Steroid-sparing properties of sargramostim in patients with corticosteroid-dependent Crohn's disease: a randomised, double-blind, placebo-controlled, phase 2 study. Sargramostim for active Crohn's disease. Natalizumab for active Crohn's disease. Natalizumab induction and maintenance therapy for Crohn's disease. Oral budesonide for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Fat composition may be a clue to explain the primary therapeutic effect of enteral nutrition in Crohn's disease: results of a double blind randomised multicentre European trial. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. A randomized, double-blind, controlled withdrawal trial in Crohn's disease patients in long-term remission on azathioprine. Comparison of amino acid v peptide based enteral diets in active Crohn's disease: clinical and nutritional outcome. Budesonide CIR capsules (once or twice daily divided-dose) in active Crohn's disease: a randomized placebo-controlled study in the United States.
Although treatment with corticosteroids induces remission in Crohn's disease, prolonged exposure to corticosteroids is undesirable. This randomised clinical trial evaluated the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (sargramostim), an activator of innate immunity, in corticosteroid-dependent patients with Crohn's disease.
                Patients were randomised in a 2:1 ratio, to sargramostim 6 microg/kg subcutaneously once daily or placebo for up to 22 weeks. The study consisted of (1) an adjunctive phase (weeks 1-4) in which patients received study drug plus corticosteroid therapy; (2) a forced corticosteroid tapering phase (weeks 4-14); and (3) an observation phase (4 weeks) in which patients received study drug plus prednisone < or =7.5 mg. The primary endpoint was corticosteroid-free remission (Crohn's Disease Activity Index (CDAI) < or =150) 4 weeks after corticosteroid elimination. Secondary endpoints were corticosteroid-free response (CDAI decreased by > or =100) and induction of remission in patients who reduced the dose of corticosteroid to 2.5-7.5 mg.
                Eighty-seven patients were randomised to sargramostim and 42 to placebo. Significantly more sargramostim-treated patients than placebo patients achieved corticosteroid-free remission (18.6% vs 4.9%; p = 0.03). Similar differences were seen for corticosteroid-free response and in patients who tapered corticosteroids to 2.5-7.5 mg/day. Sargramostim treatment was also associated with significant improvements in health-related quality of life. Patients who received sargramostim were more likely to experience musculoskeletal pain, injection site reactions and dyspnoea.
                Sargramostim was more effective than placebo for inducing corticosteroid-free remission in patients with Crohn's disease with corticosteroid dependence. Sargramostim may provide significant benefit in this population if these findings are confirmed. Sargramostim, granulocyte-macrophage colony-stimulating factor, a hematopoietic growth factor, stimulates cells of the intestinal innate immune system. Preliminary studies suggest sargramostim may have activity in Crohn's disease. To evaluate this novel therapeutic approach, we conducted a randomized, placebo-controlled trial.
                Using a 2:1 ratio, we randomly assigned 124 patients with moderate-to-severe active Crohn's disease to receive 6 mug of sargramostim per kilogram per day or placebo subcutaneously for 56 days. Antibiotics and aminosalicylates were allowed; immunosuppressants and glucocorticoids were prohibited. The primary end point was a clinical response, defined by a decrease from baseline of at least 70 points in the Crohn's Disease Activity Index (CDAI) at the end of treatment (day 57). Other end points included changes in disease severity and the health-related quality of life and adverse events.
                There was no significant difference in the rate of the primary end point of a clinical response defined by a decrease of at least 70 points in the CDAI score on day 57 between the sargramostim and placebo groups (54 percent vs. 44 percent, P=0.28). However, significantly more patients in the sargramostim group than in the placebo group reached the secondary end points of a clinical response defined by a decrease from baseline of at least 100 points in the CDAI score on day 57 (48 percent vs. 26 percent, P=0.01) and of remission, defined by a CDAI score of 150 points or less on day 57 (40 percent vs. 19 percent, P=0.01). The rates of either type of clinical response and of remission were significantly higher in the sargramostim group than in the placebo group on day 29 of treatment and 30 days after treatment. The sargramostim group also had significant improvements in the quality of life. Mild-to-moderate injection-site reactions and bone pain were more common in the sargramostim group, and three patients in this group had serious adverse events possibly or probably related to treatment.
