Reliability and Responsiveness of Clinical and Endoscopic Outcome Measures in Crohn's Disease.

BACKGROUND: Regulatory guidance for Crohn's disease trials recommends coprimary efficacy end points that evaluate both symptoms and mucosal inflammation. We aimed to characterize the operating properties of commonly used disease activity assessments alone and in combination. METHODS: Endoscopic and clinical data were available for 129 participants from the Study of Biologic and Immunomodulator Naïve Patients in Crohn's Disease trial. Readers scored the Simple Endoscopic Score for Crohn's Disease and the Crohn's Disease Endoscopic Index of Severity using standardized conventions. Index reliability was determined using intraclass correlation coefficients. Index responsiveness was assessed using standardized effect sizes based upon treatment assignment. Outcomes were evaluated for optimal sensitivity to treatment effect. RESULTS: Substantial inter-rater reliability was observed when the Simple Endoscopic Score for Crohn's Disease and Crohn's Disease Endoscopic Index of Severity were used as continuous measures (intraclass correlation coefficient, 0.64; 95% confidence interval [CI], 0.50-0.73; and 0.62 95% CI, 0.36-0.77) compared with moderate reliability when dichotomized (0.46; 95% CI, 0.26-0.65; and 0.51; 95% CI, 0.00-0.78). The Simple Endoscopic Score for Crohn's Disease, Crohn's Disease Endoscopic Index of Severity, patient-reported outcome-2, and Crohn's Disease Activity Index were similarly responsive (standardized effect size, 0.43, 95% CI, 0.05-0.81; 0.38, 95% CI, 0.0-0.76; 0.53, 95% CI, 0.15-0.91). A composite outcome of Crohn's Disease Activity Index score <150 and Crohn's Disease Endoscopic Index of Severity score <6 was most sensitive to treatment effect (28.9%; 95% CI, 11.0%-46.8%; P = .003). CONCLUSION: Endoscopic indices were more reliable as continuous measures. Composite outcomes including endoscopy improved sensitivity to treatment effect.

This study largely supports current regulatory guidance for Crohn's disease trials recommending coprimary efficacy end points evaluating both symptoms and mucosal inflammation. Continuous endoscopic measures are most reliable and improve sensitivity to treatment effect when employed in composite outcomes.

Standardizing Scoring Conventions for Crohn's Disease Endoscopy: An International RAND/UCLA Appropriateness Study.

BACKGROUND AND AIMS: Endoscopic assessment of disease activity is integral for evaluating treatment response in patients with Crohn's disease (CD). We aimed to define appropriate items for evaluating endoscopic activity and conventions for consistent endoscopic scoring rules in CD. METHODS: A 2-round modified RAND/University of California at Los Angeles Appropriateness Method study was conducted. A panel of 15 gastroenterologists used a 9-point Likert scale to rate the appropriateness of statements pertaining to the Simple Endoscopic Score for CD, Crohn's Disease Endoscopic Index of Severity, and additional items relevant to endoscopy scoring in CD. Each statement was voted as appropriate, uncertain, or inappropriate based on the median panel rating and presence of disagreement. RESULTS: Panelists voted that it is appropriate for all ulcers to contribute to endoscopic scoring in CD, including aphthous ulcers, ulcerations at a surgical anastomosis, and anal canal ulcers (scored in the rectum). Endoscopic healing should reflect an absence of ulcers. Narrowing should be defined as a clear decrease in luminal diameter; stenosis should be defined by an impassable narrowing, and if occurring at the junction of 2 segments, scored in the distal segment. Scarring and inflammatory polyps were considered inappropriate for including in the affected area score. The optimal method for defining ulcer depth remains uncertain. CONCLUSIONS: We outlined scoring conventions for the Simple Endoscopic Score for CD and Crohn's Disease Endoscopic Index of Severity, noting that both scores have limitations. Therefore, we identified priorities for future research and steps for developing and validating a more representative endoscopic index in CD.

Existing Bowel Preparation Quality Scales Are Reliable in the Setting of Centralized Endoscopy Reading.

