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Efficacy studies

RCTs


Rutgeerts P, Sandborn WJ, Feagan BG, et al.

Infliximab for induction and maintenance therapy for ulcerative colitis. New England Journal of Medicine. Vol. 353(23)(pp 2462-2476), 2005.


Abstract:


Two randomised, double-blind, placebo-controlled studies - the Active Ulcerative Colitis Trials 1 and 2 (ACT1 and ACT2, respectively) - evaluated the efficacy of infliximab for induction and maintenance therapy in adults with UC. In each study, 364 patients with moderate-to-severe active UC despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every 8 weeks through week 46 (in ACT1) or week 22 (in ACT2). Patients were followed for 54 weeks in ACT1 and 30 weeks in ACT2. In ACT1, 69% of patients who received 5 mg of infliximab and 61% of those who received 10 mg had a clinical response at week 8, as compared with 37% 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%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. In ACT2, 64% of patients who received 5 mg of infliximab and 69% of those who received 10 mg had a clinical response at week 8, as compared with 29% of those who received placebo (P<0.001 for 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 ACT1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45% and 44%, respectively) than did those who received placebo (20%, P<0.001 for both comparisons). The authoprs concluded that patients with moderate-to-severe active UC treated with infliximab at weeks 0, 2, and 6 and every 8 weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo.
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. Vol. 128(7)(pp 1805-1811), 2005.


Abstract:


This was a randomised double-blind trial of infliximab or placebo in severe to moderately severe UC not responding to conventional treatment. Patients were randomised to infliximab/placebo either on day 4 after the initiation of corticosteroid treatment if they fulfilled the index criteria for fulminant UC on day 3 or on day 6-8 if they fulfilled index criteria on day 5-7 for a severe or moderately severe acute attack of UC. Results were analysed according to the intention-to-treat principle. The primary end point was colectomy or death 3 months after randomisation. Secondary end points were clinical and endoscopic remission at that time in patients who did not undergo operation. Results: Forty-five patients were included (24 infliximab and 21 placebo). No patient died. Seven patients in the infliximab group and 14 in the placebo group had a colectomy (P =. 017; OR, 4.9; 95% confidence interval, 1.4-17) within 3 months after randomisation. No serious side effects occurred. Three patients in the placebo group required operation for septic complications. Conclusions: Infliximab 4-5 mg/kg is an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of UC not responding to conventional treatment.
Armuzzi A, De Pascalis B, Lupascu A, et al.

Infliximab in the treatment of steroid-dependent ulcerative colitis. European Review for Medical & Pharmacological Sciences. Vol. 8(5)(pp 231-233), 2004.


Abstract:


The authors evaluated the efficacy of infliximab in the management of steroid-dependent UC. They report preliminary data from a randomised, open-label, methylprednisolone-controlled trial of infliximab in the induction and maintenance of remission of patients with moderate-to-severe steroid-dependent UC. Twenty patients received either 3 infusion of infliximab (5 mg/kg) at 0, 2 and 6 weeks and thereafter every 8 weeks (group A) or methylprednisolone (0,7-1 mg/kg) daily for 1 week followed by a tapering regimen up to the minimal dose to maintain a symptom-free condition (group B). Clinical remission was defined as a DAI score less than 3. Results: Ten patients in group A (DAI: 8.9 +/- 1.4) achieved remission after the first infusion (DAI: 1.6 +/- 0,7; p = 0.005) and steroids were progressively discontinued. At present (mean follow-up: 9.8 +/- 1.1 months), 9 out of 10 patients maintain clinical remission, while one patient relapsed at 3 months. Ten patients in group B (DAI: 8.7 +/- 1.4) reached clinical remission at 1 week (DAI: 1.9 +/- 0.3; p = 0.005). Eight out of 10 patients were maintained at a minimal steroid dosage without any relapse at 9.7 +/- 1.0 months follow-up. Two patients relapsed at 6 and 8 months, respectively. Conclusions: Infliximab seems to be as effective as steroids in the management of moderate-to-severe steroid-dependent UC. These preliminary data suggest the potential efficacy of repeated treatment with infliximab for short-term maintenance of remission and steroid withdrawal in glucocorticoid-dependent UC.
Ochsenkuhn T, Sackmann M, Goke B.

Infliximab for acute, not steroid-refractory ulcerative colitis: A randomized pilot study. European Journal of Gastroenterology & Hepatology. Vol. 16(11)(pp 1167-1171), 2004.


