Comparison between high dose 5-aminosalicylic acid and 6-methylprednisolone in active Crohn's ileocolitis. A multicenter randomized double-blind study. German 5-ASA Study Group. European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment. A comparison of budesonide and mesalamine for active Crohn's disease. International Budesonide-Mesalamine Study Group. Effect of sulphasalazine in patients with active Crohn's disease: a controlled double-blind study. [Successful acute treatment of chronic inflammatory intestinal diseases with oral 5-aminosalicylic acid]. Sulphasalazine and prednisone compared with sulphasalazine for treating active Crohn disease. A double-blind, randomized, multicenter trial. Oral Pentasa in the treatment of active Crohn's disease: A meta-analysis of double-blind, placebo-controlled trials. 5-Aminosalicylic acid in the treatment of Crohn's disease. A 16-week double-blind, placebo-controlled, multicentre study with Pentasa. Slow-release 5-amino-salicylic acid (Pentasa) for the treatment of active Crohn's disease. A randomized, double-blind, placebo-controlled trial of the oral mesalamine (5-ASA) preparation, Asacol, in the treatment of symptomatic Crohn's colitis and ileocolitis. Mesalamine capsules for the treatment of active Crohn's disease: results of a 16-week trial. Pentasa Crohn's Disease Study Group. Mesalamine in the treatment of mild to moderate active Crohn's ileitis: results of a randomized, multicenter trial. Effect of a slow-release 5'-aminosalicylic acid preparation on disease activity in Crohn's disease. National Cooperative Crohn's Disease Study: results of drug treatment. A randomized, double-blind, placebo-controlled trial of olsalazine for active Crohn's disease.
The value of 5-aminosalicylic acid (5-ASA) in Crohn's disease (CD) is still under discussion. In a previous study 2 g 5-ASA per day were inferior to a standard glucocorticoid treatment with 6-methylprednisolone (6-MPred) (Can J Gastroenterol 1990; 4: 446-51). In the present study we tested whether in active CD response rates to 4.5 g 5-ASA/day were not different from those to 6-MPred.
                Multicenter randomized double-blind double-dummy trial. 34 patients with active CD (CDAI > 150) were included. 17 patients were in the 5-ASA group (Salofalk, 4.5 g/day), 17 patients in the 6-MPred group (Urbason, initial dose 48 mg/day, weekly tapering). Duration of treatment was 8 weeks. Main outcome measure was remission of CD (CDAI < 150) and decrease of at least 60 points.
                Both groups were comparable with respect to demographic and clinical parameters. The median CDAI decrease in the 5-ASA group was 85, in the 6-MPred group 122 (p = 0.7437). The median AUC of the CDAI in the 5-ASA group was 1027, in the 6-MPred group 950 (p = 0.137). The median AUC of the CDAI per treatment day was 22.94 in the 5-ASA group, and 17.33 in the 6-MPred group (p = 0.0555). On an intention-to-treat basis remission rates after 8 weeks were 40.0% in the 5-ASA group and 56.3% in the 6-MPred group (p = 0.5867).
