Slow-release 5-amino-salicylic acid (Pentasa) for the treatment of active Crohn's disease

Digestion 1990;45:88-92© 1990 S. Kargcr AG, Basel 0012-2823/90/0452-0088S2.75/0Slow-Release 5-Amino-Salicylic Acid (Pentasa®) for the Treatment of Active Crohn’s DiseaseY.R. Mahida. D.P. JewellGastroenterology Unit, Radcliffe Infirmary, Oxford, UKKey Words. 5-Amino-salicylic acid •Pentasa® •Mesalazine •Crohn’s diseaseAbstract. 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.Sulphasalazine is of proven benefit in the treatment of patients with ulcerative colitis [1,2] and it is now clear that the 5-amino- salicylic acid (5-ASA) moiety of the drug is the active component [3, 4], Whether sul­phasalazine is effective in the treatment of patients with Crohn’s disease is much less clear-cut. Van Hees et al. [5] reported that sulphasalazine in a dose of 4-6 g was signifi­cantly better than placebo for active Crohn’s disease, regardless of the anatomical loca­tion of the disease. On the other hand, the National Co-Operative Crohn’s Disease Study [6] found that sulphasalazine was only effective in patients with colonic disease. The same study did not find that it was effec­tive in the long-term, and four studies have failed to show that sulphasalazine reduces the relapse rate following surgical resection[6-9].In one small trial, the beneficial effect of sulphasalazine in active Crohn’s colitis ap­peared to be attributable to the 5-ASA moi­ety [10], Recently a group of patients with Crohn’s disease were treated with a slow- release preparation of 5-ASA for a period of6 weeks [11]. 72% of patients improved clin­ically and with respect to an activity index.Slow-release tablets of 5-ASA, as opposedto delayed-release 5-ASA, consist of granulesof 5-ASA coated with ethyl cellulose. The thickness of the coating is controlled to en­sure constant release characteristics. Phar­macokinetic studies in man have shown thatthis preparation delivers high concentrationsof 5-ASA to the ileum and colon [12], Hence,01A M5-Amino-Salicylic Acid for Crohn’s Disease89it might be more efficient at treating ileal Crohn’s disease than sulphasalazine. This pi­lot trial was, therefore, set up to assess the efficacy of slow-release 5-ASA in patients with active Crohn’s disease.Patients and MethodsPatients40 patients were admitted to a randomised dou­ble-blind trial of Pentasa®. Patients were admitted if they had evidence of active disease as indicated by symptoms, physical examination and inflammatory indicators - erythrocyte sedimentation rate (ESR), C- reactive protein (CRP), orosomucoids-, but who were not judged sufficiently ill to warrant corticosteroids. If the distribution of disease had not been docu­mented within the last year, barium radiology and/or colonoscopy were performed. Patients already receiv­ing corticosteroids or azathioprine were excluded but not if they were on sulphasalazine. The latter drug was stopped on entry into the trial.Patients under the age of 18 were not admitted, neither were those with fistulae, severe perianal dis­ease or ileostomy. Pregnancy, coexisting liver or renal disease, and hypersensitivity to salicylates were other exclusion criteria. Women of child-bearing age were advised not to conceive during the study.Trial DesignA double-blind design was employed. Patients were randomised to receive Pentasa or dummy tab­lets according to a pre-arranged schedule which was held by the hospital pharmacist. Randomization was performed in blocks of 6 patients to ensure an equal balance. The dose schedule was 2 tablets Pentasa (500 mg) 3 times a day and the trial period was 6 weeks.AssessmentPatients were assessed on entry and at 6 weeks. Details of their general well-being, stool frequency and consistency, abdominal pain and the presence of extra-intestinal manifestations, abdominal mass or fistulae were obtained. This allowed the index of dis­ease activity of Harvey and Bradshaw [13] to be cal­culated. Improvement was defined as a reduction in score by 2 or more points. In addition, a full bloodTable 1. Demographic detailsPentasa DummySexMale119Female911AgeMean32.735Range18-5019-74Disease distributionIleal913Ileo-colic51Colonic66Length of history,Mean ± SD, years7.9±8.6 6.8 ± 8.2count, a biochemical screen, ESR. CRP and orosomu-coid was obtained; urinalysis was also performed. Compliance was assessed by tablet counting.EthicsThe study had the approval of the central Oxford Research and Ethics Committee.StatisticsAnalysis was performed using Fisher's exact testand a paired Student’s t test.ResultsTable 1provides the demographic details.The 20 patients who received Pentasa were closely matched with respect to age, sex, dis­tribution of disease and length of history tothe 20 who received dummy tablets. Theywere also well matched for activity indexand for laboratory indicators of inflamma­tion (table 2).On an intention-to-treat basis, 8 patients (40%) treated with Pentasa improved as judged by a fall in their activity score of 2 points or more compared with 7 patients (35%) receiving dummy tablets (p >0.1).01A M90Mahida/Jewell Table 2. Laboratory indicators of inflammation before and after the trial period (means ± SD)Pentasa Dummybefore after before afterHarvey-Bradshaw score 5.2+1.8 4.6± 3.5 5.0± 1.3 4.4 ±2.5 ESR19.2 ± 12.319.8 ±13.030.3 ±21.929.4±23.8 CRP 1.5 ±1.4 2.7 ±3.5 2.1 ±2.8 2.5 ± 2.9 Orosomucoids89.8 ±22.4101.6 ± 44.492.1 ±26.498.2 ± 35.5 Hb12.8± 1.312.6 ± 1.313.3 ± 2.113.4 ± 2.4 WBC8.4+ 1.99.3±2.98.8±2.58.5 ± 3.2 Albumin39.5±4.339.2± 3.639.6 ±3.439.5 ±4.4 For all, before vs. after: p >0.01.Table 3. Number of patients improving by disease distributionPentasa Dummytotal improved total improved Ileal93135Ileo-colic5210 Colonic6462 Although the numbers are too small for meaningful analysis, there was a trend for colonic disease to respond to Pentasa better than to the dummy tablet (table 3).Table 2 also gives data of ESR, CRP and orosomucoid before and after the trial peri­od. No significant differences were observed and, when analysed for site of disease, no trend was shown in favour of Pentasa.11patients failed to complete the 6-week trial period. In the Pentasa group, 4 (all with ileal disease) were withdrawn for deteriorat­ing symptoms and 3 for intolerance. The rea­sons for intolerance were abdominal disten­sion and pain (1), and malaise (2). Symp­toms improved on withdrawal. In those re­ceiving dummy tablets, 3 (2 ileal, 1colonic) withdrew because of clinical deteriorationand 1for intolerance (nausea).No abnormalities in urea, creatinine, bili­rubin, aspartate, transaminase, alkaline phosphatase or urinalysis were noted duringthe study.DiscussionThe role of sulphasalazine for the treat­ment of active Crohn’s disease is not proven.The National Co-Operative Crohn’s DiseaseStudy [6] found that sulphasalazine in adaily dose of 2 g appeared to be beneficialonly for patients with colonic disease. How­ever, using larger doses (4-6 g daily), VanHees et al. [5] claimed significant improve­ment compared with placebo in patients, re­gardless of the site of disease.Since 5-ASA is released from sulphasala­zine by bacterial action [14], it is likely thatthe concentration of 5-ASA in the ileum may01AM5-Amino-Salicylic Acid for Crohn’s Disease91not be sufficient to influence ileal disease even though bacterial counts may rise in the presence of inflammation. Hence, the de­layed release forms of 5-ASA may be more appropriate for small intestinal disease. Pen- tasa, in particular, has been shown to deliver high concentrations of 5-ASA to the ileal mucosa [12].Two of the major difficulties of assessing therapy in patients with Crohn’s disease are the criteria by which disease activity is judged [ 15] and the diversity of the disease. The latter dictates that large numbers of pa­tients are required to allow adequate statisti­cal analysis. The present trial was set up as a pilot study in order to determine whether a large-scale trial was justified. The results showed no overall improvement over a 6- week period, either assessed by the Harvey- Bradshaw clinical activity score or by labora­tory indicators of inflammation. There ap­peared to be a trend in favour of 5-ASA for patients with colonic disease as shown by the activity index. It was also noteworthy that 4 patients with ileal disease treated with Pen- tasa had to be withdrawn for worsening dis­ease whereas all 6 with colonic disease com­pleted the trial. This trend supports a pre­vious study which showed that Pentasa re­duced the faecal excretion of 11'In-labelled granulocytes in patients with mildly active Crohn’s colitis [16].Recently, the results of another double­blind trial of Pentasa in 67 patients with active Crohn’s disease have been published [ 17], The dose was similar to that used in the present study (1.5 g) but the trial period ex­tended over 16 weeks. No statistical differ­ences were observed in the outcome of either the Pentasa-treated or placebo groups, as shown by a reduction in the Crohn’s disease activity index.In conclusion, the data so far do not sup­port a major therapeutic role for Pentasa forthe treatment of active Crohn’s disease.There may be some effect in patients with colonic disease but large trials will be re­quired to demonstrate this with certainty. A recently published abstract suggests that a delayed-release form of mesalazine (Claver-sal) may be beneficial for maintaining remis­sion of Crohn’s disease, especially when it affects the ileum [18]. This observation willalso require confirmation by other studies.References1Misiewicz JJ, Lennard-Jones JE, Connell AM, ctal: Controlled trial of sulphasalazinc in mainte­nance therapy for ulcerative colitis. 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Scand J Gastroenterol 1987;22:877-883.18 Thomson ABR: 'MesalVClaversal' (5-ASA) pre­vents relapse and maintains remission of inactiveCrohn’s disease. Gastroenterol Int 1988:1 (suppl1): 165.Received: April 14, 1989Received in revised form: October 17, 1989D.P. JewellGastroenterology UnitRadcliffe InfirmaryWoodstock RoadOxford OX2 6HE (UK)1AM。