BACKGROUND: Development of bowel preparation products has been based upon colon cleansing rating by a local endoscopist. It is unclear how bowel preparation scales perform when centrally evaluated. AIMS: To evaluate the reliability of bowel preparation quality scales when assessed by central readers. METHODS: Four central readers evaluated 52 videos in triplicate, 2 weeks apart, during the entire endoscopic procedure (insertion/withdrawal of the colonoscope) and exclusively on colonoscope withdrawal using the Boston Bowel Preparation Scale (BBPS), Chicago Bowel Preparation scale, Harefield Cleansing Scale, Ottawa Bowel Preparation Quality Scale (OBPQS), Aronchick score, a visual analogue scale, and additional items proposed in a modified Research and Development/University of California Los Angeles appropriateness process. Reliability was assessed with intraclass correlation coefficients. RESULTS: Intraclass correlation coefficients (95% confidence interval) for inter-rater reliability of the quality scales ranged from 0.51 to 0.65 (consistent with moderate to substantial inter-rater reliability) during the entire procedure. Corresponding intraclass correlation coefficients for intra-rater reliability ranged from 0.69 to 0.77 (consistent with substantial intra-rater reliability). Reliability was highest in the right colon and lowest in the left colon. No differences were observed in reliability when assessed for the procedure overall (insertion/withdrawal) relative to assessment on withdrawal alone. CONCLUSION: All five bowel preparation quality scales had moderate to substantial inter-rater reliability. Panelists considered the Aronchick score too simplistic for clinical trials and recognized that assessment of residual fluid in the Ottawa Bowel Preparation Quality Scale was not amenable to central assessment.

Evaluating the optimum number of biopsies to assess histological inflammation in ulcerative colitis: a retrospective cohort study.

BACKGROUND: The optimal ulcerative colitis biopsy protocol is unclear. AIM: To evaluate the number of biopsies required to accurately assess microscopic disease activity in ulcerative colitis METHODS: Biopsies from patients with ≥4 rectosigmoid samples, and clinical and endoscopic data, were retrospectively obtained from a prospective biobank. Histology and endoscopic videos were read blindly. A 4-biopsy Robarts Histopathology Index (RHI) reference score, consisting of the worst item-level ratings from four biopsies, was compared to 1-, 2- and 3-biopsy estimates. Agreement was determined using bivariate errors-in-variable regression analysis (acceptance interval: ±8.25). Endoscopic activity and disease location subgroup analyses were also performed. RESULTS: Forty-six patients had ≥4 rectosigmoid biopsies available (N = 287). The 2-biopsy (tolerance interval: -7.66, 4.79) and 3-biopsy (tolerance interval: -4.86, 3.46) RHI scores demonstrated acceptable agreement with 4-biopsy scores. One-biopsy scores demonstrated unacceptable agreement (tolerance interval: -13.99, 7.78). Mean RHI scores using the 2-, 3- and 4-biopsy approaches were similar (6.1 ± 9.6 P = 0.36; 6.8 ± 10.5, P = 0.7; 7.5 ± 11.2), whereas the 1-biopsy estimate was lower (4.4 ± 8.1, P = 0.06). Histological remission rates were identical for the 2-, 3- and 4-biopsy methods (65.2%, P = 1.0). Subgroup analysis demonstrated that three biopsies were required in patients with endoscopically active disease. Sampling additional colonic locations yielded lower histological remission rates compared to rectosigmoid sampling alone (33.3% vs 61.9%, P = 0.1). CONCLUSIONS: A minimum of two - conservatively, three - biopsies are required to reliably assess disease activity in a single colonic segment using the RHI. Further studies are needed of endoscopically active patients and sampling locations. These results have implications for biopsy strategies in clinical trials and practice.

Responsiveness of Endoscopic Indices of Disease Activity for Crohn's Disease.

OBJECTIVES: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however neither instrument is fully validated. We evaluated the responsiveness to change of the SES-CD and CDEIS using data from a trial of adalimumab, a drug therapy of known efficacy. METHODS: Paired video recordings (N=112) of colonoscopies (baseline and week 8-12) obtained from patients with CD who participated in a trial of adalimumab therapy were reviewed in random order, in duplicate, by four central readers (56 pairs of videos by 2 groups of readers). Responsiveness of the SES-CD and the CDEIS was evaluated by comparing correlations between the observed and pre-specified predictions of change scores for these endoscopic indices with a global endoscopic evaluation of severity (GELS), a patient reported outcome (PRO2), and the Crohn's disease activity index (CDAI), and by calculation of the standardized effect size, and Guyatt's Responsiveness statistic (GRS) using 2 definitions of change; (1) treatment assignment and (2) an absolute change in total PRO2 of 50. The potential application of effect size estimates was demonstrated by calculating hypothetical sample sizes for comparing two independent groups. The impact of removing stenosis as an index item and adjusting for the number of segments observed was also assessed. RESULTS: Changes in both endoscopic instruments and the GELS were highly correlated. The SES-CD displayed numerically higher effect sizes for both definitions of change. The standardized effect size and GRS estimates (95% confidence interval) for the SES-CD based on treatment assignment were 0.84 (0.53, 1.15) and 0.79 (0.48, 1.09). Corresponding values for the CDEIS were 0.72 (0.42, 1.02) and 0.75 (0.45, 1.06). The standardized effect size and GRS estimates for the SES-CD based on an absolute change in total PRO2 of 50 points or greater were 0.76 (0.49, 1.02) and 0.93 (0.64, 1.21). Corresponding values for CDEIS were 0.70 (0.44, 0.97), 0.83 (0.55, 1.10). Removal of stenosis as an index item and adjusting for observed segments did not improve responsiveness estimates. CONCLUSIONS: Although both the SES-CD and CDEIS are valid measures of endoscopic disease activity that are moderately responsive to changes in endoscopic disease activity, the SES-CD displayed numerically greater responsiveness in this data set.