                Response rates to 5-ASA or 6-MPred were not significantly different although there was a trend towards a higher efficacy of 6-MPred. 5-ASA may be considered as alternative treatment in patients with activer CD who are intolerant to or refuse glucocorticoids. A multicenter double-blind study of the effectiveness of sulfasalazine and 6-methylprednisolone, alone and in combination, was conducted on 452 patients with Crohn's disease. One hundred sixty patients were previously untreated; 292 patients were previously treated. The Crohn's disease activity index (CDAI) was used to determine whether a patient had active (CDAI greater than or equal to 150, n = 215) or quiescent disease (CDAI less than 150, n = 237). Treatment of active disease consisted of high-dose 6-methylprednisolone, 6-methylprednisolone combined with 3 g of sulfasalazine, 3 g of sulfasalazine alone, or placebo, and lasted 6 wk. Patients in remission received maintenance doses of one of these drug regimens for periods of up to 2 yr. One hundred ninety-two patients completed the 2-yr study period. Results were evaluated using life-table analysis and outcome ranking. These methods showed 6-methylprednisolone to be the most effective drug in overall comparison of all patients (p less than 0.001); in previously treated patients (p less than 0.001); and in subgroups: active disease (p less than 0.001), only small bowel disease (p less than 0.05), and both small bowel and colon disease (p less than 0.05). Combination of 6-methylprednisolone and sulfasalazine was the most effective regimen in previously untreated patients (p less than 0.05) and when disease was localized in the colon (p less than 0.001). Sulfasalazine alone was least effective in overall comparison of all patients (p less than 0.05) and in all strata. Drug treatment was of no significant benefit to patients with quiescent disease. Continuous administration of low doses of 6-methylprednisolone, or the combination regimen, was beneficial in patients who responded initially to treatment of active disease. The addition of sulfasalazine, however, offered no advantage. Crohn's disease is often treated with glucocorticoids or mesalamine. We compared the efficacy and safety of controlled-ileal-release budesonide capsules and slow-release mesalamine tablets in patients with active Crohn's disease affecting the ileum, the ascending colon, or both.
                In a double-blind, multicenter trial, we enrolled 182 patients with scores of 200 to 400 on the Crohn's Disease Activity Index (with higher scores indicating greater disease activity) and randomly assigned 93 to receive 9 mg of budesonide once daily and 89 to receive 2 g of mesalamine twice daily for 16 weeks. The primary efficacy variable was clinical remission, defined as a score of 150 or less on the Crohn's Disease Activity Index.
                In the analysis of all patients who received at least one dose of study drug, the rates of remission after 8 weeks of treatment were 69 percent in the budesonide group and 45 percent in the mesalamine group (P=0.001); the respective rates after 16 weeks of treatment were 62 percent and 36 percent (P<0.001). Seventy-seven patients in the budesonide group completed the 16 weeks of treatment, as compared with 50 patients in the mesalamine group (P<0.001). The numbers of patients with adverse events were similar in the two groups, but those assigned to budesonide had fewer severe adverse events. Among patients who completed 16 weeks of treatment, the morning plasma cortisol value was normal in 67 percent of budesonide-treated patients and 83 percent of mesalamine-treated patients (P=0.06); 90 percent and 100 percent, respectively, had normal increases in cortisol in response to cosyntropin (P=0.02).
                In patients with active Crohn's disease affecting the ileum, the ascending colon, or both, a controlled-ileal-release formulation of budesonide was more effective in inducing remission than a slow-release formulation of mesalamine. The response of active Crohn's disease to sulphasalazine (4-6 g per day) has been studied in a placebo-controlled trial. The study was carried out at two hospitals. From August 1977 to August 1979 all patients with established Crohn's disease were examined for their eligibility for the trial. A nine-item index of inflammatory activity was used as the primary measure of response. The variables in this index were serum albumin, ESR, body weight released to height, abdominal mass, temperature, stool consistency, bowel resection, and extraintestinal symptoms related to Crohn's disease. A favourable response to therapy was defined as a decrease of the activity index with 25% or more at the end of the trial period, compared with the initial value. Twenty-six patients (13 in each treatment group) have been followed up for six months. The response of active Crohn's disease to sulphasalazine was significantly better than to placebo. The effectiveness of oral 5-aminosalicylic acid (0.5 g t.i.d.) and of salazosulfapyridine (1.0 g t.i.d.) was compared in a randomized controlled study in two groups with 30 patients each with ulcerative colitis and with Crohn's disease. Persistent complaints within the first 5 days were treated with additional methyl-prednisolone (40 mg/d initially). After treatment for 8 weeks patients with ulcerative colitis showed morphologic remissions in 60% of the 5-aminosalicylic acid group and in 53% of the salazosulfapyridine group. Clinical improvement was achieved in 86% in both groups. Clinical improvement in Crohn's disease was seen in 87% of patients of the 5-aminosalicylic acid group and in 80% of the salazosulfapyridine group. This was evidenced by the significant fall (P = 0,0001) of the mean activity index. Additional steroid medication was nearly equal in both treatment groups. There were no side effects during treatment with 5-aminosalicylic acid. In contrast, salazosulfapyridine had to be withdrawn in four patients due to signs of intolerance. 5-Aminosalicylic acid can thus be considered a valuable alternative to conventional treatment on the basis of equal effectiveness as salazosulfapyridine and lack of undesirable side effects. To determine whether sulphasalazine plus prednisone is more effective than sulphasalazine alone in treating active Crohn disease.
