Gut: first published as 10.1136/gut.30.5.675 on 1 May 1989. Downloaded from CGit, 1989, 30, 675-679 Clinical trial Olsalazine or sulphasalazine in first attacks of ulcerative colitis? A double blind study

S S C RAO, S A C DUNDAS, C D HOLDSWORTH, P A CANN, K R PALMER, AND C L CORBETT From the Royal Hallamshire Hospital, Sheffield, Western General Hospital, Edinburgh and District Genieral Hospital, Worksop

SUMMARY Olsalazine (2 g/day) and sulphasalazine (3 g/day) were compared in a double blind three centre trial in 37 patients presenting with first attack of distal colitis. Sigmoidoscopic appearances, rectal biopsies, and symptom and stool diary records were used to assess benefit and adverse effects. Both groups showed a similar decrease in stool frequency (p<0001). The proportion of unformed stools was also decreased, but to a lesser extent (p<005) in those taking olsalazine (78% v 55%; p

5-aminosalicylic acid has been shown to be the active colitis`' and as effective as sulphasalazine in main- therapeutic principle of sulphasalazine, 1-3 and is taining remission. Its efficacy as primary treatment, useful in the treatment of ulcerative colitis.'4 Its however, has not been established. exact mechanism of action is not known but it may act In a randomised double blind, double dummy, by blocking prostaglandin synthesis in the mucosa -7 multicentre clinical trial, we have compared the short and/or as an anti-oxidant by suppressing oxidative term efficacy and tolerance of olsalazine and sulpha- metabolism of polymorphonuclear leucocytes.' salazine in new patients presenting with colitis. Olsalazine consists of two molecules of 5-ASA linked together by an azo bond.9"' After oral ingestion, most Methods of the drug reaches the colon where it is split by colonic bacteria to release 5-ASA.9" PATI ENTS Approximately 80% of patients intolerant of All patients studied were outpatient referrals with sulphasalazine can tolerate olsalazine." "In control- their first attack of mild or moderately severe ulcera- led trials of patients, a majority of whom were tive colitis,' confirmed by sigmoidoscopic and histo- withdrawn from sulphasalazine, olsalazine has been logical evidence, and negative stool culture for shown to be superior to placebo in the treatment of pathogens. Patients were excluded if they had severe Address for correspondence: Dr C D Holdsworth, Gastroenterology Unit. colitis or were considered sufficiently ill to require Royal Hallamshire Hospital, Glossop Road, Sheffield Sit) 2JF. corticosteroids or had hepatic or renal dysfunction. Accepted for publication 14 October 1988. The study was carried out in three centres, but 675 Gut: first published as 10.1136/gut.30.5.675 on 1 May 1989. Downloaded from

676 Rao, Dundas, Holdsworth, Cann, Palmer, and Corbett

Table 1 Details ofpatients at trial entry disease was considered to be in remission if the stools did not contain any blood (macroscopically), there Olsalazine Sulphasalazine were no more than two bowel actions per day and there was no systemic disturbance. A scoring system Patients (n) 20 17 Male:female 9:11 8:9 was used in which a change of at least one grade Mean age: years (range) 46 (19-77) 42 (21-71) constituted one point which was positive for improve- Mean duration of history: months 3.7 (1-12) 4.4 (0.5-13) ment and negative for deterioration. Diary infor- (range) mation was used to determine mean daily stool Sigmoidoscopic appearance: Mild 3 0 frequency, the percentage of stools that were Moderate 9 10 unformed, and the proportion of bloody stools Severe 8 7 during the first three days and the last three days of Daily stool frequency (mean (SD)) 4 3 (1.9) 3 9 (1.9) treatment. Overall improvement was assessed and was defined as a positive change in at least two of the following criteria: sigmoidoscopic appearances, the majority of patients (32) were entered from histological appearances, clinical severity, and Sheffield. The extent of disease was determined by percentage of bloody stools. sigmoidoscopy and/or barium enema. All of the patients had proctosigmoiditis or left sided colitis. TREATMENT REGIMEN The clinical details of the patients are shown in In a preliminary study, we carried out a double blind, Table 1. double dummy comparison of 2 g olsalazine with 4 g Patients were randomly allocated to receive either sulphasalazine (enteric coated), administered daily olsalazine or sulphasalazine along with physically in four equally divided doses. All doses for the first indistinguishable dummies containing mainly potato three days contained placebo only, and the full daily starch. The drugs were provided in sealed blister dose was attained by gradual increase over a further packs and were taken four times a day in equally four days. Eleven patients were entered in this study divided doses. At each visit the patients were asked which was terminated as a high proportion of patients to return the empty packs as a test of their compli- had experienced intolerable adverse effects. After ance. The duration of the study was four weeks. At breaking the code it was apparent that all four http://gut.bmj.com/ entry and at four weeks, the patients were assessed patients who had received olsalazine had tolerated clinically and underwent sigmoidoscopy and rectal the drug and improved clinically. In contrast, only biopsy, and had blood samples taken for estimating two of the seven patients who received sulphasala- haemoglobin, WCC, ESR, and liver biochemistry. zine tolerated the drug and improved clinically, the They also provided stool samples for microbiological other five having to stop the drug because of intoler- analysis and urine samples for analysis by dip sticks able adverse effects. These were nausea and dyspep-