Effect of Standardised Scoring Conventions on Inter-rater Reliability in the Endoscopic Evaluation of Crohn's Disease.

BACKGROUND AND AIMS: The Crohn's Disease Endoscopic Index of Severity [CDEIS] and Simplified Endoscopic Score for Crohn's Disease [SES-CD] demonstrate consistent overall intra- and inter-rater reliability. However, the reliability of some index items is relatively poor. We evaluated scoring conventions to improve the reliability of these items. METHODS: Five gastroenterologists with no previous experience scoring the CDEIS or SES-CD were trained on their use. A total of 65 video recordings of colonoscopies were scored blindly by each gastroenterologist before and after additional training on index scoring conventions. Intra-class correlation coefficients [ICCs] assessed the effect of application of these conventions on the reliability of the CDEIS, SES-CD, and a Global Evaluation of Lesion Severity [GELS] score. RESULTS: Following training on scoring conventions, inter-rater ICCs (95% confidence interval [CI]) for the total SES-CD score increased from 0.78 [0.71, 0.85] to 0.85 [0.79, 0.89]. The ICCs for the total CDEIS and GELS scores were not affected: corresponding inter-rater ICCs were 0.74 [0.65, 0.81] and 0.49, [0.38, 0.61] before and 0.73 [0.65, 0.81] and 0.53 [0.42, 0.64] following application of scoring conventions. Estimations of ulcer depth, surface area, anatomical location, and stenosis were important sources of variability. CONCLUSIONS: Use of scoring conventions previously developed by expert central readers enhanced the reliability of the SES-CD but did not similarly affect the CDEIS or GELS. As the SES-CD is more likely to be reliable than the CDEIS and can be optimised with targeted training, it is the preferred instrument for use in clinical trials.

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.

BACKGROUND: Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial. OBJECTIVES: To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis. SEARCH METHODS: The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included. SELECTION CRITERIA: Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes. MAIN RESULTS: Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported. AUTHORS' CONCLUSIONS: Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).

Methotrexate for maintenance of remission in Crohn's disease.

BACKGROUND: Safe and effective long-term treatments that reduce the need for corticosteroids are needed for Crohn's disease. Although purine antimetabolites are moderately effective for maintenance of remission patients often relapse despite treatment with these agents. Methotrexate may provide a safe and effective alternative to more expensive maintenance treatment with TNF-α antagonists. This review is an update of a previously published Cochrane review. OBJECTIVES: To conduct a systematic review of randomized trials examining the efficacy and safety of methotrexate for maintenance of remission in Crohn's disease. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED, EMBASE, and the Cochrane IBD/FBD Group Specialized Trials Register were searched from inception to June 9, 2014. Study references and review papers were also searched for additional trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared methotrexate to placebo or any other active intervention for maintenance of remission in Crohn's disease were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome measure was the proportion of patients maintaining clinical remission as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). We calculated the pooled risk ratio (RR) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria. MAIN RESULTS: Five studies (n = 333 patients) were included in the review. Three studies were judged to be at low risk of bias. Two studies were judged to be at high risk of bias due to blinding. Intramuscular methotrexate was superior to placebo for maintenance of remission at 40 weeks follow-up. Sixty-five per cent of patients in the intramuscular methotrexate group maintained remission compared to 39% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 76 patients).The number needed to treat to prevent one relapse was four. A GRADE analysis indicated that the overall quality of evidence supporting this outcome was moderate due to sparse data (40 events). There was no statistically significant difference in maintenance of remission at 36 weeks follow-up between oral methotrexate (12.5 mg/week) and placebo. Ninety per cent of patients in the oral methotrexate group maintained remission compared to 67% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 22 patients). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to very sparse data (17 events). A pooled analysis of two small studies (n = 50) showed no statistically significant difference in continued remission between oral methotrexate (12.5 mg to 15 mg/week) and 6-mercaptopurine (1 mg/kg/day) for maintenance of remission. Seventy-seven per cent of methotrexate patients maintained remission compared to 57% of 6-mercaptopurine patients (RR 1.36, 95% CI 0.92 to 2.00). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was very low due to high risk of bias in one study (no blinding) and very sparse data (33 events). One small (13 patients) poor quality study found no difference in continued remission between methotrexate and 5-aminosalicylic acid (RR 2.62, 95% CI 0.23 to 29.79). A pooled analysis of two studies (n = 145) including one high quality trial (n = 126) found no statistically significant difference in maintenance of remission at 36 to 48 weeks between combination therapy (methotrexate and infliximab) and infliximab monotherapy. Fifty-four percent of patients in the combination therapy group maintained remission compared to 53% of monotherapy patients (RR 1.02, 95% CI 0.76 to 1.38, P = 0.95). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to high risk of bias in one study (no blinding) and sparse data (78 events). Adverse events were generally mild in nature and resolved upon discontinuation or with folic acid supplementation. Common adverse events included nausea and vomiting, symptoms of a cold, abdominal pain, headache, joint pain or arthralgia, and fatigue. AUTHORS' CONCLUSIONS: Moderate quality evidence indicates that intramuscular methotrexate at a dose of 15 mg/week is superior to placebo for maintenance of remission in Crohn's disease. Intramuscular methotrexate appears to be safe. Low dose oral methotrexate (12.5 to 15 mg/week) does not appear to be effective for maintenance of remission in Crohn's disease. Combination therapy (methotrexate and infliximab) does not appear to be any more effective for maintenance of remission than infliximab monotherapy. The results for efficacy outcomes between methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Large-scale studies of methotrexate given orally at higher doses for maintenance of remission in Crohn's disease may provide stronger evidence for the use of methotrexate in this manner.