                Randomized, double-blind, placebo-controlled trial.
                Multicenter trial in one university hospital and nine general hospitals.
                Patients with active Crohn disease and a Van Hees Activity Index of 140 or more. Of 71 patients who were randomly assigned, 60 completed treatment and were analyzed.
                For 16 weeks, 30 patients received sulphasalazine, 6 g/d (or 4 g/d if adverse effects occurred) and prednisone, 30 mg/d initially. Prednisone therapy was tapered in increments of 5 mg/2 wk to 10 mg/d after 8 weeks. Thirty other patients received sulphasalazine and a placebo.
                In the first 6 weeks of treatment, the Van Hees Activity Index decreased to a median of 70% (interquartile range, 57% to 81%) of the initial value in patients treated with sulphasalazine and prednisone and to a median of 87% (interquartile range, 70% to 94%) in patients treated with sulphasalazine alone (P = 0.001). In the last 4 weeks of treatment, the corresponding figures were 63% (interquartile range, 40% to 75%) and 70% (interquartile range, 54% to 90%) (P = 0.10). The Crohn's Disease Activity Index decreased in the first 6 weeks to a median of 65% (interquartile range, 57% to 86%) in patients receiving sulphasalazine and prednisone and to a median of 75% (interquartile range, 58% to 101%) in patients receiving sulphasalazine alone (P = 0.13). In the last 4 weeks of treatment, the corresponding figures were 65% (interquartile range, 42% to 90%) and 76% (interquartile range, 49% to 110%) (P = 0.19).
                The use of prednisone in addition to sulphasalazine in patients with active Crohn disease results in a significantly faster initial improvement, but not in a significantly better result after 16 weeks of treatment, when disease activity is measured by the Van Hees Activity Index. The aim of this study was to perform a meta-analysis of the efficacy results from 3 placebo-controlled multicenter clinical trials of slow-release mesalamine (Pentasa) for the acute treatment of mild to moderate Crohn's disease.
                Three trials fulfilled the selection criteria (double-blind, placebo-controlled, randomized studies in adult patients treated with Pentasa 4 g/day for active Crohn's disease). The efficacy and safety was evaluated in these trials by using the Crohn's Disease Activity Index (CDAI) as the primary efficacy variable. The study duration was 16 weeks in all 3 trials. The total numbers of patients were 304 in the Pentasa 4-g/day treatment groups and 311 in the placebo groups. A meta-analysis was performed based on the study reports.
                For the intent-to-treat patients in the Pentasa groups, the overall mean reduction of the CDAI from baseline to the final visit was -63 points. The corresponding CDAI change in the placebo groups was -45 points; the net difference was -18 points. Compared with placebo, the 4-g/day dose of Pentasa was associated with a statistically significant overall improvement in the CDAI from baseline to the final visit (P = 0.04). When the meta-analysis was restricted to protocol correct patients, the effect of Pentasa became more pronounced (overall mean reduction of -83 CDAI points; P = 0.02, compared with placebo). Contrary to the consistent effects with Pentasa, the trial-specific reductions of the CDAI with placebo differed significantly between the trials.