(BM-Test-5L, Boehringer). All patients were pro- sia in three patients, headache, dizziness, and on September 29, 2021 by guest. Protected copyright. vided with diaries in which they recorded the date arthralgia in one patient, and a rash in one other and time of defecation, the presence of blood and the patient. All patients except the one who developed a consistency of stool (formed or unformed) and poss- rash, experienced adverse symptoms only after ible adverse effects. An interim clinical assessment receiving the full dose of sulphasalazine, implying was carried out at two weeks. Any patient who that the greater number ofwithdrawals was caused by experienced an adverse effect was seen promptly and dose related intolerance of sulphasalazine. The study if necessary was withdrawn from the study. was therefore redesigned using the same dose of Sigmoidoscopic appearance were graded as olsalazine (2 g/day) but a lower dose of enteric coated follows: normal=0, mild=1 (granular mucosa with sulphasalazine (3 g/day). The drugs were, as before, minimal or no bleeding), moderate=2 (definite provided in sealed blister packs and were adminis- contact bleeding), severe=3 (spontaneous bleeding). tered four times a day, full dosage being attained The rectal biopsy specimens were examined blind by gradually over seven days. one observer (SACD) and the degree of inflamma- tion was graded as follows: absent =0 (no evidence of ETHICAL CONSIDERATIONS inflammation), mild=1 (chronic glandular damage The protocol for the study was approved by the with definite increase in inflammatory cells), Ethical Committee of the Sheffield Health Authority moderate=2 (changes of mild inflammation plus in October, 1984, and all patients gave a written small foci of ulceration, severe=3 (changes of informed consent. moderate inflammation plus crypt abscess formation and widespread ulceration). The clinical severity was STATISTICAL ANALYSIS graded using Truelove and Witts criteria.`1 The The significance of the differences in the stool Gut: first published as 10.1136/gut.30.5.675 on 1 May 1989. Downloaded from

Olsalazine or sulphasalazine infirst attacks ofulcerative colitis? A double blindstudy 677

Table 2 Changes in sigmoidoscopic appearance, TOLERANCE histological grade, clinical and overall response There were no drug related haematological or biochemical abnormalities in any of our patients. Olsalazine Sulphasalazine Stool examination was negative for pathogens and (n= 18) (n= 13) urine analysis showed no abnormalities, except in Sigmoidoscopic response one patient who had glycosuria at entry, and was later Improved 15 (83%) 11(84%) diagnosed as having type II diabetes mellitus. Unchanged 3 (17%) 2 (16%) Worse 0 0 Histological response Olsalazine Improved 8 (44%) 6 (46%) Eighteen of 20 (90%) patients tolerated this drug Unchanged 10 (56%) 7 (54%) without any adverse effects. One patient experienced Worse 0 0 an exacerbation of diarrhoea and reported Clinical response that the Improved 16(89%) 10 (77%) stools were predominantly watery rather than Unchanged 2 (11%) 3 (23%) bloody. One other patient developed headache and Worse 0 0 nasal stuffiness. These adverse effects resolved after Overall response cessation of therapy. Improved 15 (83%) 9 (69%) Worse 0 0 Sulphasalazine No significant differences between treatments. Thirteen of 17 (76%) patients tolerated this drug. Adverse effects were encountered in four patients, of whom two experienced dyspepsia and nausea, one an Table 3 Influence oftreatment on stoolpattern exacerbation of bloody diarrhoea, and one myalgia, headache, and dizziness. Olsalazine Sulphasalazine The difference in tolerance between the two (n = 18) (n = 13) groups was not statistically significant (x2=0*45). Entry 4 weeks Entry 4 weeks STOOL FREQUENCY AND CONSISTENCY Daily stool frequency 4.4(2.0) 21 (1*2)* 3.9(1.7) 1-8(0.6)* There was a similar improvement (p<0-001) in the http://gut.bmj.com/ (mean (SD)) mean daily stool frequency in both groups of patients Unformed stools (% 78 55* 72 28* of total for group) (Table 2). An improvement (p<0.001) in the propor- Bloody stools (% of 61 22* 67 37* tion of unformed stools was seen in both groups of total for group) patients, but patients in the olsalazine group showed a smaller reduction (p<0-05) than patients in the *p<0-001. sulphasalazine group (Table 2). There was a reduc-