Methotrexate for induction of remission in ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Corticosteroids and 5-aminosalicylates are the most commonly used therapies. However, many patients require immunosuppressive therapy for steroid-refractory and steroid-dependent disease. Methotrexate is a medication that is effective for treating a variety of inflammatory diseases, including Crohn's disease. This review was performed to determine the effectiveness of methotrexate treatment in UC patients. This review is an update of a previously published Cochrane review. OBJECTIVES: To assess the efficacy and safety of methotrexate for induction of remission in patients with UC. SEARCH METHODS: MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register were searched from from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. SELECTION CRITERIA: Randomized controlled trials comparing methotrexate with placebo or an active comparator in patients with active ulcerative colitis were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome measure was the proportion of patients who achieved clinical remission and withdrawal from steroids as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). We calculated the risk ratio (RR) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria. MAIN RESULTS: Two studies (n = 101 patients) were included in the review. One study (n = 67) compared oral methotrexate 12.5 mg/week) to placebo. The other study (n = 34) compared oral methotrexate (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) and 5-aminosalicylic acid (3 g/day). The placebo-controlled study was judged to be at low risk of bias. The other study was judged to be at high risk of bias due to an open-label design. There was no statistically significant difference in clinical remission rates between methotrexate and placebo patients. Forty-seven per cent (14/30) of methotrexate patients achieved clinical remission and complete withdrawal from steroids during the study period compared to 49% (18/37) of placebo patients (RR 0.96, 95% CI 0.58 to 1.59. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). There were no statistically significant differences in the proportion of patients who achieved clinical remission and withdrawal from steroids in the study comparing oral methotrexate to 6-mercaptopurine and 5-aminosalicylic acid. At 30 weeks, 58% (7/12) of methotrexate patients achieved clinical remission and withdrawal from steroids compared to 79% (11/14) of 6-mercaptopurine patients (RR 0.74, 95% CI 0.43 to 1.29) and 25% of 5-aminosalicylic acid patients (RR 2.33, 95% CI 0.64 to 8.49). GRADE analyses indicated that the overall quality of the evidence was very low due to very sparse data (18 and 9 events respectively) and and high risk of bias. In the placebo-controlled trial two patients (7%) were withdrawn from the methotrexate group due to adverse events (leucopenia, migraine) compared to one patient (3%) who had a rash in the placebo group (RR 2.47, 95% CI 0.23 to 25.91). Adverse events experienced by methotrexate patients in the active comparator study included nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia. AUTHORS' CONCLUSIONS: Although methotrexate was well-tolerated, the studies showed no benefit for methotrexate over placebo or active comparators. The results for efficacy outcomes between methotrexate and placebo, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration would be effective for induction therapy is unknown. At present there is no evidence supporting the use of methotrexate for induction of remission in active ulcerative colitis. A trial in which larger numbers of patients receive a higher dose of oral methotrexate should be considered. Currently there are two large ongoing placebo-controlled trials (METEOR and MERIT-UC) assessing the efficacy and safety of intramuscular or subcutaneous methotrexate in patients with active UC which may help resolve the evidence supporting the use of methotrexate as therapy for active of ulcerative colitis.

