ORIGINAL ARTICLE
Low-dose Infliximab for Induction and Maintenance Treatment in Chinese Patients With Moderate to Severe Active Ulcerative Colitis Xue-Liang Jiang, MD,* Hui-Fei Cui, MD,w Jing Gao, MS,* and Hua Fan, MD*
Goal: To evaluate the efficacy of low-dose (3.5 mg/kg) infliximab for induction and maintenance treatment in Chinese patients with ulcerative colitis. Background: Treatment with 4 to 5 mg/kg of infliximab also proved to be effective in treating moderate to severe ulcerative colitis. At present there is no relevant study on the effectiveness of infliximab doses lower than 4 mg/kg in patients with ulcerative colitis. Study: A prospective, randomized, double-blind, placebo-controlled, and single-centered study was designed. A total of 123 patients (from 17 provinces of China) with moderate to severe active ulcerative colitis despite treatment with concurrent drugs received placebo or low-dose (3.5 mg/kg) or standard-dose (5 mg/ kg) infliximab intravenously at weeks 0, 2, and 6 and then every 8 weeks through week 22. Patients were followed up for 30 weeks. Results: Overall, 73% and 78% of patients who received low-dose (3.5 mg/kg) and standard-dose (5 mg/kg) infliximab, respectively, had clinical responses at week 8, as compared with 37% of patients who received placebo (P < 0.01 for both comparisons with placebo). The number of patients who received low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab with a clinical response at week 30 (63% and 66%, respectively) was more than the patients who received placebo (27%, P < 0.01 for both comparisons). Conclusions: Chinese patients with moderate to severe active ulcerative colitis treated with low-dose (3.5 mg/kg) or standarddose (5 mg/kg) infliximab at weeks 0, 2, and 6 and every 8 weeks thereafter were more likely to have a clinical response at weeks 8 and 30 than those who received placebo.
with steroid-refractory ulcerative colitis.2 Immunosuppressants or surgery is used to treat such patients. However, immunosuppressants have more adverse effects such as bone marrow suppression and liver dysfunction. Surgery will result in lower quality of life in patients. Accordingly, new treatments for ulcerative colitis are needed.3 Infliximab has opened a new path for the treatment of moderate to severe active ulcerative colitis for nearly 10 years. It is reported that treatment with infliximab can alleviate symptoms and signs, induce and maintain clinical remission, accelerate mucosal healing, and discontinue glucocorticoid in patients with moderate to severe ulcerative colitis without satisfactory response to traditional treatment.4,5 No significant statistical differences were observed between the clinical therapeutic efficacy of high-dose (10 mg/kg) and standard-dose (5 mg/kg) infliximab treatment for active ulcerative colitis.3 Infliximab doses at 4 to 5 mg/kg also proved effective in the treatment of medium to severe ulcerative colitis.6 No research has at present been conducted on the efficacy of infliximab doses lower than 4 mg/kg in the treatment of patients with ulcerative colitis. Currently, studies on efficacy, safety, or dosage of infliximab are lacking in China. Therefore, based on the studies conducted in other countries, a 30-week study on low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab in Chinese patients with moderate to severe ulcerative colitis was performed.
Key Words: ulcerative colitis, infliximab, low dose
PATIENTS AND METHODS
(J Clin Gastroenterol 2015;49:582–588)
Patients
U
lcerative colitis is a chronic nonspecific inflammatory bowel disease characterized by intestinal mucosal ulcer, rectal bleeding, diarrhea, and abdominal pain. The incidence of ulcerative colitis has gradually increased1 in recent decade in China. The main traditional therapeutic drugs for this disease are amino salicylic acid, glucocorticoid, and immunosuppressants (including purine metabolites and cyclosporin). The effect is unsatisfactory for the patients
Received for publication July 24, 2014; accepted February 23, 2015. From the *Department of Gastroenterology, Chinese PLA General Hospital of Jinan Military Command; and wCollege of Pharmaceutical Science, Shandong University, Jinan, Shandong Province, China. The authors declare that they have nothing to disclose. Reprints: Xue-Liang Jiang, MD, Department of Gastroenterology, Chinese PLA General Hospital of Jinan Military Command, 25 Shifanlu, Jinan 250031, Shandong Province, China (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
A total of 123 subjects (from 17 provinces of China) diagnosed with moderate to severe ulcerative colitis from December 2008 to December 2013 in Jinan Military General Hospital were enrolled according to the Montreal classification.7 All eligible patients had an established diagnosis of ulcerative colitis. This study was approved by the Ethics Committee of Jinan Military General Hospital, and written informed consent forms were obtained from all participants. Inclusion criteria were as follows: (1) subjects’ participation in the study was voluntary, and all subjects had to sign the informed consent form before the enrollment; (2) subjects should be aged between 18 and 65 years, irrespective of sex; (3) moderate to severe active ulcerative colitis was diagnosed using endoscopy and biopsy 1 week before treatment; (4) eligible patients had active ulcerative colitis with a Mayo score of 6 to 12 points8 and an endoscopic score of Z2 points (Table 1), despite concurrent treatment with corticosteroids only or in combination with azathioprine and drugs containing 5-aminosalicylates.
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TABLE 1. The Modified Mayo Score*
Mayo Score Stool frequencyw 0 = Normal no. stools for this patient 1 = 1-2 stools more than normal 2 = 3-4 stools more than normal 3 = 5 or more stools more than normal Subscore, 0-3 Rectal bleedingz 0 = No blood seen 1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool most of the time 3 = Blood alone passes Subscore, 0-3 Findings on endoscopy 0 = Normal or inactive disease 1 = Mild disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 3 = Severe disease (spontaneous bleeding, ulceration) Subscore, 0-3 Physician’s global assessmenty 0 = Normal 1 = Mild disease 2 = Moderate disease 3 = Severe disease *The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease. Data are from Schroeder and colleagues.9 wEach patient serves as his or her own control to establish the degree of abnormality of the stool frequency. zThe daily bleeding score represents the most severe bleeding of the day. yThe physician’s global assessment acknowledges the 3 other criteria, the patient’s daily recollection of abdominal discomfort and general sense of well-being, and other observations, such as physical findings and the patient’s performance status.
Exclusion criteria were as follows: (1) patients who had been diagnosed with Crohn’s disease (CD), or clinical findings suggestive of CD or indeterminate colitis; (2) a recent medical history of active infection, chronic infection, or repeated infection; special attention was paid to patients with positive tuberculin skin tests using purified protein derivative and standard chest radiographs (including active tuberculosis and latent tuberculosis infection), hepatitis B virus infection; (3) patients with congestive heart failure; (4) children and patients under pregnancy; (5) patients allergic to mouse proteins; (6) patients with demyelinating diseases of the nervous system; (7) patients with malignancy (both present and previous); (8) patients with severe ulcerative colitis requiring intravenous steroids; (9) patients who received corticosteroids or drugs containing 5-aminosalicylates rectally within 2 weeks before screening; (10) patients who were previously exposed to infliximab or any other anti–tumor necrosis factor (TNF); (11) patients who did not respond to corticosteroids within the preceding 18 months or who could not tolerate corticosteroids; (12) patients who did not respond to azathioprine or mercaptopurine within the preceding 5 years or who could not tolerate these drugs, and patients who did not respond to drugs containing 5-aminosalicylates within the preceding 18 months or who could not tolerate such drugs; (13) patients with cytomegalovirus colitis.
Study Design Eligible patients were randomly assigned in a 1:1:1 ratio to receive intravenous infusions of infliximab (Remicade; Copyright
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Infliximab for Induction and Maintenance Treatment
100 mg/bottle) at a low dose of 3.5 mg/kg or a standard dose of 5 mg/kg or placebo at weeks 0, 2, and 6 and then every 8 weeks through week 22. Patients were followed up through week 30. In this study, central randomization with a dynamic treatment allocation stratified was used based on the investigational site and whether patients had ulcerative colitis that was refractory to treatment with corticosteroid. Patients were considered to have ulcerative colitis that was refractory to corticosteroids if their symptoms did not improve after they received the equivalent of at least 40 mg of prednisone daily, administered orally for at least 2 weeks or intravenously for at least 1 week.2 Doses of concomitant drugs were maintained at the same level except for corticosteroids, which were tapered by 5 mg/wk after week 8 until a dose of 20 mg/d was reached. Thereafter, the dose was reduced by 2.5 mg/wk until discontinuation.