                The meta-analysis of 3 large, double-blind, randomized studies in the treatment of active Crohn's disease confirms that Pentasa 4 g/day is superior to placebo in reducing the CDAI but the clinical significance of the magnitude of this difference is not clear. The response to 5-aminosalicylic acid (5-ASA) in mild and moderately active Crohn's disease localized in the small bowel was studied in a randomized, double-blind, placebo-controlled trial in four centres. Sixty-seven patients were included, of whom 30 were treated with 1500 mg slow-release 5-ASA/day (Pentasa) for a scheduled period of 16 weeks. In the 5-ASA group 40% of the patients improved, versus 30% of the placebo-treated group ('intent to treat' basis; p greater than 0.1). Four of the patients treated with 5-ASA left the study owing to disease deterioration, versus 10 of the placebo-treated patients (p greater than 0.2). Seventeen patients were secondarily excluded, and the remaining 50 patients (23 receiving 5-ASA) were reevaluated in greater detail. No statistically significant differences in outcome were shown. Three patients (one given 5-ASA) were withdrawn from the study because of presumed side effects, but no serious adverse reactions were recorded. The present results indicate that 5-ASA, at least in the dosage used, is not superior to placebo. Nevertheless, trends towards a beneficial effect in Crohn's disease in the small bowel justify further clinical trials with a larger dosage of 5-ASA. A double-blind, placebo-controlled trial of a slow-release preparation of 5-amino-salicylic acid (Pentasa) has been performed in 40 patients with active Crohn's disease. Over a 6-week period, Pentasa (1.5 g daily) was no different to the dummy tablet in terms of clinical activity (Harvey-Bradshaw Index) or laboratory indicators of inflammation. No serious adverse reactions occurred. Oral mesalamine (Asacol) in a dose of 3.2 g/day was administered in a 16-week placebo-controlled trial in 38 patients for the treatment of mildly to moderately active Crohn's colitis or ileocolitis. Eighteen patients continued a stable dose of prednisone of no more than 20 mg/day and 20 patients did not take prednisone. Changes in the Crohn's Disease Activity Index (CDAI) were used as the primary measure of efficacy. Oral mesalamine was effective in achieving partial or complete remission in 60% of patients as compared with 22% of placebo-treated patients. However, only 20 of 38 patients completed the 17-week study. The others withdrew early because of worsening of symptoms or were dropouts counted as failures. The high percentage of early withdrawals prevented comparison of mean 17-week CDAI scores. Although the number of patients in this study was relatively small, Asacol 3.2 g/day appears to be safe and effective treatment for mildly to moderately active Crohn's colitis and ileocolitis as compared with placebo, and this regimen is an option for treatment of patients who fail or are intolerant of sulfasalazine. Mesalamine is released from sulfasalazine in the colon and benefits colonic Crohn's disease. The mesalamine used in this study releases the drug throughout the small bowel and colon. Therefore, this study was designed to detect benefit for Crohn's disease involving the small bowel alone or both the colon and small bowel.
                This double-blind, randomized, multicenter prospective controlled trial compared placebo and three daily doses of mesalamine in 310 patients. The primary outcome criterion was change in the Crohn's Disease Activity Index (CDAI) from baseline to final study visit.
                Patients taking 4 g/day mesalamine experienced a decrease of 72 CDAI points compared with 21 points in the placebo group (P < 0.01). Remission occurred in 43% of the 4-g group and 18% of the placebo group. Patients with ileum-only disease showed a 93-point improvement on 4 g mesalamine, compared with a 2-point improvement in similar patients on placebo. Mesalamine in this trial was not associated with clinically significant toxicity.
                This controlled-release mesalamine preparation is safe and effective at 4 g/day as a single agent in treatment of active Crohn's disease of the ileum and colon. The efficacy of 5-aminosalicylic acid (mesalamine) in the treatment of flare-ups of Crohn's disease is controversial. In previous studies, different locations and pathological behavior of Crohn's disease could have obscured the efficacy of these drugs that deliver their substance in different intestinal sites. The present study tested two different mesalamine formulations with 6-methylprednisolone in mild to moderate active Crohn's ileitis.