Abstract:


Infliximab, has shown to be effective in the treatment of steroid-refractory UC in pilot studies. The authors therefore evaluated whether infliximab can achieve remission in patients with acute ulcerative pancolitis who were not steroid-refractory. Methods and design: Patients were eligible if they had acute disease with a modified Truelove and Witts activity score of more than 10 for at least 2 weeks and if they were currently not receiving immunomodulators or more than 10 mg/day prednisolone. Patients were randomly assigned to receive either 3 intravenous infusions of infliximab at 5 mg/kg (group A) or high-dose prednisolone (1.5 mg/ kg body weight) daily for 2 weeks, followed by 1 mg/kg for 1 week, followed by a weekly reduction of 5 mg (group B). Therapy success was defined as clinical response in terms of a decrease of more than 5 points from the baseline score and to less than 10 points total after 3 weeks as well as after 13 weeks. Results: Thirteen patients (7 women, 6 men) were randomised (6 for group A and 7 for group B). The median baseline activity scores were 13.5 (12-18) in group A and 14.0 (11-18) in group B. Five of 6 patients in group A and 6 of 7 patients in group B showed therapy success after 3 weeks as well as after 13 weeks. Conclusions Infliximab could be effective in the treatment of acute moderate or severe UC. The obtained data call for larger controlled trials.
Probert CSJ, Hearing SD, Schreiber S, et al.

Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: A randomised controlled trial. Gut. Vol. 52(7)(pp 998-1002), 2003.


Abstract:


The authors conducted a randomised placebo controlled trial of infliximab (5 mg/kg) in the treatment of glucocorticoid resistant UC. Infusions were given at weeks 0 and 2. Disease activity and quality of life were recorded over 8 weeks of follow up. Remission was defined as an UC symptom score (UCSS) of ≤2 and/or Baron score of 0 at week 6. Patients not in remission were offered open label infliximab 10 mg/kg and reviewed 2 weeks later. Results: After 2 weeks, there was no statistically significant difference between the infliximab and placebo groups in the proportion of patients with a Baron score of 0 (13% (3/23) v 5% (1/19) (95% confidence interval (CI) -9% to 24%); p=0.74). After 6 weeks, remission (UCSS ≤2) rates were 39% (9/23) versus 30% (6/20) (95% CI -19 to 34%; p=0.76). The median improvement in UCSS was 3 for the infliximab group and 2.5 for the placebo group (p=0.82, Mann-Whitney U test). A Baron score of 0 was likely in either group (26% (6/23) v 30% (6/20) (95% CI -30% to 23%); p=0.96). Improvement in the IBDQ and EuroQol was not significantly different between the groups (p=0.22 and 0.3, respectively, Mann-Whitney U test). Twenty eligible patients were given open labelled infusions. Remission was achieved in 3/11 (27%) patients initially treated with infliximab and in 1/9 (11%) patients treated with placebo. Conclusion: These data do not support the use of infliximab in the management of moderately active glucocorticoid resistant UC.
Sands BE, Tremaine WJ, Sandborn WJ, et al.

Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: A pilot study. Inflammatory Bowel Diseases. Vol. 7(2)(pp 83-88), 2001.


Abstract:


The authors report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory UC. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory UC.

Non-randomised studies


Jakobovits SL, Jewell DP, Travis SPL.

Infliximab for the treatment of ulcerative colitis: Outcomes in Oxford from 2000 to 2006. Alimentary Pharmacology & Therapeutics. Vol. 25(9)(pp 1055-1060), 2007.


Abstract:


Aims: To review the rate of colectomy after infliximab for UC and to identify factors that might predict the need for colectomy. Methods: The authors conducted a retrospective cohort study of patients with active UC treated with infliximab between 2000 and 2006. The primary outcome was colectomy-free survival. Disease and treatment characteristics and complications were documented. Results: Thirty patients were treated with infliximab for refractory UC. Sixteen (53%) came to colectomy a median of 140 days after their first infusion (range 4-607). There was no difference in colectomy between those receiving infliximab for acute severe UC failing intravenous steroids (8/14) and out-patients with steroid-refractory UC (8/16). Only 17% (5/30) achieved a steroid-free remission after a median follow-up of 13 months (range 2-72). Univariate analysis showed that a younger age at diagnosis of colitis was significantly associated with an increased rate of colectomy (27.5 years vs. 38.7 years, P = 0.016). Conclusion: Over half the patients studied came to colectomy. Of those avoiding colectomy, only 5 (17%) sustained a steroid-free remission.
Rossetti S, Actis GC, Fadda M, et al.