Follow-up and Safety and Efficacy Evaluations Patients were evaluated at weeks 0, 2, 6, 8, 14, 22, and 30. The Mayo score (Table 1) was determined at weeks 0, 8, and 30 for patients. A partial Mayo score (Mayo score without endoscopy) was determined at all visits. Clinical response was defined as a decrease in the total Mayo score of at least 3 points and at least 30% from the baseline values, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1.8 Clinical remission was defined as a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point. Mucosal healing was defined as an absolute subscore for endoscopy of 0 or 1.8 Clinical response, clinical remission, and mucosal healing were assessed at weeks 8 and 30. Patients who had a clinical response and who were in clinical remission at each time were considered to have a sustained clinical response and sustained clinical remission, respectively. Adverse events and concomitant drugs were recorded at each visit. Adverse events including infusion reaction, delayed hypersensitivity (serum sickness sample response), drug-induced lupus erythematosus, and infection were monitored, and the time of occurrence, severity, duration, treatment, and outcome of adverse events were recorded. Serum specimens for the identification of antibodies against infliximab and antinuclear antibodies were collected at weeks 0 and 30, as described previously.10 Samples positive for antinuclear antibodies were tested for antibodies against double-stranded DNA.
Statistical Analysis The primary end point was a clinical response at week 8. Secondary end points were clinical response or clinical remission with discontinuation of corticosteroids at week 30, clinical remission and mucosal healing at weeks 8 and 30, and clinical response at week 8 in patients with a medical history of disease refractory to corticosteroids. Patients who received prohibited drug because of lack of efficacy or loss of response to the study drug, who discontinued the study drug because of lack of efficacy, or who underwent a colectomy or ostomy were not considered to have had a clinical response, to be in clinical remission, or to have had mucosal healing from the time of the event onward, regardless of their Mayo score. In addition, patients with insufficient data for the assessment of response were not considered to have had a
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clinical response, to be in clinical remission, or to have had mucosal healing at that visit. Demographic and baseline characteristics were compared using the w2 test or the Fisher exact test for categorical variables and analysis of variance for van der Waerden normal scores for continuous variables. A 2-sided Cochran-Mantel-Haenszel w2 test, at a significance level of 0.05, stratified according to the corticosteroid-refractory status and the location of the study center, was used to compare dichotomous end points (ie, clinical response, clinical remission, mucosal healing, and clinical remission with discontinuation of corticosteroids) among the treatment groups. All efficacy analyses used intention-to-treat methods. Safety comparisons were performed using the Fisher exact test and were based on the combination of the 2 groups receiving infliximab as compared with the placebo group. Sample size: in Active Ulcerative Colitis Trial 2 (ACT2),3 64% of patients who received 5 mg/kg of infliximab and 69% of those who received 10 mg/kg had a clinical response at week 8, as compared with 29% of those who received placebo (P < 0.001 for both comparisons with placebo). Assuming a response rate of 30% in the placebo group and a 2-sided probability of 0.05, it was estimated that 40 patients would be needed in each group to give the study a statistical power of 95% to detect an improvement in the response rate to 64%.
RESULTS Characteristics of the Patients A total of 123 patients underwent randomization: 41 were assigned to receive placebo, 41 were assigned to receive 3.5 mg/kg of infliximab (low dose), and 41 were assigned to receive 5 mg/kg of infliximab (standard dose). The baseline characteristics of the patients were similar (Table 2). Treatment was discontinued prematurely by 19 (46.3%) patients in the placebo group, 8 (19.5%) patients in
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the 3.5 mg/kg infliximab group, and 7 (17.1%) patients in the 5 mg/kg infliximab group (Fig. 1). More than twice as many patients in the placebo group as in the other 2 groups prematurely discontinued the infusions (Fig. 1).
Efficacy Overall, 73.1% (30/41) of patients who received lowdose infliximab (3.5 mg/kg) and 78.1% (32/41) of those who received standard-dose infliximab (5 mg/kg) had a clinical response at week 8, as compared with 36.6% (15/41) of those who received placebo (P < 0.01 for both comparisons with placebo) (Fig. 2A, Table 3). The number of patients who received low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab with a clinical response at week 30 (63% and 66%, respectively) was more than the patients who received placebo (27%, P < 0.01 for both comparisons) (Fig. 2A, Table 3). The rates of clinical response were similar between the subpopulations of patients who were corticosteroid-refractory and those who were not corticosteroid-refractory (Table 3). The proportions of patients with a clinical remission and mucosal healing at weeks 8 and 30 in the infliximab groups were higher than those in the placebo group (P < 0.05, Figs. 2B, C). The proportions of patients with a sustained clinical response or remission were significantly higher in the infliximab groups than in the placebo group (Table 3). The partial Mayo scores provide evidence of clinical improvement as early as week 2 (Table 3). At baseline, 52.8% (65/123) of patients were receiving corticosteroids. The baseline median daily corticosteroid dose was 20 mg/d. The decreases in the median daily corticosteroid doses were greater among patients in the infliximab groups than among those in the placebo group (Table 3). Similarly, the proportions of patients who were in clinical remission and had discontinued corticosteroids at week 30 were higher in the infliximab groups than those in the placebo group.
TABLE 2. Patient Demographics and Baseline Characteristics
Characteristics Male [n (%)] Age (mean ± SD) (y) Weight (mean ± SD) (kg) Nonsmoker [n (%)] Duration of disease (y) Colonic area involved [n (%)] Left-sided colitis Pancolitis Severity [n (%)] Moderate disease Severe disease C-reactive protein (mean ± SD) (mg/L) Blood sedimentation (mean ± SD) (mm/h) Concomitant medication [n (%)] Corticosteroids Z20 mg/d 5-aminosalicylates Immunosuppressants (azathioprine) Corticosteroid-refracteory disease [n (%)]
Placebo (n = 41)
3.5 mg/kg of Infliximab (n = 41)
5 mg/kg of Infliximab (n = 41)
P
25 (60.9) 34.5 ± 14.9 61.2 ± 15.7 28 (68.3) 4.4 ± 2.6
24 (58.5) 34.1 ± 13.8 63.1 ± 13.6 29 (70.7) 4.3 ± 2.5
26 (63.4) 34.3 ± 14.3 62.8 ± 14.9 28 (68.3) 4.4 ± 2.8
0.90 0.87 0.56 0.37 0.85
17 (41.5) 24 (58.5)
15 (36.6) 26 (63.4)
16 (39.1) 25 (60.9)
0.90 0.39
16 (39.1) 25 (60.9) 35.1 ± 17.8 45.7 ± 24.8
17 (41.5) 24 (58.5) 35.7 ± 16.1 46.2 ± 26.4
15 (36.6) 26 (63.4) 35.8 ± 22.6 44.2 ± 22.3
0.91 0.39 0.91 0.47
21 14 35 13 12
(51.2) (34.1) (85.4) (31.7) (29.3)
22 15 36 12 11
(53.7) (34.6) (87.8) (29.3) (26.7)
22 14 34 12 12
(53.7) (34.1) (82.9) (29.3) (29.3)
0.97 0.82 0.82 0.96 0.96
P-values for all categorical variables are based on a 2-side w2 test, P-values for all continuous variables are based on the analysis of variance for the van der Waerden.
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FIGURE 1. Enrollment and treatment. Overall, 41 patients with moderate to severe ulcerative colitis were randomly assigned to receive placebo intravenously, 41 patients were assigned to receive low-dose infliximab (3.5 mg/kg) and 41 patients were assigned to receive standard-dose infliximab (5 mg/kg) at weeks 0, 2, 6, 14, and 22. Patients were followed for 30 weeks. The efficacy and safety populations consisted of all 123 patients who underwent randomization, all of whom received at least 1 dose of study drug.
