Double-Blind Comparison of Slow-Release 5-Aminosalicylateand Sulfasalazine in Remission Maintenance in Ulcerative Colitis

Transcription

1 GASTROENTEROLOGY 1988;95: ALIMENTARY TRACT Double-Blind Comparison of Slow-Release 5-Aminosalicylateand Sulfasalazine in Remission Maintenance in Ulcerative Colitis CHRIS J. J. MULDER, GUIDO N. J. TYTGAT, IRENE T. WETERMAN, WILLEM DEKKER, PAUL BLOK, MAX SCHRIJVER, and HERBERT V.D. HEIDE Department of Gastroenterology-Hepatology, Academic Medical Center, Amsterdam; Department of Gastroenterology, Academic Hospital, Leiden; Department of Gastroenterology, Elisabeth Gasthuis, Haarlem; Department of Pathology, Municipal Medical and Health Center, Haarlem; and Department of Internal Medicine, Bronovo Hospital. The Hague, the Netherlands The results of a clinical trial comparing slowrelease 5-aminosalicylic acid tablets (Pentasa) and enteric-coated sulfasalazine tablets (Salazopyrin) with regard to the efficacy of maintaining ulcerative colitis patients in remission for 12 mo and with regard to safety of treatment are reported. Seventyfive patients with ulcerative colitis in remission for between 1 mo and 5 yr were included for analysis. Forty-nine men and 26 women, aged between 18 and 79 yr, received either Pentasa t.i.d. (1500 mg) plus Salazopyrin placebo or Salazopyrin t.i.d. (3 g) plus Pentasa placebo daily. Patients were assessed clinically, endoscopically, and histologically before and 3, 6, 9, and 12 mo after the start of treatment. Life-table analysis showed ongoing remission after 6 and 12 mo for Pentasa to be 63% (26 of 41) and 54% (22 of 41) and for Salazopyrin 72% (22 of 31) and 46% (14 of 31). These differences were not statistically significant. Three patients treated with Salazopyrin were withdrawn because of severe erythrodermia, anxiety and backache, and pregnancy, respectively. One patient on Salazopyrin experienced transient rises in serum urea, creatinine, and lactic dehydrogenase and another patient in this group reported slight reversible loss of hair. In the Pentasa group no side effects were recorded. We conclude that Pentasa is a well-tolerated drug, equally effective as Salazopyrin in maintenance of remission of ulcerative colitis. keep the condition of the patient stable, maintaining remission whenever possible. Sulfasalazine (salicylazosulfapyridine) has been shown to be effective in treating acute attacks of UC (1,2) and also in maintaining remission (3-5). However, tolerance to the drug is often poor (6). Sulfasalazine consists of sulfapyridine and 5-aminosalicylic acid (5-ASA) joined by an azo-bond, which is split by bacteria in the colon, releasing the constituents. The sulfapyridine moiety is now known to cause the majority of the adverse reactions of sulfasalazine, including allergy, whereas the 5-ASA moiety has been shown to be the active component in inflammatory bowel disease (7-11). The latter drug has been investigated in oral, enema, and suppository forms in active colitis and in refractory proctitis (7-14). 5-Aminosalicylic acid cannot be given by mouth as it is unstable in acid and is rapidly absorbed by the small intestine. Delivery systems have been developed to bypass this problem. The Pentasa tablets used in this study have been designed to release 5-ASA slowly and in a phdependent way. Part of the active substance is released and about a third absorbed in the small intestine; therefore, the majority is available for activity in the distal ileum and colon (15,16). 5- Aminosalicylic acid coated with an acrylic-based resin has been tested for maintenance therapy in UC (17,18). The natural history of ulcerative colitis (UC) is characterized by periods of remission interspersed with exacerbations. The aim of therapy is to Abbreviations used in this paper: 5-ASA, 5-aminosalicylic acid; UC, ulcerative colitis by the American Gastroenterological Association /88/$3.50