                This study was negative for the primary end point, but findings for the secondary end points suggest that sargramostim therapy decreased disease severity and improved the quality of life in patients with active Crohn's disease.
                Copyright 2005 Massachusetts Medical Society. In chronic inflammatory conditions such as Crohn's disease, the migration of leukocytes from the circulation into the parenchyma and their activation within inflammatory sites are mediated in part by alpha4 integrins.
                We conducted a double-blind, placebo-controlled trial of the alpha4 integrin-specific humanized monoclonal antibody natalizumab in 248 patients with moderate-to-severe Crohn's disease. Patients were randomly assigned to receive one of four treatments: two infusions of placebo; one infusion of 3 mg of natalizumab per kilogram of body weight, followed by placebo; two infusions of 3 mg of natalizumab per kilogram; or two infusions of 6 mg of natalizumab per kilogram. Infusions were given four weeks apart. Outcomes included changes in scores for the Crohn's Disease Activity Index (higher scores indicate more severe disease), the health-related quality of life, and C-reactive protein levels.
                The group given two infusions of 6 mg of natalizumab per kilogram did not have a significantly higher rate of clinical remission (defined by a score of less than 150 on the Crohn's Disease Activity Index) than the placebo group at week 6 (the prospectively defined primary end point in the efficacy analysis). However, both groups that received two infusions of natalizumab had higher remission rates than the placebo group at multiple time points. Natalizumab also produced a significant improvement in response rates (defined by a reduction of at least 70 points in the score on the Crohn's Disease Activity Index). The highest remission rate was 44 percent and the highest response rate was 71 percent (at week 6 in the group given two infusions of 3 mg per kilogram). Overall, the two infusions of 6 mg of natalizumab per kilogram and of 3 mg per kilogram had similar effects. The quality of life improved in all natalizumab groups; C-reactive protein levels improved in groups receiving two infusions of natalizumab. The rates of adverse events were similar in all four groups.
                Treatment with the selective adhesion-molecule inhibitor natalizumab increased the rates of clinical remission and response, improved the quality of life and C-reactive protein levels, and was well tolerated in patients with active Crohn's disease.
                Copyright 2003 Massachusetts Medical Society Natalizumab, a humanized monoclonal antibody against alpha4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue.
                We conducted two controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active Crohn's disease. In the first trial, 905 patients were randomly assigned to receive 300 mg of natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index (CDAI) score of at least 70 points, at week 10. In the second trial, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive 300 mg of natalizumab or placebo every four weeks through week 56. The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150).
                In the first trial, the natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respectively; P=0.05) and remission (37 percent and 30 percent, respectively; P=0.12) at 10 weeks. Continuing natalizumab in the second trial resulted in higher rates of sustained response (61 percent vs. 28 percent, P<0.001) and remission (44 percent vs. 26 percent, P=0.003) through week 36 than did switching to placebo. Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the natalizumab group in the second trial. In an open-label extension study, a patient treated with natalizumab died from progressive multifocal leukoencephalopathy, associated with the JC virus, a human polyomavirus.
                Induction therapy with natalizumab for Crohn's disease resulted in small, nonsignificant improvements in response and remission rates. Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks. The benefit of natalizumab will need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy. (ClinicalTrials.gov numbers, NCT00032786 and NCT00032799.)
                Copyright 2005 Massachusetts Medical Society. Corticosteroids are the most efficacious drugs for inducing remission in active Crohn's disease, but their benefits are frequently offset by serious side effects. Budesonide is a corticosteroid with high topical antiinflammatory activity but low systemic activity because of extensive hepatic metabolism. We investigated the efficacy and safety of an oral controlled-ileal-release preparation of budesonide in patients with active Crohn's disease involving the ileum or ileum and proximal colon.
                In a double-blind, multicenter trial, 258 patients were randomly assigned to receive placebo or one of three doses of budesonide--3, 9, or 15 mg daily. The primary outcome measure was clinical remission, as defined by a score of 150 or less on the Crohn's disease activity index.