Safety Patients were treated for a mean of 15.1 weeks in the placebo group, 22.6 weeks in the 3.5 mg infliximab group, and 22.3 weeks in the 5 mg infliximab group (Table 4). The proportions of patients with adverse events were similar in the placebo group and the 2 infliximab groups (Table 4). Serious adverse events occurred in 9.8% (4/41) of patients in the placebo group, 4.9% (2/41) of patients receiving 3.5 mg of infliximab, and 7.3% (3/41) of patients receiving 5 mg of infliximab. Two patients in the placebo group discontinued treatment because of an adverse event, whereas no patient in the 3.5 mg infliximab group and 1 patient in the 5 mg infliximab discontinued treatment because of an adverse event (Table 4). Tumors and nervous system diseases were not observed. The incidence of infections was similar among the groups in both studies (Table 4). Serious infection occurred in 1 (2.4%) patient in the 5 mg infliximab group, no serious infection occurred in the placebo group and in the 3.5 mg infliximab group. Infusion reactions occurred in 2 (4.9%) patients in the placebo group, 2 (4.9%) patients in the 3.5 mg infliximab group, and 3 (7.3%) patients in the 5 mg infliximab group. No possible delayed hypersensitivity reaction occurred and no Copyright
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patient in either group who had a positive test for antibodies had a serious infusion reaction or an anaphylactic reaction. Liver and kidney functions were normal in all patients.
Antibodies Against Infliximab Among 78 patients with serum samples available for the assessment of antibodies against infliximab, 4 (5.1%) patients had positive tests for antibodies at some point after the first infusion of infliximab (Table 4), 12 (15.4%) patients had negative tests (undetectable serum infliximab concentrations), and 62 (79.5%) patients had inconclusive tests (negative for antibodies in the presence of detectable serum infliximab concentrations). A clinical response at week 30 occurred in 2 of 4 (50.0%) patients with positive tests for antibodies, as compared with 7 of 12 (58.3%) patients with negative tests and 40 of 62 (64.5%) patients with inconclusive tests. The antinuclear antibodies developed in 2 patients in the placebo group and 5 patients in the low-dose (3.5 mg) infliximab group and 5 patients in the standard-dose (5 mg) infliximab group. The anti–double-stranded DNA antibodies were negative in placebo group, 1 patient from low-dose (3.5 mg) infliximab group and 2 patients from standard-dose (5 mg) group (Table 4). Only 1 patient who received 5 mg of infliximab had a lupus-like reaction.
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FIGURE 2. Proportion of patients with a clinical response (A), in clinical remission (B), and with mucosal healing (C) at weeks 8 and 30.
DISCUSSION Infliximab is an anti-TNF and monoclonal humanmouse chimeric immunoglobulin G1 antibody composed of human constant regions and murine variable regions and comprising 25% original murine antibodies and 75% original human antibodies. In 1997, infliximab was approved by the United States Food and Drug Administration for the treatment of CD. In 2005, it was approved for the treatment of ulcerative colitis. Infliximab is one of the biological agents with the longest duration of use and most abundant evidence-based medical information used in the treatment of inflammatory bowel disease. It is also the earliest biological agent approved in the treatment of ulcerative colitis. Infliximab possesses high-affinity binding to both transmembrane and soluble TNF-a, and can thus inhibit the binding of TNF-a to its receptor resulting in a loss of TNF activity.11 Although the mechanism played by infliximab in the treatment of ulcerative colitis remains unclear, it has been listed as a Class-A drug applicable in the treatment of moderate to severe active steroid-refractory or steroiddependent ulcerative colitis in the guidelines of the American College of Gastroenterology (ACG).12 Jiang13 was the first to report the efficacy and safety of infliximab in China, a fact
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which has already been verified in several studies conducted in other countries. The results demonstrated that the treatment with infliximab was effective rapidly. In a majority of patients, symptoms such as stool frequency were improved or remitted within 1 week. The clinical response rate was >70% and the remission rate was >50%. In terms of the dosage of infliximab, the ACG-recommended dosage for ulcerative colitis is 5 mg/kg. Documented active ulcerative colitis trials 1 and 2 (ACT-1 and ACT-2) showed that the clinical response rates of the infliximab 5 and 10 mg/kg groups were 69.4% and 61.5%, respectively, at week 8 in the ACT-1 trial,3 whereas the clinical remission rates were 38.8% and 32%, respectively. In the ACT-2 trial, the clinical response rates of the infliximab 5 and 10 mg/kg groups were 64.5% and 69.2%, respectively, whereas the clinical remission rates were 33.9% and 33%, respectively. In both trials, no significant difference (P > 0.05) was observed in the clinical response rates or the clinical remission rates between the infliximab 5 and 10 mg/kg groups at week 8. The results suggest that higher doses of infliximab do not bring about higher clinical efficacy. Jarnerot et al6 observed the rates of colon resection, mortality, endoscopic mucosal healing, and clinical remission in 24 patients who received infliximab (dosage close to 5 mg/kg) and in 21 patients in the control group in a randomized-controlled trial. The results of this trial suggest that treatment of moderate to severe active ulcerative colitis by 4 to 5 mg/kg of infliximab is both effective and safe. No studies were conducted to evaluate the efficacy of lowerdosage (< 4 mg/kg) infliximab in the treatment of ulcerative colitis. This study was the first to use 3.5 mg/kg infliximab intravenous treatment. The results of this study show that infliximab (low dose of 3.5 mg/kg and standard dose of 5 mg/kg) is effective in patients who have moderate to severe active ulcerative colitis despite the use of conventional treatment, in terms of clinical response and remission. As compared with patients who received placebo, patients who received infliximab (low dose of 3.5 mg/kg and standard dose of 5 mg/kg) were significantly more likely to have a clinical response and be in clinical remission at weeks 8 and 30. Similarly, patients who received infliximab (low dose of 3.5 mg/kg and standard dose of 5 mg/kg) were significantly more likely to have mucosal healing at weeks 8 and 30. The results of the study also compared the severity of the patients with ulcerative colitis (treated with 3.5 mg/kg infliximab) with the method aforementioned in the ACT-1 and ACT-2 groups3; yet at week 8, the clinical response rate and the endoscopic mucosal healing rate observed were similar to those observed in patients treated with 5 and 10 mg/kg infliximab in the ACT-1 and ACT-2 groups. The clinical remission rate, however, was higher in the 3.5 mg/kg group of the present study than in the 5 and 10 mg/kg groups observed in the ACT-1 and ACT-2 groups at week 8. At week 30, the clinical response rate, the clinical remission rate, and the endoscopic mucosal healing rate were similar to those of the 3.5 and 5 mg/kg groups observed in this study. Also, the clinical response rate and the endoscopic mucosal healing rate were similar between the present study and the ACT-1 and ACT-2 trials. However, the clinical remission rate observed in the 3.5 mg/kg group (the present study) was higher than those of the 5 mg/ kg groups in the ACT-1 and ACT-2 groups. It is suggested that patients with ulcerative colitis in our group might present a higher sensitivity to infliximab. Further studies
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TABLE 3. Primary and Secondary Efficacy Results
Variables
Placebo (n = 41)
Clinical response Week 8 [n (%)] 15 (36.6) P* Week 30 [n (%)] 11 (26.8) P* Refractory to corticosteroid therapy at week 4/12 (33.3) 8 [n/total (%)] P# Not refractory to corticosteroid therapy at 7/29 (24.1) week 8 [n/total (%)] P* Clinical remission Week 8 [n (%)] 9 (21.9) P* Week 30 [n (%)] 10 (24.4) P* Partial Mayo score [median (interquartile range)]w Baseline 6.0 (5.0-6.0) Week 2 5.0 (4.0-7.0) Week 6 5.0 (4.0-7.0) Week 8 5.0 (3.0-7.0) Week 30 6.0 (3.0-7.0) Mucosal healing Week 8 [n (%)] 10 (24.4) P* Week 30 [n (%)] 9 (21.9) P* Daily corticosteroid dose [median (interquartile range)] (mg) Baseline 20.0 (10.0-30.0) Week 8 20.0 (10.0-30.0) Week 30 20.0 (5.0-30.0) Clinical remission and discontinued use of corticosteroid Week 30 [n/total (%)] 1/21 (4.7) P*
3.5 mg/kg of Infliximab (n = 41)
5 mg/kg of Infliximab (n = 41)
30 (73.1) 0.001 26 (63.4) 0.001 8/11 (72.7)
32 (78.1) 0.00 27 (65.8) 0.001 9/12 (75.0)
0.1 22/30 (73.3)
0.1 23/29 (79.3)
0.00
0.00
21 (51.2) 0.006 20 (48.8) 0.022
22 (53.7) 0.003 21 (51.2) 0.012
6.0 4.0 3.0 3.0 4.0
6.0 4.0 3.0 2.0 3.0
(5.0-6.0) (3.0-5.0) (2.0-5.0) (2.0-5.0) (1.0-5.0)
23 (56.1) 0.003 21 (51.2) 0.006
(5.0-6.0) (2.0-5.0) (1.0-5.0) (1.0-4.0) (1.0-5.0)
24 (58.5) 0.002 22 (53.7) 0.003
20.0 (10.0-30.0) 20.0 (10.0-30.0) 7.5 (0.0-20.0)
20.0 (10.0-30.0) 20.0 (10.0-30.0) 5.0 (0.0-20.0)
8/21 (38.1) 0.04
9/22 (41.0) 0.03
A partial Mayo score is the Mayo score without the endoscopic subscore. *P-values for all categorical variables are based on a 2-side w2 test. #P-values are based on the Fisher exact test. wThe Mayo score ranges from 0 to 12, with higher scores indicating severer disease.