2 1450 MULDER ET AL. GASTROENTEROLOGY Vol. 95, No.6 Until now clinical experience with Pentasa tablets has been limited to small groups of patients. This study was designed to compare the efficacy and safety of 5-ASA acid microgranules coated with a semipermeable membrane of ethyl cellulose (Pentasa) with sulfasalazine for maintenance of remission in UC. Materials and Methods Study Design This study was designed as a double-blind, doubledummy, randomized multicenter study. The aim was to compare the efficacy of 12 mo of treatment with slowrelease 5-ASA tablets (Pentasa) and sulfasalazine entericcoated tablets (Salazopyrin E.C) in preventing relapse in patients with UC in remission and to compare the incidence of side effects and the tolerance to these two treatments. Ulcerative colitis was diagnosed by assessing the usual clinical, endoscopic, and histologic criteria (19-21). The study was conducted under the provisions of the Declaration of Helsinki. Patients Male and female outpatients, aged 2:18 yr, with UC in remission for between 1 mo and 5 yr who had not taken steroids (either orally or as an enema) or azathioprine during at least 1 mo before entry were included. Excluded were all pregnant and lactating women, women of childbearing potential not taking adequate contraceptive measures, patients who were likely to be unreliable to follow the instructions properly, patients allergic to aspirin, other salicylates, or sulfonamides, patients with malignant disease, and patients with renal disease, especially those with analgesic nephritis. Randomization According to a double-blind randomization code, patients were either allocated to treatment with active Pentasa tablets + placebo Salazopyrin E.C tablets or to placebo Pentasa tablets + active Salazopyrin E.C tablets. Medication Patients received either 6 tablets (1500 mg) of Pentasa plus 6 placebo tablets of Salazopyrin E.C or 6 placebo tablets of Pentasa plus 6 tablets (3 g) of Salazopyrin E.C daily. The patients were instructed to take their daily dosage in three doses before or after the main meals. The duration of treatment was 12 mo. Tpe placebo tablets were identical in appearance, weight, and taste. Assessments Before the start of the study, all relevant medical and family history data were noted, including symptoms, duration of disease, previous therapy, response to previ- ous therapy, allergy, and all other (concomitant) therapy previously taken by the patient. Patients were assessed clinically, endoscopically (recto/sigmoidoscopy) (20), and histologically (21) before and 3, 6, 9, and 12 mo after the start of treatment. At endoscopy the mucosal color, vessel pattern, granularity, presence of valves, distention, polypoid structures, ulcers, spontaneous hemorrhage, and mucopurulent covering were studied and a wipe-test was performed to determine friability. Overall, endoscopy was scored from normal through mild, moderate, and severe abnormality to very severe abnormality. As for histology, the biopsy specimens were examined for edema and hemorrhage in the mucosa and submucosa, for quality and quantity of mucosal cellular infiltrate, and for epithelial architecture of the crypts. They were finally scored as normal, little inflammation, medium inflammation, severe inflammation, or UC in remission. Patients were assessed immediately if symptoms developed or if side effects occurred. After the completion of the study it was to be determined whether a patient had remained in remission or not. The following criteria were used to assess this: If all the data obtained at each visit were assessed as "normal" or "in remission," the patient was considered to have remained in remission. If at any time during the study all the data obtained were not considered to be "normal" or "in remission" or if the investigator had given a prescription for additional treatment (e.g., enemas), then the patient was considered to have experienced relapse. In case of abnormalities in only one or two of the assessment groups (clinical, endoscopic, histologic), the patient's data were discussed by the monitor with a blinded investigator. In this way a final judgment as to whether the patient had remained in remission or not was given. Relevant laboratory data were obtained during every visit [erythrocyte sedimentation rate, hemoglobin, hematocrit, leukocytes, thrombocytes, albumin, alkaline phosphatase, total protein, y-glutamyl transaminase, urea, creatinine, lactic dehydrogenase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and urine (protein, glucose, and sediment)). During each visit the patients were asked whether any unusual event had occurred during the preceding period. The patients were not asked for specific signs or symptoms. Side effects were recorded on special forms. Statistics Before evaluating the results of therapy, it was checked whether the groups were comparable per treatment and per center. This was done using analysis of variance, Student's t-test, y tests, Fisher's test (two-sided), and Mantel-Haenszel y tests where appropriate. The data concerning the remission rates were statistically evaluated using life-table analysis with the SAS statistical package and the log-rank test was applied to detect significant differences.