                After eight weeks of treatment, remission occurred in 51 percent of the patients in the group receiving 9 mg of budesonide (95 percent confidence interval, 39 to 63 percent), 43 percent of those receiving 15 mg (95 percent confidence interval, 31 to 55 percent), and 33 percent of those receiving 3 mg (95 percent confidence interval, 21 to 44 percent), as compared with 20 percent of those receiving placebo (P < 0.001, P = 0.009, and P = 0.13, respectively). Improvements in the quality of life, as measured by the patients' responses to the inflammatory bowel disease questionnaire, paralleled these remission rates. Location of disease, prior surgical resection, and previous use of corticosteroids did not affect the outcome. A total of 119 patients (46 percent) were withdrawn from the study before the trial ended, 96 because of insufficient therapeutic effects, 13 because of adverse reactions, and 10 because of noncompliance. Budesonide caused a dose-related reduction in basal and corticotropin-stimulated plasma cortisol concentrations but was not associated with clinically important corticosteroid-related symptoms or other toxic effects.
                In an eight-week trial, an oral controlled-release preparation of budesonide at an optimal daily dose of 9 mg was well tolerated and effective against active Crohn's disease of the ileum and proximal colon. Adalimumab induced clinical remission after four weeks in patients with active Crohn's disease in the CLASSIC I trial.
                To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn's disease in a follow-on randomised controlled trial (CLASSIC II).
                In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn's disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open-label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re-randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open-label arm and received adalimumab 40 mg every other week. With non-response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non-response or disease flare could switch to open-label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI <150) in randomised patients through week 56.
                Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p<0.05). In all, 204 patients entered the open-label arm. Of these, 93 (46%) were in clinical remission at week 56. Adalimumab was generally well-tolerated in all patients.
                Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn's disease naive to anti-TNF treatment. Dietary fat has been suggested to determine the therapeutic effect of enteral diets in Crohn's disease.
                To assess the efficacy of two whole protein based diets with different fat compositions (n6 polyunsaturated fatty acids v monounsaturated fatty acids) in inducing clinical remission in active Crohn's disease compared with steroids.
                Sixty two patients with active Crohn's disease were randomised to receive, for not more than 4 weeks: (a) a polymeric enteral diet containing 35 g of lipids per 1000 kcal, high in oleate (79%) and low in linoleate (6.5%) (PEN1), (b) an identical enteral diet except for the type of fat which was high in linoleate (45%) and low in oleate (28%) (PEN2), or (c) oral prednisone (1 mg/kg/day). Diets were double blindly administered. The steroid group received a conventional ward diet. Treatment failure was considered when remission was not achieved at week 4. Clinical activity and biological and nutritional parameters were monitored. Independent predictors of remission were identified by stepwise logistic regression analysis.
                Overall remission rates (by intention to treat) were 20% (4/20) for PEN1, 52% (12/23) for PEN2, and 79% (15/19) for steroids (overall p=0.001; p<0.0005 steroids v PEN1, and p=0.056 PEN2 v PEN1). After excluding those patients who were non-compliant during the first week (per protocol analysis), remission rates were 27%, 63%, and 79%, respectively (p=0.008, steroids and PEN2 v PEN1). After adjusting for confounding variables, PEN1 remained significantly associated with a poor response.
                The type of dietary fat may be of importance for the primary therapeutic effect of enteral nutrition in active Crohn's disease. This study evaluated the efficacy and safety of adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody administered subcutaneously, in the maintenance of response and remission in patients with moderate to severe Crohn's disease (CD).
                Patients received open-label induction therapy with adalimumab 80 mg (week 0) followed by 40 mg (week 2). At week 4, patients were stratified by response (decrease in Crohn's Disease Activity Index > or =70 points from baseline) and randomized to double-blind treatment with placebo, adalimumab 40 mg every other week (eow), or adalimumab 40 mg weekly through week 56. Co-primary end points were the percentages of randomized responders who achieved clinical remission (Crohn's Disease Activity Index score <150) at weeks 26 and 56.
                The percentage of randomized responders in remission was significantly greater in the adalimumab 40-mg eow and 40-mg weekly groups versus placebo at week 26 (40%, 47%, and 17%, respectively; P < .001) and week 56 (36%, 41%, and 12%, respectively; P < .001). No significant differences in efficacy between adalimumab eow and weekly were observed. More patients receiving placebo discontinued treatment because of an adverse event (13.4%) than those receiving adalimumab (6.9% and 4.7% in the 40-mg eow and 40-mg weekly groups, respectively).