are needed to analyze whether this difference is related to the disease course and other concurrent drugs. The efficacy in the present study is similar between the 2 doses (low dose of 3.5 mg/kg and standard dose of 5 mg/kg) of infliximab. Inducing and maintaining the clinical response and the clinical remission and minimizing the use of corticosteroids are unmet goals in the treatment of patients with ulcerative colitis, particularly those who have no responses to corticosteroids, azathioprine, or mercaptopurine.14 In the present study, at baseline, 52.8% (65/123) of the patients received corticosteroids. The baseline median daily corticosteroid dose was 20 mg/d. The decreases in the median daily corticosteroid doses were greater in patients of the infliximab groups than those in the placebo group. Similarly, the proportions of patients, who were in clinical remission and who discontinued corticosteroids at week 30, were higher in the infliximab groups than in the placebo group. As treatment with corticosteroid is associated with considerable morbidity,15 this corticosteroid-sparing effect is likely to be clinically meaningful. The rate of development of antibodies against infliximab after the 3-dose induction regimen and after the maintenance dose every 8 weeks in the patients with ulcerative colitis in our studies was similar to that reported Copyright
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for patients with CD.16,17 In contrast to previous experience,3 infusion reactions were similar in the patients who had positive tests for antibodies and those without antibodies. Most of these infusion reactions were mild. The clinical response at week 30 was similar in patients with positive or inconclusive tests for antibodies and those with negative antibody tests. However, these findings should be interpreted with caution because of the small number of patients with positive tests for antibodies. In the present study, the proportions of patients reporting any adverse event were similar among the 3 groups. Liver and kidney functions were normal in all patients. Other adverse events such as tumors and diseases of the nervous system did not occur. The rate of adverse events in this study was lower than those in the ACT-1 and ACT-2 trials.3 Besides due to strict labeling and transfusion speed control, this lower rate might be related to steroid resistance, concurrent steroid treatments, lower infliximab doses, and less frequent administration of infliximab. Others reported that adverse events of infliximab included aggravated or induced moderate congestive heart failure, malignant tumors, drug-induced lupus erythematosus, demyelinating diseases of the central nervous system, lymphoma, etc.18 The most common adverse events are
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TABLE 4. Summary of Safety and Immunogenicity Analyses for All Patients Who Underwent Randomization
Placebo (n = 41)
Variables Mean duration of treatment (wk) Mean duration of follow-up (wk) Any adverse event [no. patients (%)] Serious adverse events [no. patients (%)] Adverse events leading to discontinuation of study drug [no. patients (%)] Adverse events leading of particular interest [no. patients (%)] Pneumonia Infections [no. patients (%)] Infections requiring antimicrobial treatment [no. patients (%)] Serious infections [no. patients (%)] Acute infusion reaction (any adverse occuringr2 h after start of infusion) [no. patients (%)] Possible delayed hypersensitivity reaction [no. patients (%)] Antibodies against infliximab [no. patients/total no (%)] Antinuclear antibodies [no. patients/total no (%) ] Anti–double-stranded DNA antibodies [no. patients/total no (%)]
3.5 mg/kg of Infliximab (n = 41)
15.1 27.6 16 (39.0) 4 (9.8) 2 (4.9)
22.6 30.0 16 (39.0) 2 (4.9) 0 (0.0)
0 5 (12.2) 2 (4.9) 0 2 (4.9)
0 5 (12.2) 2 (4.9) 0 2 (4.9)
0 — 2/30 (6.6) 0/34 (0.0)
0 2/38 (5.3) 5/31 (16.1) 1/35 (3.2)
5 mg/kg of Infliximab (n = 41) 22.3 30.0 17 (41.5) 3 (7.3) 1 (2.4) 1 6 3 1 3
(2.4) (14.6) (7.3) (2.4) (7.3)
0 2/40 (5.0) 5/30 (16.7) 2/36 (5.6)
P* ND ND 1.000 0.479 0.257
1 1 1 1 1 — 0.324 0.542
ND indicates not done; em-dash, not applicable. *P-values are based on the Fisher exact test for the comparison of the combined infliximab groups with the placebo group.
tuberculosis infection and tumors. In the United States, about 130 patients contracted lung tuberculosis during treatment with infliximab from 2001 to 2006.19 Mor et al20 reported that infliximab increased the risk of postoperative complications after colectomy. No nervous system damage, tumors or lupoid changes were observed in this study. In conclusion, Chinese patients with moderate to severe active ulcerative colitis treated with low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab at weeks 0, 2, and 6 and every 8 weeks thereafter were more likely to have a clinical response at weeks 8 and 30 than those patients who received placebo.
9.
10.
11. 12.
REFERENCES 1. Wang Y, Ouyang Q. APDW 2004 Chinese IBD Working Group. Ulcerative colitis in china: retrospective analysis of 3100 hospitalized patients. J Gastroenterol Hepatol. 2007;22:1450–1455. 2. Maltese P, Palm L, Sfara C, et al. Glucocorticoid resistance in Crohn’s disease and ulcerative colitis: an association study investigating GR and FKBPS gene polymorphisms. Pharmacogenomics J. 2012;12:432–438. 3. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J med. 2005;353:2462–2476. 4. Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Rev Gastroenterol Mex. 2006;71:351–401. 5. Clark M, Colombel JF, Feagan BC, et al. American Gastroenterological Association consensus development conference on the use of biologics in the treatment of inflammatory bowel disease. Gastroenterology. 2007;133:312–339. 6. Jarnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology. 2005; 128:1805–1811. 7. Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55:749–753. 8. D’Haens G, Sandborn WJ, Feagan BG, et al. A review of activity indices and efficacy end points for clinical trials of
13. 14.