3 December AMINOSALlCYLlC ACID IN UC 1451 Table 1. Initial Patient Data Pentasa Salazopyrin p n Sex (M/F) 29/12 20/14 NS Age Mean ± SD (yr) 43.3 ± ± 11.5 Range (yr) NS Duration of disease Mean ± SD (yr) 9.7 ± ± 8.4 Range (yr) 0.5 ± ± 40 NS Duration of remission before the trial Mean ± SD (mo) 13.6 ± ± 10.1 NS Range (mo) Median (mo) NS Extent of disease Proctitis 11 7 Proctosigmoiditis Left-sided colitis Pancolitis 8 4 NS Salazopyrin therapy during NS month before entry (n) NS, not significant. Results Dropouts Three patients dropped out of the study before the first follow-up visit. One patient (Salazopyrin) considered the tablets unpalatable and 2 patients stopped the therapy because of lack of motivation (Pentasa 1, Salazopyrin 1). Dropouts were not included in the analysis. Protocol Violations Six patients on Pentasa and 6 patients on Salazopyrin did not fulfil the inclusion criteria: they had not been in complete remission at least 1 mo before entry into the study. These patients were only included in the safety analysis. Patients Seventy-five patients, 49 men and 26 women, with ages ranging from 18 to 79 yr were available for analysis. Forty-one were treated with Pentasa and 34 with Salazopyrin. Eight of the 41 patients in the Pentasa group stopped the trial medication after they had experienced a relapse, despite the investigator's request to continue. Four patients in the Salazopyrin group did the same. Another 3 patients in the Salazopyrin group were withdrawn: one developed severe erythrodermia 5 wk after the start of treatment, another complained of anxiety and backache 6 wk after the start of treatment, and the third left the study after 3 mo of therapy because of pregnancy (a healthy baby was born), but she continued open Salazopyrin therapy. Patient Characteristics Both groups were comparable for all parameters per treatment and per center. All except 2 patients had been on sulfasalazine before the study (Table 1). Evaluation of Efficacy in Maintaining Remission The data of 41 patients treated with Pentasa and 34 patients treated with Salazopyrin in four centers were included in the life-table analysis for calculating the remission rates. The results are shown in Figure 1. No significant differences between the two treatments were revealed ct = 0.14, df = 1, P > 0.70). The final remission rates were 54% for Pentasa and 46% for Salazopyrin, with 95% confidence intervals of 38%-69% for Pentasa and 29%-64% for Salazopyrin. The difference is 8% in favor of Pentasa, with a 95% confidence interval of -16% to +31%. Safety Analysis Laboratory findings. One patient on Pentasa had transient slight abnormalities in the urinary sediment (bacteria, leukocytes, and erythrocytes) at 3 and 9 mo. One patient on Salazopyrin had a transient rise in serum urea, creatinine, and lactic dehydrogenase after 3 mo of therapy. Eighteen days later the values were normalized. The possibility of a laboratory error was considered. Tolerance. One patient on Salazopyrin dropped out almost immediately because she thought the tablets were unpalatable. Two patients receiving Salazopyrin, one developing severe erythrodermia and another anxietylbackache, were dis- % remission o Therapy -- Pentasa Salazopyrin '---, , Figure 1. Remission rates. - months after start of therapy, '-

4 1452 MULDER ET AL. GASTROENTEROLOGY Vol. 95, No.6 cussed above as withdrawals. Another patient on Salazopyrin reported slight loss of hair during the treatment, which seemed to recover after treatment was stopped. Discussion No statistically significant differences were revealed between Pentasa and Salazopyrin with respect to their ability to maintain remission in Uc. There was a slight trend in favor of Pentasa as it maintained remission in 54% of patients over the year whereas the figure for Salazopyrin was 46%. Several studies have been published showing that 5-ASA, when delivered to the colon in a suitable form, is effective in UC (16). This study not only provides additional evidence of 5-ASA being the active moiety of sulfasalazine but also demonstrates that, when given in the Pentasa slow-release preparation, it is at least as effective as the "parent drug." It has already been argued that Pentasa, on theoretical grounds, should constitute an advance with regard to tolerance. Should adverse reactions be observed they will in all likelihood be limited to those ascribed to the salicylates in general. The rate at which the patient is able to acetylate absorbed 5-ASA may playa major part in the frequency and severity of side effects. In this study Pentasa lived up to expectations as no adverse reactions were recorded. In contrast, 3 patients in the Salazopyrin group suffered side effects. Hair loss during Salazopyrin therapy was recently reported by others too (22). One patient in our study had to be withdrawn because of severe erythrodermia. It is well known that sulfasalazine can cause reactions necessitating discontinuation