Methotrexate for induction of remission in refractory Crohn's disease.

BACKGROUND: Although corticosteroids are effective for induction of remission of Crohn's disease, many patients relapse when steroids are withdrawn or become steroid dependent. Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine or 6-mercaptopurine therapy. This systematic review is an update of previously published Cochrane reviews. OBJECTIVES: The primary objective was to assess the efficacy and safety of methotrexate for induction of remission in patients with active Crohn's disease in the presence or absence of concomitant steroid therapy. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized register from inception to June 9, 2014 for relevant studies. Conference proceedings and reference lists were also searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials of methotrexate compared to placebo or an active comparator for treatment of active refractory Crohn's disease in adult patients (> 17 years) were considered for inclusion. DATA COLLECTION AND ANALYSIS: The primary outcome was failure to enter remission and withdraw from steroids. Secondary outcomes included adverse events, withdrawal due to adverse events, serious adverse events and quality of life. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis. The Cochrane risk of bias tool was used to assess the methodological quality of included studies. The GRADE approach was used to assess the overall quality of evidence supporting the primary outcome. MAIN RESULTS: Seven studies (495 patients) were included. Four studies were rated as low risk of bias. Three studies were rated as high risk of bias due to open label or single-blind designs. The seven studies differed with respect to participants, intervention, and outcomes to the extent that meta-analysis was considered to be inappropriate. GRADE analyses indicated that the quality of evidence was very low to low for most outcomes due to sparse data and inadequate blinding. Three small studies which employed low dose oral methotrexate showed no statistically significant difference in failure to induce remission between methotrexate and placebo or between methotrexate and 6-mercaptopurine. For the study using 15 mg/week of oral methotrexate 33% (5/15) of methotrexate patients failed to enter remission compared to 11% (2/18) of placebo patients (RR 3.00, 95% CI 0.68 to 13.31). For the study using 12.5 mg/week of oral methotrexate 81% (21/26) of methotrexate patients failed to enter remission compared to 77% (20/26) of placebo patients (RR 1.05, 95% CI 0.79 to 1.39). This study also had an active comparator arm, 81% (21/26) of methotrexate patients failed to enter remission compared to 59% (19/32) of 6-mercaptopurine patients (RR 1.36, 95% CI 0.97 to 1.92). For the active comparator study using 15 mg/week oral methotrexate, 20% (3/15) of methotrexate patients failed to enter remission compared to 6% of 6-mercaptopurine patients (RR 3.20, 95% CI 0.37 to 27.49). This study also had a 5-ASA arm and found that methotrexate patients were significantly more likely to enter remission than 5-ASA patients. Twenty per cent (3/15) of methotrexate patients failed to enter remission compared to 86% (6/7) of 5-ASA patients (RR 0.23, 95% CI 0.08 to 0.67). One small study which used a higher dose of intravenous or oral methotrexate (25 mg/week) showed no statistically significant difference between methotrexate and azathioprine. Forty-four per cent (12/27) of methotrexate patients failed to enter remission compared to 37% of azathioprine patients (RR 1.20, 95% CI 0.63 to 2.29). Two studies found no statistically significant difference in failure to enter remission between the combination of infliximab and methotrexate and infliximab monotherapy. One small study utilized intravenous methotrexate (20 mg/week) for 5 weeks and then switched to oral (20 mg/week). Forty-five per cent (5/11) of patients in the combination group failed to enter remission compared to 62% of infliximab patients (RR 0.73, 95% CI 0.31 to 1.69). The other study assessing combination therapy utilized subcutaneous methotrexate (maximum dose 25 mg/week). Twenty-four per cent (15/63) of patients in the combination group failed to enter remission compared to 22% (14/63) of infliximab patients (RR 1.07, 95% CI 0.57 to 2.03). A large placebo-controlled study which employed a high dose of methotrexate intramuscularly showed a statistically significant benefit relative to placebo. Sixty-one per cent of methotrexate patients failed to enter remission compared to 81% of placebo patients (RR 0.75, 95% CI 0.61 to 0.93; number needed to treat, NNT=5). Withdrawals due to adverse events were significantly more common in methotrexate patients than placebo in this study. Seventeen per cent of methotrexate patients withdrew due to adverse events compared to 2% of placebo patients (RR 8.00, 95% CI 1.09 to 58.51). The incidence of adverse events was significantly more common in methotrexate patients (63%, 17/27) than azathioprine patients (26%, 7/27) in one small study (RR 2.42, 95% CI 1.21 to 4.89). No other statistically significant differences in adverse events, withdrawals due to adverse events or serious adverse events were reported in any of the other placebo-controlled or active comparator studies. Common adverse events included nausea and vomiting, abdominal pain, diarrhea, skin rash and headache. AUTHORS' CONCLUSIONS: There is evidence from a single large randomized trial which suggests that intramuscular methotrexate (25 mg/week) provides a benefit for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Lower dose oral methotrexate does not appear to provide any significant benefit relative to placebo or active comparator. However, these trials were small and further studies of oral methotrexate may be justified. Comparative studies of methotrexate to drugs such as azathioprine or 6-mercaptopurine would require the randomization of large numbers of patients. The addition of methotrexate to infliximab therapy does not appear to provide any additional benefit over infliximab monotherapy. However these studies were relatively small and further research is needed to determine the role of methotrexate when used in conjunction with infliximab or other biological therapies.

Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease.

BACKGROUND & AIMS: Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone. METHODS: In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. RESULTS: Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated. CONCLUSIONS: The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis.

BACKGROUND & AIMS: Interobserver differences in endoscopic assessments contribute to variations in rates of response to placebo in ulcerative colitis (UC) trials. We investigated whether centralized review of images could reduce these variations. METHODS: We performed a 10-week, randomized, double-blind, placebo-controlled study of 281 patients with mildly to moderately active UC, defined by an Ulcerative Colitis Disease Activity Index (UCDAI) sigmoidoscopy score ≥2, that evaluated the efficacy of delayed-release mesalamine (Asacol 800-mg tablet) 4.8 g/day. Endoscopic images were reviewed by a single expert central reader. The primary outcome was clinical remission (UCDAI, stool frequency and bleeding scores of 0, and no fecal urgency) at week 6. RESULTS: The primary outcome was achieved by 30.0% of patients treated with mesalamine and 20.6% of those given placebo, a difference of 9.4% (95% confidence interval [CI], -0.7% to 19.4%; P = .069). Significant differences in results from secondary analyses indicated the efficacy of mesalamine. Thirty-one percent of participants, all of whom had a UCDAI sigmoidoscopy score ≥2 as read by the site investigator, were considered ineligible by the central reader. After exclusion of these patients, the remission rates were 29.0% and 13.8% in the mesalamine and placebo groups, respectively (difference of 15%; 95% CI, 3.5%-26.0%; P = .011). CONCLUSIONS: Although mesalamine 4.8 g/day was not statistically different from placebo for induction of remission in patients with mildly to moderately active UC, based on an intent-to-treat analysis, the totality of the data supports a benefit of treatment. Central review of endoscopic images is critical to the conduct of induction studies in UC; ClinicalTrials.gov Number, NCT01059344.

Methotrexate for induction of remission in refractory Crohn's disease.