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medical therapy in adults with ulcerative colitis. Gastroenterology. 2007;132:763–786. Schroeder KW, Tremaine WJ, Ilstrup DM, et al. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987; 317:1625–1629. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol. 2004;2:542–553. Ten Hove T, van Montfrans C, Peppelenbosch MP, et al. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut. 2002;50:206–211. Kornbluth A, Sachar BD. The Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guideline in adults: American College of Gastroenterology, practice parameters Committee. Am J Gastroenterol. 2010;105:501–523. Jiang XL. The clinical observation of infliximab treatment for steroid-refractory ulcerative colitis. Chinese J Dig. 2010; 30:564–565. Kornbluth A, Marion JF, Salomon P, et al. How effective is current medical therapy for severe ulcerative and Crohn’s colitis? An analytic review of selected trials. J Clin Gastroenterol. 1995;20:280–284. Stein RB, Hanauer SB. Comparative tolerability of treatments for inflammatory bowel disease. Drug Saf. 2000;23:429–448. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–1549. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–885. Hoentjen F, Bodegraven AA. Safety of anti-tumor necrosis factor therapy in inflammatory bowel disease. World J Gastroenterol. 2009;15:2067–2073. Raval A, Akhaval-Toyserkani G, Brinker A, et al. Brief communication characteristics of spontaneous cases of tuberculosis associated with infliximab. Ann Intern Med. 2007;147:699–702. Mor IJ, Vogel JD, da Luz Moreira A, et al. Infliximab in ulcerative colitis is associated with an increased risk of postoperative complications after restorative proctocolectomy. Dis Colon Rectum. 2008;51:1202–1207.
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Low-dose Infliximab for Induction and Maintenance Treatment in Chinese Patients With Moderate to Severe Active Ulcerative Colitis Xue-Liang Jiang, MD,* Hui-Fei Cui, MD,w Jing Gao, MS,* and Hua Fan, MD*
Goal: To evaluate the efficacy of low-dose (3.5 mg/kg) infliximab for induction and maintenance treatment in Chinese patients with ulcerative colitis. Background: Treatment with 4 to 5 mg/kg of infliximab also proved to be effective in treating moderate to severe ulcerative colitis. At present there is no relevant study on the effectiveness of infliximab doses lower than 4 mg/kg in patients with ulcerative colitis. Study: A prospective, randomized, double-blind, placebo-controlled, and single-centered study was designed. A total of 123 patients (from 17 provinces of China) with moderate to severe active ulcerative colitis despite treatment with concurrent drugs received placebo or low-dose (3.5 mg/kg) or standard-dose (5 mg/ kg) infliximab intravenously at weeks 0, 2, and 6 and then every 8 weeks through week 22. Patients were followed up for 30 weeks. Results: Overall, 73% and 78% of patients who received low-dose (3.5 mg/kg) and standard-dose (5 mg/kg) infliximab, respectively, had clinical responses at week 8, as compared with 37% of patients who received placebo (P < 0.01 for both comparisons with placebo). The number of patients who received low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab with a clinical response at week 30 (63% and 66%, respectively) was more than the patients who received placebo (27%, P < 0.01 for both comparisons). Conclusions: Chinese patients with moderate to severe active ulcerative colitis treated with low-dose (3.5 mg/kg) or standarddose (5 mg/kg) infliximab at weeks 0, 2, and 6 and every 8 weeks thereafter were more likely to have a clinical response at weeks 8 and 30 than those who received placebo.
with steroid-refractory ulcerative colitis.2 Immunosuppressants or surgery is used to treat such patients. However, immunosuppressants have more adverse effects such as bone marrow suppression and liver dysfunction. Surgery will result in lower quality of life in patients. Accordingly, new treatments for ulcerative colitis are needed.3 Infliximab has opened a new path for the treatment of moderate to severe active ulcerative colitis for nearly 10 years. It is reported that treatment with infliximab can alleviate symptoms and signs, induce and maintain clinical remission, accelerate mucosal healing, and discontinue glucocorticoid in patients with moderate to severe ulcerative colitis without satisfactory response to traditional treatment.4,5 No significant statistical differences were observed between the clinical therapeutic efficacy of high-dose (10 mg/kg) and standard-dose (5 mg/kg) infliximab treatment for active ulcerative colitis.3 Infliximab doses at 4 to 5 mg/kg also proved effective in the treatment of medium to severe ulcerative colitis.6 No research has at present been conducted on the efficacy of infliximab doses lower than 4 mg/kg in the treatment of patients with ulcerative colitis. Currently, studies on efficacy, safety, or dosage of infliximab are lacking in China. Therefore, based on the studies conducted in other countries, a 30-week study on low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab in Chinese patients with moderate to severe ulcerative colitis was performed.
Key Words: ulcerative colitis, infliximab, low dose
PATIENTS AND METHODS
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Patients
U
lcerative colitis is a chronic nonspecific inflammatory bowel disease characterized by intestinal mucosal ulcer, rectal bleeding, diarrhea, and abdominal pain. The incidence of ulcerative colitis has gradually increased1 in recent decade in China. The main traditional therapeutic drugs for this disease are amino salicylic acid, glucocorticoid, and immunosuppressants (including purine metabolites and cyclosporin). The effect is unsatisfactory for the patients
Received for publication July 24, 2014; accepted February 23, 2015. From the *Department of Gastroenterology, Chinese PLA General Hospital of Jinan Military Command; and wCollege of Pharmaceutical Science, Shandong University, Jinan, Shandong Province, China. The authors declare that they have nothing to disclose. Reprints: Xue-Liang Jiang, MD, Department of Gastroenterology, Chinese PLA General Hospital of Jinan Military Command, 25 Shifanlu, Jinan 250031, Shandong Province, China (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
A total of 123 subjects (from 17 provinces of China) diagnosed with moderate to severe ulcerative colitis from December 2008 to December 2013 in Jinan Military General Hospital were enrolled according to the Montreal classification.7 All eligible patients had an established diagnosis of ulcerative colitis. This study was approved by the Ethics Committee of Jinan Military General Hospital, and written informed consent forms were obtained from all participants. Inclusion criteria were as follows: (1) subjects’ participation in the study was voluntary, and all subjects had to sign the informed consent form before the enrollment; (2) subjects should be aged between 18 and 65 years, irrespective of sex; (3) moderate to severe active ulcerative colitis was diagnosed using endoscopy and biopsy 1 week before treatment; (4) eligible patients had active ulcerative colitis with a Mayo score of 6 to 12 points8 and an endoscopic score of Z2 points (Table 1), despite concurrent treatment with corticosteroids only or in combination with azathioprine and drugs containing 5-aminosalicylates.
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TABLE 1. The Modified Mayo Score*
Mayo Score Stool frequencyw 0 = Normal no. stools for this patient 1 = 1-2 stools more than normal 2 = 3-4 stools more than normal 3 = 5 or more stools more than normal Subscore, 0-3 Rectal bleedingz 0 = No blood seen 1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool most of the time 3 = Blood alone passes Subscore, 0-3 Findings on endoscopy 0 = Normal or inactive disease 1 = Mild disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 3 = Severe disease (spontaneous bleeding, ulceration) Subscore, 0-3 Physician’s global assessmenty 0 = Normal 1 = Mild disease 2 = Moderate disease 3 = Severe disease *The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease. Data are from Schroeder and colleagues.9 wEach patient serves as his or her own control to establish the degree of abnormality of the stool frequency. zThe daily bleeding score represents the most severe bleeding of the day. yThe physician’s global assessment acknowledges the 3 other criteria, the patient’s daily recollection of abdominal discomfort and general sense of well-being, and other observations, such as physical findings and the patient’s performance status.