of therapy (6). In this study we did not monitor plasma levels or urinary excretion of 5-ASA or its main metabolite acetyl-5-asa. However, a Danish group recently published the results of Pentasa and Salazopyrin urine and plasma level determinations in patients with UC and Crohn's disease (23,24). Although these studies do not involve a direct comparison of similar patient groups, we believe that it can be concluded that 1.5 g/day Pentasa is probably as safe as Salazopyrin as far as the 5-ASA moiety is concerned. This study shows that Pentasa is another promising slow-release 5-ASA preparation, equally effective in maintaining remission in colitis and therefore especially useful in patients unable to take sulfasalazine (25). References 1. Baron JH, Connell AM, Lennard-Jones JE, Avery Jones F. Sulphasalazine and salicylazosulphadimidine in ulcerative colitis. Lancet 1962;i:l Dick AP, Grayson MJ, Carpenter RG, Petrie A. Controlled trial of sulphasalazine in the treatment of ulcerative colitis. Gut 1964;5: Misiewicz n, Connell AM, Lennard-Jones JE, Baron JH, Avery Jones F. Controlled trial of sulfasalazine in maintenance therapy of ulcerative colitis. Lancet 1965;i: Dissanayake AS, Truelove SC. A controlled therapeutic trial of long-term maintenance treatment of ulcerative colitis with sulfasalazine. Gut 1973;14: Azad Khan AK, Howes DT, Piris J, Truelove SC. Optimum dose of sulfasalazine for maintenance treatment in ulcerative colitis. Gut 1980;21: Das KM, Eastwood MA, McManus JPA, Sireus W. Adverse reactions during salicylazosulphapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med 1973;289: Azad Khan AK, Piris J, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 1977;ii: Klotz U, Maier K, Fischer C, Heikel K. Therapeutic efficacy of sulphasalazine and its metabolites in patients with ulcerative colitis and Crohn's disease. N Engl J Med 1980;303: Van Hees PAM, Bakker JH, Van Tongeren JHM. Effect of sulphapyridine, 5-aminosalicylic acid and placebo in patients with idiopathic proctitis: a study to determine the active therapeutic moiety of sulphasalazine. Gut 1980;21: Campieri M, Lanfranchi GA, Bazzocchi G, et al. Treatment of ulcerative colitis with high-dose 5-aminosalicylic acid. Lancet 1981;ii: Rasmussen SN, Binder V, Maier K, et al. Treatment of Crohn's disease with peroral 5-aminosalicylic acid. Gastroenterology 1983;85: Willoughby CP, Campieri M, Lanfranchi G, Truelove SC, Jewell DP. 5-Aminosalicylic acid (Pentasa) in enema form for the treatment of active ulcerative colitis. Ital J Gastroenterol 1986;18: Friedman LS, Richter JM, Kirkham SE, DeMonaco HJ, May RJ. 5-Aminosalicylic acid enemas in refractory distal ulcerative colitis: a randomized, controlled trial. Am J Gastroenterol 1986;81: Campieri M, Lanfranchi GA, Bertoni F, et al. A double-blind trial to compare the effects of 4-aminosalicylic acid to 5- aminosalicylic acid in topical treatment of ulcerative colitis. Digestion 1984;29: Rasmussen SN, Bondesen S, Hvidberg EF, et al. 5-Aminosalicylic acid in a slow-release preparation: bioavailability, plasma level, and excretion in humans. Gastroenterology 1982 ;83 : Christensen LA, Sanchez G, Rasmussen SN, et al. The influence of intestinal transit time on 5-ASA from Pentasa (abstr). Gastroenterology 1986;90: Dew MJ, Ryder REJ, Evans N, Evans BK, Rhodes J. Colonic release of 5-aminosalicylic acid from an oral preparation in active ulcerative colitis. Br J Clin Pharmacol 1983;16: Dew MJ, Hughes P, Harries AD, Williams G, Evans BK, Rhodes J. Maintenance of remission in ulcerative colitis with oral preparation of 5-aminosalicylic acid. Br Med J 1982;285: Tytgat GNJ, van Olffen G. Role of ileocolonoscopy in diagnosis and follow up of inflammatory bowel disease. Acta Endosc 1983;13: Van der Heide H, van den Brandt-Gradel V, Tytgat GNJ, Endert E, Schipper M, Dekker W. Comparison of Beclomethasone-dipropionate and prednisolone-21-phosphate enemas

5 December AMINOSALICYLIC ACID IN UC 1453 in distal ulcerative colitis. J Clin Gastroenterol 1988;10: Morson BC, Dawson LMP. Gastrointestinal pathology. 2nd ed. Oxford, London, Edinburgh, Melbourne: Blackwell, Codeluppi PL, Chahin NJ, Merighi A, Rigo G, Manenti F. A complication of SASP therapy: hair loss. Dig Dis Sci 1987;32: Rasmussen SN, Lauritsen K, Tage-Jensen U, et al. 5-Aminosalicylic acid in the treatment of Crohn's disease. Scand J GastroenteroI1987;22: Bondesen S, Nielsen OH, Schou JB, et al. Steady-state kinetics of 5-aminosalicylic acid and sulphapyridine during sulfasal- azine prophylaxis in ulcerative colitis. Scand J Gastroenterol 1986;21 : Mulder CU, Tytgat GNJ, Dekker W, Terpstra IJ. Pentasa in lieu of sulfasalazine. Ann Intern Med 1988;108: Received June 24, Accepted April 21, Address requests for reprints to: Dr. C.J.J. Mulder, Department of Gastroenterology-Hepatology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. The authors thank Jenny Peeters and Janke Turksema for secretarial assistance.