BACKGROUND: Although corticosteroids are effective for induction of remission of Crohn's disease, many patients relapse when steroids are withdrawn or become steroid dependent. Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine or 6-mercaptopurine therapy. This systematic review is an update of a previously published Cochrane review. OBJECTIVES: The primary objective was to assess the efficacy and safety of methotrexate for induction of remission in patients with active Crohn's disease in the presence or absence of concomitant steroid therapy. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized register from inception to June 27, 2012 for relevant studies. Conference proceedings and reference lists were also searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials of methotrexate compared to placebo or an active comparator for treatment of active refractory Crohn's disease in adult patients (> 17 years) were considered for inclusion. DATA COLLECTION AND ANALYSIS: The primary outcome was failure to failure to enter remission and withdrawal from steroids. Secondary outcomes included adverse events, withdrawal due to adverse events, serious adverse events and quality of life. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention to treat basis. The Cochrane risk of bias tool was used to assess the methodological quality of included studies. The GRADE approach was used to assess the overall quality of evidence supporting the primary outcome. MAIN RESULTS: Seven studies (495 patients) were included. Four studies were rated as low risk of bias. Three studies were rated as high risk of bias due to open label or single-blind designs. The seven studies differed with respect to participants, intervention, and outcomes to the extent that it was considered to be inappropriate to pool the data for meta-analysis. Three small studies which employed low doses of oral methotrexate showed no statistically significant difference in failure to induce remission between methotrexate and placebo or between methotrexate and 6-mercaptopurine. For the study using 15 mg/week of oral methotrexate 33% (5/15) of methotrexate patients failed to enter remission compared to 11% (2/18) of placebo patients (RR 3.00, 95% CI 0.68 to 13.31). For the study using 12.5 mg/week of oral methotrexate 81% (21/26) of methotrexate patients failed to enter remission compared to 77% (20/26) of placebo patients (RR 1.05, 95% CI 0.79 to 1.39). This study also had an active comparator arm, 81% (21/26) of methotrexate patients failed to enter remission compared to 59% (19/32) of 6-mercaptopurine patients (RR 1.36, 95% CI 0.97 to 1.92). For the active comparator study using 15 mg/week oral methotrexate, 20% (3/15) of methotrexate patients failed to enter remission compared to 6% of 6-mercaptopurine patients (RR 3.20, 95% CI 0.37 to 27.49). This study also had a 5-ASA arm and found that methotrexate patients were significantly more likely to enter remission than 5-ASA patients. Twenty per cent (3/15) of methotrexate patients failed to enter remission compared to 86% (6/7) of 5-ASA patients (RR 0.23, 95% CI 0.08 to 0.67). One small study which used a higher dose of intravenous or oral methotrexate (25 mg/week) showed no statistically significant difference between methotrexate and azathioprine. Forty-four per cent (12/27) of methotrexate patients failed to enter remission compared to 37% of azathioprine patients (RR 1.20, 95% CI 0.63 to 2.29). Two studies found no statistically significant difference in failure to enter remission between the combination of infliximab and methotrexate and infliximab monotherapy. One small study utilized intravenous methotrexate (20 mg/week) for 5 weeks and then switched to oral (20 mg/week). Forty-five per cent (5/11) of patients in the combination group failed to enter remission compared to 62% of infliximab patients (RR 0.73, 95% CI 0.31 to 1.69) The other study assessing combination therapy utilized subcutaneous methotrexate (maximum dose 25 mg/week). Twenty-four per cent (15/63) of patients in the combination group failed to enter remission compared to 22% (14/63) of infliximab patients (RR 1.07, 95% CI 0.57 to 2.03). A large placebo-controlled study which employed a high dose of methotrexate intramuscularly showed a statistically significant benefit relative to placebo. Sixty-one per cent of methotrexate patients failed to enter remission compared to 81% of placebo patients (RR 0.75, 95% CI 0.61 to 0.93; number needed to treat, NNT=5). Withdrawals due to adverse events were significantly more common in methotrexate patients than placebo in this study. Seventeen per cent of methotrexate patients withdrew due to adverse events compared to 2% of placebo patients (RR 8.00, 95% CI 1.09 to 58.51). The incidence of adverse events was significantly more common in methotrexate patients (63%, 17/27) than azathioprine patients (26%, 7/27) in one small study (RR 2.42, 95% CI 1.21 to 4.89). No other statistically significant differences in adverse events, withdrawals due to adverse events or serious adverse events were reported in any of the other placebo-controlled or active comparator studies. Common adverse events included nausea and vomiting, abdominal pain, diarrhea, skin rash and headache. AUTHORS' CONCLUSIONS: There is evidence from a single large randomized trial which suggests that intramuscular methotrexate (25 mg/week) provides a benefit for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Lower dose oral methotrexate does not appear to provide any significant benefit relative to placebo or active comparator. However, these trials were small and further studies of oral methotrexate may be justified. Comparative studies of methotrexate to drugs such as azathioprine or 6-mercaptopurine would require the randomization of large numbers of patients. The addition of methotrexate to infliximab therapy does not appear to provide any additional benefit over infiximab monotherapy. However these studies were relatively small and further research is needed to determine the role of methotrexate when used in conjunction with infliximab or other biological therapies.

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.

BACKGROUND: Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial. OBJECTIVES: To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis. SEARCH METHODS: The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to June 2012. A manual search was also performed using references from these articles as well as review articles, and proceedings from major gastrointestinal meetings. Authors of maintenance trials were asked about unpublished studies. SELECTION CRITERIA: Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes. MAIN RESULTS: Six studies including 286 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalamine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). All of the studies which used active comparators were open label. When placebo and active comparator studies were pooled to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported. AUTHORS' CONCLUSIONS: Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (Issue 1, 2007).

Sargramostim (GM-CSF) for induction of remission in Crohn's disease: a cochrane inflammatory bowel disease and functional bowel disorders systematic review of randomized trials.