Exclusion criteria were as follows: (1) patients who had been diagnosed with Crohn’s disease (CD), or clinical findings suggestive of CD or indeterminate colitis; (2) a recent medical history of active infection, chronic infection, or repeated infection; special attention was paid to patients with positive tuberculin skin tests using purified protein derivative and standard chest radiographs (including active tuberculosis and latent tuberculosis infection), hepatitis B virus infection; (3) patients with congestive heart failure; (4) children and patients under pregnancy; (5) patients allergic to mouse proteins; (6) patients with demyelinating diseases of the nervous system; (7) patients with malignancy (both present and previous); (8) patients with severe ulcerative colitis requiring intravenous steroids; (9) patients who received corticosteroids or drugs containing 5-aminosalicylates rectally within 2 weeks before screening; (10) patients who were previously exposed to infliximab or any other anti–tumor necrosis factor (TNF); (11) patients who did not respond to corticosteroids within the preceding 18 months or who could not tolerate corticosteroids; (12) patients who did not respond to azathioprine or mercaptopurine within the preceding 5 years or who could not tolerate these drugs, and patients who did not respond to drugs containing 5-aminosalicylates within the preceding 18 months or who could not tolerate such drugs; (13) patients with cytomegalovirus colitis.
Study Design Eligible patients were randomly assigned in a 1:1:1 ratio to receive intravenous infusions of infliximab (Remicade; Copyright
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Infliximab for Induction and Maintenance Treatment
100 mg/bottle) at a low dose of 3.5 mg/kg or a standard dose of 5 mg/kg or placebo at weeks 0, 2, and 6 and then every 8 weeks through week 22. Patients were followed up through week 30. In this study, central randomization with a dynamic treatment allocation stratified was used based on the investigational site and whether patients had ulcerative colitis that was refractory to treatment with corticosteroid. Patients were considered to have ulcerative colitis that was refractory to corticosteroids if their symptoms did not improve after they received the equivalent of at least 40 mg of prednisone daily, administered orally for at least 2 weeks or intravenously for at least 1 week.2 Doses of concomitant drugs were maintained at the same level except for corticosteroids, which were tapered by 5 mg/wk after week 8 until a dose of 20 mg/d was reached. Thereafter, the dose was reduced by 2.5 mg/wk until discontinuation.
Follow-up and Safety and Efficacy Evaluations Patients were evaluated at weeks 0, 2, 6, 8, 14, 22, and 30. The Mayo score (Table 1) was determined at weeks 0, 8, and 30 for patients. A partial Mayo score (Mayo score without endoscopy) was determined at all visits. Clinical response was defined as a decrease in the total Mayo score of at least 3 points and at least 30% from the baseline values, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1.8 Clinical remission was defined as a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point. Mucosal healing was defined as an absolute subscore for endoscopy of 0 or 1.8 Clinical response, clinical remission, and mucosal healing were assessed at weeks 8 and 30. Patients who had a clinical response and who were in clinical remission at each time were considered to have a sustained clinical response and sustained clinical remission, respectively. Adverse events and concomitant drugs were recorded at each visit. Adverse events including infusion reaction, delayed hypersensitivity (serum sickness sample response), drug-induced lupus erythematosus, and infection were monitored, and the time of occurrence, severity, duration, treatment, and outcome of adverse events were recorded. Serum specimens for the identification of antibodies against infliximab and antinuclear antibodies were collected at weeks 0 and 30, as described previously.10 Samples positive for antinuclear antibodies were tested for antibodies against double-stranded DNA.
Statistical Analysis The primary end point was a clinical response at week 8. Secondary end points were clinical response or clinical remission with discontinuation of corticosteroids at week 30, clinical remission and mucosal healing at weeks 8 and 30, and clinical response at week 8 in patients with a medical history of disease refractory to corticosteroids. Patients who received prohibited drug because of lack of efficacy or loss of response to the study drug, who discontinued the study drug because of lack of efficacy, or who underwent a colectomy or ostomy were not considered to have had a clinical response, to be in clinical remission, or to have had mucosal healing from the time of the event onward, regardless of their Mayo score. In addition, patients with insufficient data for the assessment of response were not considered to have had a
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clinical response, to be in clinical remission, or to have had mucosal healing at that visit. Demographic and baseline characteristics were compared using the w2 test or the Fisher exact test for categorical variables and analysis of variance for van der Waerden normal scores for continuous variables. A 2-sided Cochran-Mantel-Haenszel w2 test, at a significance level of 0.05, stratified according to the corticosteroid-refractory status and the location of the study center, was used to compare dichotomous end points (ie, clinical response, clinical remission, mucosal healing, and clinical remission with discontinuation of corticosteroids) among the treatment groups. All efficacy analyses used intention-to-treat methods. Safety comparisons were performed using the Fisher exact test and were based on the combination of the 2 groups receiving infliximab as compared with the placebo group. Sample size: in Active Ulcerative Colitis Trial 2 (ACT2),3 64% of patients who received 5 mg/kg of infliximab and 69% of those who received 10 mg/kg had a clinical response at week 8, as compared with 29% of those who received placebo (P < 0.001 for both comparisons with placebo). Assuming a response rate of 30% in the placebo group and a 2-sided probability of 0.05, it was estimated that 40 patients would be needed in each group to give the study a statistical power of 95% to detect an improvement in the response rate to 64%.
RESULTS Characteristics of the Patients A total of 123 patients underwent randomization: 41 were assigned to receive placebo, 41 were assigned to receive 3.5 mg/kg of infliximab (low dose), and 41 were assigned to receive 5 mg/kg of infliximab (standard dose). The baseline characteristics of the patients were similar (Table 2). Treatment was discontinued prematurely by 19 (46.3%) patients in the placebo group, 8 (19.5%) patients in
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the 3.5 mg/kg infliximab group, and 7 (17.1%) patients in the 5 mg/kg infliximab group (Fig. 1). More than twice as many patients in the placebo group as in the other 2 groups prematurely discontinued the infusions (Fig. 1).
Efficacy Overall, 73.1% (30/41) of patients who received lowdose infliximab (3.5 mg/kg) and 78.1% (32/41) of those who received standard-dose infliximab (5 mg/kg) had a clinical response at week 8, as compared with 36.6% (15/41) of those who received placebo (P < 0.01 for both comparisons with placebo) (Fig. 2A, Table 3). The number of patients who received low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab with a clinical response at week 30 (63% and 66%, respectively) was more than the patients who received placebo (27%, P < 0.01 for both comparisons) (Fig. 2A, Table 3). The rates of clinical response were similar between the subpopulations of patients who were corticosteroid-refractory and those who were not corticosteroid-refractory (Table 3). The proportions of patients with a clinical remission and mucosal healing at weeks 8 and 30 in the infliximab groups were higher than those in the placebo group (P < 0.05, Figs. 2B, C). The proportions of patients with a sustained clinical response or remission were significantly higher in the infliximab groups than in the placebo group (Table 3). The partial Mayo scores provide evidence of clinical improvement as early as week 2 (Table 3). At baseline, 52.8% (65/123) of patients were receiving corticosteroids. The baseline median daily corticosteroid dose was 20 mg/d. The decreases in the median daily corticosteroid doses were greater among patients in the infliximab groups than among those in the placebo group (Table 3). Similarly, the proportions of patients who were in clinical remission and had discontinued corticosteroids at week 30 were higher in the infliximab groups than those in the placebo group.
TABLE 2. Patient Demographics and Baseline Characteristics
Characteristics Male [n (%)] Age (mean ± SD) (y) Weight (mean ± SD) (kg) Nonsmoker [n (%)] Duration of disease (y) Colonic area involved [n (%)] Left-sided colitis Pancolitis Severity [n (%)] Moderate disease Severe disease C-reactive protein (mean ± SD) (mg/L) Blood sedimentation (mean ± SD) (mm/h) Concomitant medication [n (%)] Corticosteroids Z20 mg/d 5-aminosalicylates Immunosuppressants (azathioprine) Corticosteroid-refracteory disease [n (%)]
Placebo (n = 41)
3.5 mg/kg of Infliximab (n = 41)
5 mg/kg of Infliximab (n = 41)
P
25 (60.9) 34.5 ± 14.9 61.2 ± 15.7 28 (68.3) 4.4 ± 2.6
24 (58.5) 34.1 ± 13.8 63.1 ± 13.6 29 (70.7) 4.3 ± 2.5
26 (63.4) 34.3 ± 14.3 62.8 ± 14.9 28 (68.3) 4.4 ± 2.8
0.90 0.87 0.56 0.37 0.85
17 (41.5) 24 (58.5)
15 (36.6) 26 (63.4)
16 (39.1) 25 (60.9)
0.90 0.39
16 (39.1) 25 (60.9) 35.1 ± 17.8 45.7 ± 24.8
17 (41.5) 24 (58.5) 35.7 ± 16.1 46.2 ± 26.4
15 (36.6) 26 (63.4) 35.8 ± 22.6 44.2 ± 22.3
0.91 0.39 0.91 0.47
21 14 35 13 12
(51.2) (34.1) (85.4) (31.7) (29.3)
22 15 36 12 11
(53.7) (34.6) (87.8) (29.3) (26.7)
22 14 34 12 12
(53.7) (34.1) (82.9) (29.3) (29.3)
0.97 0.82 0.82 0.96 0.96
P-values for all categorical variables are based on a 2-side w2 test, P-values for all continuous variables are based on the analysis of variance for the van der Waerden.