                Ninety-four patients with Crohn's ileitis (Crohn's Disease Activity Index [CDAI], 180-350) were randomly assigned to receive for 12 weeks mesalamine tablets, 4 g (35 patients); mesalamine microgranular preparation, 4 g (28 patients); and 6-methylprednisolone, 40 mg (31 patients). Mesalamine microgranular preparation was a gelatin capsule containing 400 mg of mesalamine microgranules coated with Eudragit S, which has been shown to deliver the drug in the terminal ileum.
                Patients taking mesalamine tablets experienced a decrease of CDAI median score value of 113.5 (95% confidence interval [CI], 33-149) compared with 123 (95% CI, 77-155) in the mesalamine microgranular group and 154 (95% CI, 99-197) in the 6-methylprednisolone group (P = 0.07 [NS]). Remission at the final visit occurred in 19 of 31 (61%) patients taking steroids compared with 21 of 35 (60%) patients taking mesalamine tablets and 22 of 28 (79%) patients taking microgranular mesalamine (NS). Five patients on steroids were withdrawn because of side effects, and a case of pancreatitis was related to microgranular mesalamine.
                Mesalamine in microgranular formulation seems to be equally as effective as a standard dosage of steroids in the treatment of the mild to moderate form of Crohn's ileitis. A short-term double-blind controlled trial has been performed comparing a slow-release 5'-aminosalicylic acid (5-ASA) tablet (Pentasa) with placebo in the outpatient treatment of mild and moderate active Crohn's colitis. The disease activity was measured objectively by quantitation of the faecal excretion of 111In-labelled autologous granulocytes, which directly reflects gut inflammation. Twelve patients were randomized to receive either Pentasa or placebo. After 10 days of treatment faecal granulocyte excretion fell in all patients receiving 5-ASA, while no consistent change was found in the placebo group. These results suggest that this slow-release preparation of 5-ASA should be tested in larger controlled therapeutic trials over a longer period of time. The response of active and quiescent Crohn's disease to prednisone, sulfasalazine, or azathioprine has been studied in 569 patients in a placebo-controlled, randomized, multicenter cooperative trial. The response of active symptomatic disease to prednisone or sulfasalazine was significantly better than to placebo. Response to azathioprine was better than to placebo, but the difference did not reach conventional levels of statistical significance. Patients with colonic involvement were especially responsive to sulfasalazine, and those with small bowel involvement were especially responsive to prednisone. Patients' drug therapy immediately before entry to the study significantly affected subsequent response. For patients with quiescent disease, none of the drugs was superior to placebo in prophylaxis against flare-up or recurrence. There is less than a 5% risk that a clinically significant prophylactic effect of any of the drug regimens was missed. : Olsalazine, consisting of two salicylate radicals linked by an azo-bond, is effective in the treatment of active ulcerative colitis. To test its effect in patients with mild to moderate attacks of Crohn's disease, the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) designed a multicentre, randomised, double-blind, placebo-controlled study. Ninety-one patients from four centres were randomised to receive either olsalazine, 1 g b.i.d., or matching placebo tablets. Twenty-six patients had ileal disease; 43, ileocolonic; and 22, colonic. Thirty-five of 46 patients taking olsalazine and 24 of 45 patients taking placebo were withdrawn before the end of the 4-month study. Diarrhoea was the most common reason for withdrawal from the olsalazine group, accounting for 22% of the patients, as compared with 4% in the placebo group. No other side effects were reported. There was no difference in the remission rate or withdrawal rate for active disease in the two groups. However, when an intent-to-treat analysis was performed, only eight of the 46 (17%) olsalazine-treated patients were considered to have entered remission or improved their symptoms compared with 22 of the 45 (49%) placebo-treated patients (p < 0.03). This study was unable to show that patients with mild to moderate attacks of Crohn's disease were significantly improved by treatment with olsalazine at a dose of 1 g daily. However, the potential benefit of a higher dose cannot be excluded.