The use of the anti-tumour necrosis factor monoclonal antibody-infliximab-to treat ulcerative colitis: Implications and trends beyond the available data. Digestive & Liver Disease. Vol. 36(6)(pp 426-431), 2004.


Abstract:


Infliximab has recently been added to the list of off-label therapeutic means for UC. The authors conducted a descriptive analysis of the results from studies on the use of the drug published so far. A total of 187 patients qualified for analysis. They were divided into 4 main categories, including steroid-refractory and responsive adults and children. The median frequencies of an early and a sustained response were 77 and 44.5%. These data suggest that adult non-steroid-refractory, and paediatric patients may respond with the highest frequency. While it is obligatory to wait for the yield of the ongoing controlled trials before any conclusion on these indications is drawn, the data provide seminal ideas to further investigations, including the hypothesis to inaugurate with infliximab a top-down strategy for the treatment of IBD.
Kohn A, Prantera C, Pera A, et al.

Infliximab in the treatment of severe ulcerative colitis: A follow-up study. European Review for Medical & Pharmacological Sciences. Vol. 8(5)(pp 235-237), 2004.


Abstract:


Thirteen patients with severe UC, refractory to therapy with methyl-prednisolone, 60 mg IV daily were treated with a single intravenous infusion of Infliximab 5 mg/kg. Ten out of 13 patients (77%) had a clinical response to therapy defined by a CAI ≤ 10 on 2 consecutive days. Two patients (15%) underwent total colectomy because of clinical worsening; one patient refused surgery and was lost to follow-up. Infusion with Infliximab produced no significant adverse events. The mean time of follow-up was 25.6 months (range 17-24); in this period of time 8 out of 10 patients (80%) maintained clinical remission and were able to discontinue corticosteroids therapy. Infliximab appears to be an effective agent for inducing long standing remission in refractory patients with severe UC.
Gornet J-M, Couve S, Hassani Z, et al.

Infliximab for refractory ulcerative colitis or indeterminate colitis: An open-label multicentre study. Alimentary Pharmacology & Therapeutics. Vol. 18(2)(pp 175-181), 2003.


Abstract:


The records of 30 patients treated with infliximab for UC (n = 19) or indeterminate colitis (n = 11) were reviewed. Infliximab was given because of steroid resistance (n = 18), dependence (n = 5) or intolerance (n = 7); 5 patients had failed on cyclosporin; 19 patients had a severe flare-up. Results: Median duration of follow-up was 10 months. In 28 patients with active disease, the response rate was 75% at day 7, with 43% having a complete remission, and 50% at month 1, with 32% having a complete remission. Among the 22 responders, the probability of relapse was 73% at month 6. The probability of complete remission without steroids, taking into account the re-treatment for relapse (n = 11), was 57% (95% confidence interval (CI): 45% to 69%) at month 6. The probability of colectomy was 33% (95% CI: 23% to 43%) at month 12. In indeterminate colitis, response rate was only 50% at day 7 and 30% at month 1. Concomitant use of antimetabolite agents was associated with better results. Conclusions: Infliximab was able to induce a rapid response in some patients with UC or indeterminate colitis refractory to conventional treatment. Long-term results were less favourable, with frequent relapses, and about one-third of the patients required a colectomy.
Kohn A, Prantera C, Pera A, et al.

Anti-tumour necrosis factor alpha (Infliximab) in the treatment of severe ulcerative colitis: Result of an open study on 13 patients. Digestive & Liver Disease. Vol. 34(9)(pp 626-630), 2002.


Abstract:


A series of 13 patients with severe UC, refractory to therapy with methyl-prednisolone, 60 mg daily for 7 or more days, were treated with a single intravenous infusion of Infliximab 5 mg/kg. There were 10 patients (77%) who had a clinical response to therapy defined by a clinical activity index ≤ 10 on 2 consecutive days. In 2 patients (15%) total colectomy was necessary on account of clinical worsening whilst one patient refused surgery and was lost to follow-up. All patients who responded showed very rapid clinical improvement, within 2 to 3 days of infusion. Infusion with Infliximab produced no significant adverse events. The mean time of follow-up was 10.1 months (range 5-12); during this time, 9 out of 10 patients (90%) maintained clinical remission and were able to discontinue corticosteroid therapy. Infliximab appears to be an effective agent for inducing long-standing remission in refractory patients with severe UC.

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