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FIGURE 1. Enrollment and treatment. Overall, 41 patients with moderate to severe ulcerative colitis were randomly assigned to receive placebo intravenously, 41 patients were assigned to receive low-dose infliximab (3.5 mg/kg) and 41 patients were assigned to receive standard-dose infliximab (5 mg/kg) at weeks 0, 2, 6, 14, and 22. Patients were followed for 30 weeks. The efficacy and safety populations consisted of all 123 patients who underwent randomization, all of whom received at least 1 dose of study drug.
Safety Patients were treated for a mean of 15.1 weeks in the placebo group, 22.6 weeks in the 3.5 mg infliximab group, and 22.3 weeks in the 5 mg infliximab group (Table 4). The proportions of patients with adverse events were similar in the placebo group and the 2 infliximab groups (Table 4). Serious adverse events occurred in 9.8% (4/41) of patients in the placebo group, 4.9% (2/41) of patients receiving 3.5 mg of infliximab, and 7.3% (3/41) of patients receiving 5 mg of infliximab. Two patients in the placebo group discontinued treatment because of an adverse event, whereas no patient in the 3.5 mg infliximab group and 1 patient in the 5 mg infliximab discontinued treatment because of an adverse event (Table 4). Tumors and nervous system diseases were not observed. The incidence of infections was similar among the groups in both studies (Table 4). Serious infection occurred in 1 (2.4%) patient in the 5 mg infliximab group, no serious infection occurred in the placebo group and in the 3.5 mg infliximab group. Infusion reactions occurred in 2 (4.9%) patients in the placebo group, 2 (4.9%) patients in the 3.5 mg infliximab group, and 3 (7.3%) patients in the 5 mg infliximab group. No possible delayed hypersensitivity reaction occurred and no Copyright
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patient in either group who had a positive test for antibodies had a serious infusion reaction or an anaphylactic reaction. Liver and kidney functions were normal in all patients.
Antibodies Against Infliximab Among 78 patients with serum samples available for the assessment of antibodies against infliximab, 4 (5.1%) patients had positive tests for antibodies at some point after the first infusion of infliximab (Table 4), 12 (15.4%) patients had negative tests (undetectable serum infliximab concentrations), and 62 (79.5%) patients had inconclusive tests (negative for antibodies in the presence of detectable serum infliximab concentrations). A clinical response at week 30 occurred in 2 of 4 (50.0%) patients with positive tests for antibodies, as compared with 7 of 12 (58.3%) patients with negative tests and 40 of 62 (64.5%) patients with inconclusive tests. The antinuclear antibodies developed in 2 patients in the placebo group and 5 patients in the low-dose (3.5 mg) infliximab group and 5 patients in the standard-dose (5 mg) infliximab group. The anti–double-stranded DNA antibodies were negative in placebo group, 1 patient from low-dose (3.5 mg) infliximab group and 2 patients from standard-dose (5 mg) group (Table 4). Only 1 patient who received 5 mg of infliximab had a lupus-like reaction.
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FIGURE 2. Proportion of patients with a clinical response (A), in clinical remission (B), and with mucosal healing (C) at weeks 8 and 30.
DISCUSSION Infliximab is an anti-TNF and monoclonal humanmouse chimeric immunoglobulin G1 antibody composed of human constant regions and murine variable regions and comprising 25% original murine antibodies and 75% original human antibodies. In 1997, infliximab was approved by the United States Food and Drug Administration for the treatment of CD. In 2005, it was approved for the treatment of ulcerative colitis. Infliximab is one of the biological agents with the longest duration of use and most abundant evidence-based medical information used in the treatment of inflammatory bowel disease. It is also the earliest biological agent approved in the treatment of ulcerative colitis. Infliximab possesses high-affinity binding to both transmembrane and soluble TNF-a, and can thus inhibit the binding of TNF-a to its receptor resulting in a loss of TNF activity.11 Although the mechanism played by infliximab in the treatment of ulcerative colitis remains unclear, it has been listed as a Class-A drug applicable in the treatment of moderate to severe active steroid-refractory or steroiddependent ulcerative colitis in the guidelines of the American College of Gastroenterology (ACG).12 Jiang13 was the first to report the efficacy and safety of infliximab in China, a fact
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which has already been verified in several studies conducted in other countries. The results demonstrated that the treatment with infliximab was effective rapidly. In a majority of patients, symptoms such as stool frequency were improved or remitted within 1 week. The clinical response rate was >70% and the remission rate was >50%. In terms of the dosage of infliximab, the ACG-recommended dosage for ulcerative colitis is 5 mg/kg. Documented active ulcerative colitis trials 1 and 2 (ACT-1 and ACT-2) showed that the clinical response rates of the infliximab 5 and 10 mg/kg groups were 69.4% and 61.5%, respectively, at week 8 in the ACT-1 trial,3 whereas the clinical remission rates were 38.8% and 32%, respectively. In the ACT-2 trial, the clinical response rates of the infliximab 5 and 10 mg/kg groups were 64.5% and 69.2%, respectively, whereas the clinical remission rates were 33.9% and 33%, respectively. In both trials, no significant difference (P > 0.05) was observed in the clinical response rates or the clinical remission rates between the infliximab 5 and 10 mg/kg groups at week 8. The results suggest that higher doses of infliximab do not bring about higher clinical efficacy. Jarnerot et al6 observed the rates of colon resection, mortality, endoscopic mucosal healing, and clinical remission in 24 patients who received infliximab (dosage close to 5 mg/kg) and in 21 patients in the control group in a randomized-controlled trial. The results of this trial suggest that treatment of moderate to severe active ulcerative colitis by 4 to 5 mg/kg of infliximab is both effective and safe. No studies were conducted to evaluate the efficacy of lowerdosage (< 4 mg/kg) infliximab in the treatment of ulcerative colitis. This study was the first to use 3.5 mg/kg infliximab intravenous treatment. The results of this study show that infliximab (low dose of 3.5 mg/kg and standard dose of 5 mg/kg) is effective in patients who have moderate to severe active ulcerative colitis despite the use of conventional treatment, in terms of clinical response and remission. As compared with patients who received placebo, patients who received infliximab (low dose of 3.5 mg/kg and standard dose of 5 mg/kg) were significantly more likely to have a clinical response and be in clinical remission at weeks 8 and 30. Similarly, patients who received infliximab (low dose of 3.5 mg/kg and standard dose of 5 mg/kg) were significantly more likely to have mucosal healing at weeks 8 and 30. The results of the study also compared the severity of the patients with ulcerative colitis (treated with 3.5 mg/kg infliximab) with the method aforementioned in the ACT-1 and ACT-2 groups3; yet at week 8, the clinical response rate and the endoscopic mucosal healing rate observed were similar to those observed in patients treated with 5 and 10 mg/kg infliximab in the ACT-1 and ACT-2 groups. The clinical remission rate, however, was higher in the 3.5 mg/kg group of the present study than in the 5 and 10 mg/kg groups observed in the ACT-1 and ACT-2 groups at week 8. At week 30, the clinical response rate, the clinical remission rate, and the endoscopic mucosal healing rate were similar to those of the 3.5 and 5 mg/kg groups observed in this study. Also, the clinical response rate and the endoscopic mucosal healing rate were similar between the present study and the ACT-1 and ACT-2 trials. However, the clinical remission rate observed in the 3.5 mg/kg group (the present study) was higher than those of the 5 mg/ kg groups in the ACT-1 and ACT-2 groups. It is suggested that patients with ulcerative colitis in our group might present a higher sensitivity to infliximab. Further studies