BACKGROUND: We planned to systematically review the efficacy of sargramostim (granulocyte colony stimulating factor [GM-CSF]) for remission induction in patients with Crohn's disease (CD). METHODS: A literature search to April 2011 was performed to identify all randomized trials studying sargramostim in patients with CD. The Cochrane risk of bias tool was used to evaluate study quality and the GRADE criteria were utilized to assess the overall quality of the evidence. RESULTS: Three randomized studies (total 537 patients) were identified. The risk of bias was low for the three included studies. There was no statistically significant difference in the proportion of patients who achieved clinical remission (GM-CSF 25.3%; placebo 17.5%; relative risk [RR] 1.67; 95% confidence interval [CI] 0.80-3.50; P = 0.17), or 100-point clinical response (GM-CSF 38.3%; placebo 24.8%; RR 1.71 95% CI 0.98-2.97; P = 0.06). There was no statistically significant difference in the proportion of patients (GM-CSF 95.8%; placebo 89.3%) who experienced adverse events (RR 1.07; 95% CI 0.99-1.16; P = 0.08), or serious adverse events (GM-CSF 12.0% vs. placebo 4.8%; RR 2.21; 95% CI 0.84-5.81; P = 0.11). CONCLUSIONS: Sargramostim does not appear to be more effective than placebo for induction of clinical remission or improvement in active CD. However, the GRADE analysis indicates that the overall quality of the evidence for the primary and secondary outcomes was low due to sparse data and heterogeneity, indicating that further research likely would have a significant impact on the effect estimates.

Unfractionated or low molecular weight heparin for induction of remission in ulcerative colitis: a Cochrane inflammatory bowel disease and functional bowel disorders systematic review of randomized trials.

BACKGROUND: We aimed to systematically review the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis (UC). METHODS: A literature search to April 2011 was performed to identify all randomized trials studying UFH or LMWH use in patients with UC. The Cochrane Risk of Bias Tool was used to assess study quality. RESULTS: LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission, and clinical, endoscopic, or histological improvement. High-dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (odds ratio [OR] 2.73; 95% confidence interval [CI] 1.32-5.67; P = 0.007), clinical improvement (OR 2.99; 95% CI 1.30-6.87; P = 0.01), and endoscopic improvement (OR 2.25; 95% CI 1.01-5.01; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission, or endoscopic improvement. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event. CONCLUSIONS: LMWH administered by extended colon-release tablets may be effective for the treatment of active UC. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC.

Interventions for treating microscopic colitis: a Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group systematic review of randomized trials.

OBJECTIVES: To conduct a systematic review to determine effective treatments for patients with collagenous colitis or lymphocytic colitis, the two subtypes of microscopic colitis. METHODS: Relevant papers were identified via the MEDLINE, PUBMED, and Cochrane Collaboration databases, manual searches of the references of identified papers and review papers on microscopic colitis, as well as searches of abstracts from major gastroenterological meetings. RESULTS: All studies assessing treatment of microscopic colitis had relatively small sample sizes. A total of 10 randomized trials included patients with collagenous colitis. Budesonide was studied for induction of response in three trials and for maintenance of response in two trials. The pooled odds ratio for inducing clinical response with budesonide was 12.32 (95% confidence interval, CI 5.53-27.46), and for maintaining clinical response was 8.82 (95% CI 3.19-24.37), with a number needed to treat (NNT) of 2 patients for each outcome. Budesonide also induced and maintained histological response and was well tolerated. Bismuth subsalicylate, prednisolone, and mesalamine with or without cholestyramine may be effective, whereas Boswellia serrata extract and probiotics were ineffective for treating collagenous colitis. Three randomized trials included patients with lymphocytic colitis. Budesonide was shown in one study to be effective for inducing clinical response (OR 9.00; 95% CI 1.98-40.93), with an NNT of three patients. Budesonide also induced histological response and was well tolerated. Bismuth subsalicylate and mesalamine with or without cholestyramine may be effective for treating lymphocytic colitis. No trials assessed maintenance of response in patients with lymphocytic colitis. CONCLUSIONS: Budesonide is effective and well tolerated for inducing and maintaining clinical and histological responses in patients with collagenous colitis, and for inducing clinical and histological responses in patients with lymphocytic colitis. Determining the magnitude of benefit is limited by the small sample sizes of the studies. The evidence for other agents, including bismuth subsalicylate, prednisolone, B. serrata extract, probiotics, and mesalamine with or without cholestyramine is weaker. It is not clear that any of these agents induce or maintain actual remission of collagenous or lymphocytic colitis, as opposed to clinical or histological response.

Treatment of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 integrin.

BACKGROUND & AIMS: Selective blockade of lymphocyte-vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the alpha4beta7 integrin, in patients with active Crohn's disease. METHODS: Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (>or=70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score or=100-point decrement in CDAI). Human anti-human antibody levels were measured. RESULTS: Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease. CONCLUSIONS: This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.

Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials.

CONTEXT: Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. OBJECTIVE: To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. DESIGN, SETTING, AND PATIENTS: Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn's Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. INTERVENTIONS: Patients with a Crohn's Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. MAIN OUTCOME MEASURE: Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. RESULTS: For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease. CONCLUSION: In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542.