virginia, Charlottesville; M. Cottone, Ospedaliera V. Cervello, Palermo, Italy; J.F. Dahlerup, Aarhus University Hospital,Aarhus Kommunehospital, Aarhus, Denmark; G. D’Haens, Imelda Ziekenhuis, Bonheiden, Belgium; A. DiMarino, Thomas Jefferson Uni-versity, Philadelphia; I. Dotan, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; R. Duchmann, Universitätsklinik Benjamin Franklin, Ber-lin; B. Duclos, Hôpital Hautepierre, Strasbourg, France; A. Ertan, Baylor College of Medicine, Houston; J. Fallingborg, Aalborg HospitalSouth, Aalborg, Denmark; R. Farrell, Beth Israel Deaconess Medical Center, Boston; R. Fedorak, University of Alberta, Edmonton, Alta.,Canada; T. Florin, Mater Adult Hospital, South Brisbane, Qld., Australia; P. Frankish, North Shore Hospital, Takapuna, Auckland, NewZealand; S. Friedman, Brigham & Women’s Hospital, Boston; M. Gaspari, Carolina Digestive Health Associates, Charlotte, N.C.; S. Ghosh,Hammersmith Hospital, London; P. Gibson, Box Hill Hospital, Box Hill, Vic., Australia; B. Göke, Klinikum der Universität München, Mu-nich, Germany; M. Grimm, St. George Clinical School, Kogarah, N.S.W., Australia; W. Harlan, Asheville Gastroenterology, Asheville, N.C.;A.B. Hawthorne, University Hospital of Wales, Cardiff, Wales; D. Helper, Indiana University Medical Center, Indianapolis; R. Inglese, ValleyGastroenterology Associates, Beaver Falls, Pa.; K. Isaacs, University of North Carolina Hospitals, Chapel Hill; D. James, Green Country Di-agnostics Center, Tulsa, Okla.; M. Kamm, St. Marks Hospital, London; J.A. Katz, University Hospitals of Cleveland, Cleveland; S. Katz,Long Island Clinical Research, Great Neck, N.Y.; B.P. Kaufmann, AGA Clinical Research Associates, Egg Harbor Township, N.J.; J.W. Kon-turek, Elbe Klinikum Stade, Stade, Germany; G. Koval, West Hills Gastroenterology–Portland Digestive Diseases Research Center, Port-land, Oreg.; S. Krumholz, Waterside Clinical Research Services, West Palm Beach, Fla.; G.A. Kullak-Ublick, University Hospital Zürich,Zurich, Switzerland; M. Lane, Auckland Hospital, Grafton, Auckland, New Zealand; M. Lawson, Permanente Medical Group, Sacramento,Calif.; P. Lebovitz, Allegheny Center for Digestive Health, Pittsburgh; J. Leighton, Mayo Clinic Scottsdale, Scottsdale, Ariz.; M. Lemann,Hôpital Saint Louis, Paris; H. Lochs, Charite Campus Mitte, Berlin; F. Macrae, the Royal Melbourne Hospital, Department of Gastroenter-ology, Melbourne, Vic., Australia; E. Melzer, Kaplan Medical Center, Rehovot, Israel; P. Miner, Oklahoma Foundation for Digestive Re-search, Oklahoma City; B. Mitchell, Launceston General Hospital, Gastroenterology Unit, Launceston, Tas., Australia; J. Moreau, HôpitalRangueil, Toulouse, France; A.J. Morris, Glasgow Royal Infirmary, Glasgow, Scotland; P.L. Moses, University of Vermont College of Medi-cine, South Burlington; C. Mowat, Ninewells Hospital, Dundee, Scotland; P. Munkholm, Hvidorvre Hospital, University of Copenhagen,Hvidorvre, Denmark; A.H.J. Naber, UMC St. Radboud, Nijmegen, the Netherlands; T. Naftali, Meir Hospital–Sapir Medical Center, Kfar Sa-va, Israel; J. Onken, Duke University Medical Center, Durham, N.C.; R. Panaccione, University of Calgary, Gastrointestinal Research Depart-ment of Community Health Sciences, Calgary, Alta., Canada; P. Paré, CHAUQ–Hôpital du St-Sacrement, Quebec, Que., Canada; D. Patter-son, Virginia Mason Medical Center, Seattle; P. Pavli, the Canberra Hospital, Woden, A.C.T., Australia; J.M. Pique, Hospital Clinic deBarcelona, Barcelona; G.B. Porro, University Luigi Sacco, Milan; G. Radford-Smith, Royal Brisbane Hospital, Herston, Qld., Australia; M.
Regueiro, University of Pittsburgh Medical Center, Pittsburgh; J. Rhodes, University of Liverpool, Liverpool, United Kingdom; D. Riff, Ad-vanced Clinical Research Institute, Anaheim, Calif.; D. Rubio, Hospital Clinico San Carlos, Madrid; J.S. Sabel, South Denver Gastroenterol-ogy, Englewood, Colo.; M. Safdi, Consultants for Clinical Research, Cincinnati; F. Saibil, Sunnybrook and Women’s College Health Scienc-es Center, Toronto; A. Sambueli, Hospital de Gastroenterologia, Capital Federal, Argentina; E.J. Scherl, New York Presbyterian Hospital,New York; H. Schwartz, Miami Research Associates, Miami; F. Seibold, Inselspital Bern, Bern, Switzerland; J. Shaffer, Hope Hospital,Manchester, United Kingdom; S. Shah, Gastroenterology Associates, Providence, R.I.; D.R. Silvers, Drug Research Services, Metairie, La.;D.B. Stanton, Community Clinical Trials, Orange, Calif.; H. Steinhart, Mt. Sinai Hospital, Toronto; C.D. Stone, Washington UniversitySchool of Medicine, St. Louis; A. Stronkhorst, Catharina Ziekenhuis, EJ Eindhoven, the Netherlands; J.P. Terdiman, University of Californiaat San Francisco, San Francisco; J. van der Woude, University Hospital Rotterdam, GD Rotterdam, the Netherlands; A. van Gossum, FreeUniversity Hospital Erasme, Brussels; P.A.M. van Hees, Sint Antonius Ziekenhuis, CM Nieuwegein, the Netherlands; G. Varilek, Gastroen-terology Specialties, Lincoln, Nebr.; W. Vogel, University Hospital Innsbruck, Innsbruck, Austria; P. Vyhnalek, Hospital Pardubice, Pardu-bice, Czech Republic; I. Wallace, Shakespeare Specialist Group, Milford, Auckland, New Zealand; D.I. Weinberg, Minnesota Gastroenter-ology, Plymouth; L. Wruble, Summit Research Solutions, Memphis, Tenn.; Z.H. Younes, Gastroenterology Center of the MidSouth,Memphis, Tenn.; Z. Zadorova, University Hospital Kralovske Vinohrady, Praha, Czech Republic; M. Zimmerman, Royal Perth Hospital,Perth, W.A., Australia.
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The Journal encourages investigators to register their clinical trials in a public trials registry. The members of the International Committee of Medical Journal Editors plan to consider clinical trials for publication only if they have been registered (see N Engl J Med 2004;351:1250-1). The National Library of Medicine’s www.clinicaltrials.gov is a free registry, open to all investigators, that meets Downloaded from nejm.org at MEMORIAL SLOAN KETTERING CANCER CTR on September 10, 2011. For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved.

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