                Among patients who responded to adalimumab, both adalimumab eow and weekly were significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks. Adalimumab was well-tolerated, with a safety profile consistent with previous experience with the drug. An open study reported that patients with Crohn's disease in remission who have taken azathioprine for longer than 3.5 years are at low risk of relapse when azathioprine is discontinued. To confirm this observation, we performed a multicenter, double-blind, noninferiority withdrawal study.
                Patients who were in clinical remission on azathioprine for > or = 42 months were randomized to continue azathioprine or to receive an equivalent placebo for 18 months. The primary end point was clinical relapse at 18 months.
                Forty patients were randomly assigned to receive azathioprine and 43 to receive placebo. Characteristics of patients at entry were similar in the 2 study groups. At 18 months, 3 patients had a relapse in the azathioprine group, and 9 had a relapse in the placebo group. Kaplan-Meier estimates of the relapse rate at 18 months were 8% +/- 4% and 21% +/- 6%, respectively. The hypothesis that placebo was inferior to azathioprine was not rejected (P = .195). Among the baseline variables, C-reactive protein level > 20 mg/L, time without steroids < 50 months, and hemoglobin level < 12 g/dL were found to be predictive of relapse in the multivariate analysis.
                This study shows that azathioprine withdrawal is not equivalent to continued therapy with azathioprine for maintenance of remission in patients with Crohn's disease who have been in remission on azathioprine for > or = 3.5 years. Thus, azathioprine maintenance therapy should be continued beyond 3.5 years. Elemental diets are considered an effective primary treatment for active Crohn's disease. This study examined the hypothesis that improvement occurs because of the presence of amino acids or the low fat content, or both. A randomised, controlled trial was undertaken in 40 patients with active Crohn's disease to evaluate clinical and nutritional outcomes after an amino acid based diet containing 3% fat was given by a feeding tube compared with a peptide based diet containing 33% fat. After three weeks' treatment, clinical remission occurred in 84% of patients who were given the amino acid diet and 75% of patients who received the peptide diet (p = 0.38). Plasma linoleic acid concentration was reduced after the amino acid but not the peptide diet. An increase in total body nitrogen was associated with the magnitude of nutritional depletion before treatment and at six months' follow up, only patients who showed gains in total body nitrogen after enteral nutrition had a sustained clinical remission. This study shows that peptide based high fat diets are as effective as amino acid low fat diets for achieving clinical remission in active Crohn's disease. Improved total body protein stores but not essential fatty acid depletion may be an important indicator of a sustained remission. Budesonide controlled ileal release (CIR) capsules deliver budesonide, a glucocorticosteroid with high topical and low systemic activity, to the distal ileum and the proximal colon. In four previous controlled trials in Crohn's disease, remission rates ranged from 51% to 69%. We sought to evaluate the efficacy and safety of this drug in a population of patients in the United States with Crohn's disease.
                In this multicenter, double blind, randomized trial, 200 patients in the United States with mild to moderate Crohn's disease (Crohn's Disease Activity Index [CDAI] between 200 and 450) involving the distal ileum and/or ascending colon received 9 mg of budesonide CIR once daily, 4.5 mg b.i.d., or placebos for 8 wk. The primary outcome was remission defined by a CDAI of 150 or less.
                Remission was achieved in 48%, 53%, and 33% with 9 mg once daily, 4.5 mg b.i.d., and placebos, respectively, after 8 wk of treatment. Differences between the groups were not significant. The differences in mean change from baseline CDAI between the combined budesonide and placebo groups was significant (p < 0.05). There was no difference in observed adverse events between treatment groups, although a modest decrease in plasma cortisol levels was observed relative to the placebo (p < 0.01).
                Treatment of symptomatic Crohn's disease with budesonide CIR capsules (9 mg daily) was safe, and remission rates were similar to those achieved in previous trials. Although the remission rate did not significantly differ from the placebo response in this study, there was a significant change in the mean CDAI from baseline in the combined treatment groups relative to the placebo.
Sargramostim does not appear to be more effective than placebo for induction of clinical remission or clinical improvement in patients with active Crohn's disease. However, the GRADE analysis indicates that the overall quality of the evidence for the primary (clinical remission) and secondary outcomes (clinical response) was low indicating that further research is likely to have an impact on the effect estimates.