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TABLE 3. Primary and Secondary Efficacy Results
Variables
Placebo (n = 41)
Clinical response Week 8 [n (%)] 15 (36.6) P* Week 30 [n (%)] 11 (26.8) P* Refractory to corticosteroid therapy at week 4/12 (33.3) 8 [n/total (%)] P# Not refractory to corticosteroid therapy at 7/29 (24.1) week 8 [n/total (%)] P* Clinical remission Week 8 [n (%)] 9 (21.9) P* Week 30 [n (%)] 10 (24.4) P* Partial Mayo score [median (interquartile range)]w Baseline 6.0 (5.0-6.0) Week 2 5.0 (4.0-7.0) Week 6 5.0 (4.0-7.0) Week 8 5.0 (3.0-7.0) Week 30 6.0 (3.0-7.0) Mucosal healing Week 8 [n (%)] 10 (24.4) P* Week 30 [n (%)] 9 (21.9) P* Daily corticosteroid dose [median (interquartile range)] (mg) Baseline 20.0 (10.0-30.0) Week 8 20.0 (10.0-30.0) Week 30 20.0 (5.0-30.0) Clinical remission and discontinued use of corticosteroid Week 30 [n/total (%)] 1/21 (4.7) P*
3.5 mg/kg of Infliximab (n = 41)
5 mg/kg of Infliximab (n = 41)
30 (73.1) 0.001 26 (63.4) 0.001 8/11 (72.7)
32 (78.1) 0.00 27 (65.8) 0.001 9/12 (75.0)
0.1 22/30 (73.3)
0.1 23/29 (79.3)
0.00
0.00
21 (51.2) 0.006 20 (48.8) 0.022
22 (53.7) 0.003 21 (51.2) 0.012
6.0 4.0 3.0 3.0 4.0
6.0 4.0 3.0 2.0 3.0
(5.0-6.0) (3.0-5.0) (2.0-5.0) (2.0-5.0) (1.0-5.0)
23 (56.1) 0.003 21 (51.2) 0.006
(5.0-6.0) (2.0-5.0) (1.0-5.0) (1.0-4.0) (1.0-5.0)
24 (58.5) 0.002 22 (53.7) 0.003
20.0 (10.0-30.0) 20.0 (10.0-30.0) 7.5 (0.0-20.0)
20.0 (10.0-30.0) 20.0 (10.0-30.0) 5.0 (0.0-20.0)
8/21 (38.1) 0.04
9/22 (41.0) 0.03
A partial Mayo score is the Mayo score without the endoscopic subscore. *P-values for all categorical variables are based on a 2-side w2 test. #P-values are based on the Fisher exact test. wThe Mayo score ranges from 0 to 12, with higher scores indicating severer disease.
are needed to analyze whether this difference is related to the disease course and other concurrent drugs. The efficacy in the present study is similar between the 2 doses (low dose of 3.5 mg/kg and standard dose of 5 mg/kg) of infliximab. Inducing and maintaining the clinical response and the clinical remission and minimizing the use of corticosteroids are unmet goals in the treatment of patients with ulcerative colitis, particularly those who have no responses to corticosteroids, azathioprine, or mercaptopurine.14 In the present study, at baseline, 52.8% (65/123) of the patients received corticosteroids. The baseline median daily corticosteroid dose was 20 mg/d. The decreases in the median daily corticosteroid doses were greater in patients of the infliximab groups than those in the placebo group. Similarly, the proportions of patients, who were in clinical remission and who discontinued corticosteroids at week 30, were higher in the infliximab groups than in the placebo group. As treatment with corticosteroid is associated with considerable morbidity,15 this corticosteroid-sparing effect is likely to be clinically meaningful. The rate of development of antibodies against infliximab after the 3-dose induction regimen and after the maintenance dose every 8 weeks in the patients with ulcerative colitis in our studies was similar to that reported Copyright
r
for patients with CD.16,17 In contrast to previous experience,3 infusion reactions were similar in the patients who had positive tests for antibodies and those without antibodies. Most of these infusion reactions were mild. The clinical response at week 30 was similar in patients with positive or inconclusive tests for antibodies and those with negative antibody tests. However, these findings should be interpreted with caution because of the small number of patients with positive tests for antibodies. In the present study, the proportions of patients reporting any adverse event were similar among the 3 groups. Liver and kidney functions were normal in all patients. Other adverse events such as tumors and diseases of the nervous system did not occur. The rate of adverse events in this study was lower than those in the ACT-1 and ACT-2 trials.3 Besides due to strict labeling and transfusion speed control, this lower rate might be related to steroid resistance, concurrent steroid treatments, lower infliximab doses, and less frequent administration of infliximab. Others reported that adverse events of infliximab included aggravated or induced moderate congestive heart failure, malignant tumors, drug-induced lupus erythematosus, demyelinating diseases of the central nervous system, lymphoma, etc.18 The most common adverse events are
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587
J Clin Gastroenterol
Jiang et al
Volume 49, Number 7, August 2015
TABLE 4. Summary of Safety and Immunogenicity Analyses for All Patients Who Underwent Randomization
Placebo (n = 41)
Variables Mean duration of treatment (wk) Mean duration of follow-up (wk) Any adverse event [no. patients (%)] Serious adverse events [no. patients (%)] Adverse events leading to discontinuation of study drug [no. patients (%)] Adverse events leading of particular interest [no. patients (%)] Pneumonia Infections [no. patients (%)] Infections requiring antimicrobial treatment [no. patients (%)] Serious infections [no. patients (%)] Acute infusion reaction (any adverse occuringr2 h after start of infusion) [no. patients (%)] Possible delayed hypersensitivity reaction [no. patients (%)] Antibodies against infliximab [no. patients/total no (%)] Antinuclear antibodies [no. patients/total no (%) ] Anti–double-stranded DNA antibodies [no. patients/total no (%)]
3.5 mg/kg of Infliximab (n = 41)
15.1 27.6 16 (39.0) 4 (9.8) 2 (4.9)
22.6 30.0 16 (39.0) 2 (4.9) 0 (0.0)
0 5 (12.2) 2 (4.9) 0 2 (4.9)
0 5 (12.2) 2 (4.9) 0 2 (4.9)
0 — 2/30 (6.6) 0/34 (0.0)
0 2/38 (5.3) 5/31 (16.1) 1/35 (3.2)
5 mg/kg of Infliximab (n = 41) 22.3 30.0 17 (41.5) 3 (7.3) 1 (2.4) 1 6 3 1 3
(2.4) (14.6) (7.3) (2.4) (7.3)
0 2/40 (5.0) 5/30 (16.7) 2/36 (5.6)
P* ND ND 1.000 0.479 0.257
1 1 1 1 1 — 0.324 0.542
ND indicates not done; em-dash, not applicable. *P-values are based on the Fisher exact test for the comparison of the combined infliximab groups with the placebo group.
tuberculosis infection and tumors. In the United States, about 130 patients contracted lung tuberculosis during treatment with infliximab from 2001 to 2006.19 Mor et al20 reported that infliximab increased the risk of postoperative complications after colectomy. No nervous system damage, tumors or lupoid changes were observed in this study. In conclusion, Chinese patients with moderate to severe active ulcerative colitis treated with low-dose (3.5 mg/kg) or standard-dose (5 mg/kg) infliximab at weeks 0, 2, and 6 and every 8 weeks thereafter were more likely to have a clinical response at weeks 8 and 30 than those patients who received placebo.
9.
10.
11. 12.
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