tion (p<0001) in the proportion of bloody stools in on September 29, 2021 by guest. Protected copyright. both groups of patients (Table 3).

frequency was determined by Student's paired t tests. SIGMOIDOSCOPIC AND HISTOLOGICAL The significance of improvement in disease gradings APPEARANCES was determined using Wilcoxson's paired rank-sum A similar proportion of both groups of patients tests. The changes in the sigmoidoscopy, rectal showed an improvement in sigmoidoscopic (p<0.01) biopsy and clinical severity scores (Table 2) were and histological (p<0.01) appearances (Table 2). analysed using x2 tests. The proportions of stools with different characteristics were compared using X2 tests CLINICAL IMPROVEMENT for multiway tables. There was an improvement in the clinical severity of disease (p<0-001) and overall response (p<0-01) in Results patients taking olsalazine and sulphasalazine. There was no difference in the clinical response between the PATIENT DETAILS two groups (Tables 2 and 3). Thirty nine patients were entered into the new study, of whom 21 received olsalazine and 18 received Discussion sulphasalazine. During the final analysis, one patient was excluded from each group because of non- Our study was unique in that none of the patients had compliance. The two groups were well matched for received any other therapy for ulcerative colitis age and sex distribution and for severity of disease before entering the study. Previous trials have com- activity (Table 1). pared olsalazine with placebo in patients who were Gut: first published as 10.1136/gut.30.5.675 on 1 May 1989. Downloaded from

678 Rao, Dundas, Holdsivorth, Cann, Palmer, and Corbett either withdrawn from sulphasalazine'" or were it must be pointed out that our study was conducted intolerant of this drug.'2'1 Similarly, a large study in patients with distal colitis and the tolerance of which compared the relapse prevention properties of olsalazine in this group may be different to that of olsalazine and sulphasalazine was also conducted in patients with total colitis.'2 In relapse prevention, patients whose sulphasalazine was withdrawn."1 which is the chief role of these drugs, it is established We have clearly shown that on the basis of clinical that 4 g sulphasalazine daily is more effective but response, sigmoidoscopic appearance, and histologi- tolerated by fewer patients than smaller doses."' cal changes that both drugs were effective in inducing Acceptable tolerance by most patients in our study of a remission within one month in a high proportion of 2 g olsalazine, which contains approximately as much patients with mild or moderately active distal ulcera- 5-aminosalicylic acid as 4 g sulphasalazine, suggests tive colitis. None of the patients who tolerated the that olsalazine could be the preferable drug. drug showed a deterioration in their disease activity. The histological improvement was not as striking as the improvement in sigmoidoscopic appearances or We would like to thank Pharmacia Limited for the clinical response, and is consistent with previous supply of the double dummy packs containing olsala- observations'" that there is a poor correlation zine capsules and sulphasalazine tablets, Sister Joy between the three methods of assessment and that Farnsworth for her help throughout the study and Mr microscopic evidence of active disease may be seen in J Nichols for advice with statistics. Dr Rao was the absence of sigmoidoscopic or clinical evidence of supported by a grant from the Trustees of the Former activity. Hence, although histological assessment is a United Sheffield Hospitals. more accurate measurement of disease activity, Previously published in Abstract form in Gut 1988; therapeutic benefit assessed by histological improve- 29: A705-6. ment lags behind improvement in symptoms and sigmoidoscopic appearance. Although there was a significant reduction in the References proportion of stools which were unformed in both the I Khan AKA, Piris J. Truelove SC. An experiment to groups, patients in the olsalazine group voided a determine the active therapeutic moiety of Sulphasala- significantly higher proportion of unformed stools zine. Lancet 1977; ii: 892-5. http://gut.bmj.com/ compared with patients in the sulphasalazine group 2 Van Hees PAM, Bakker JH, Van Tongeren JHM. after but not before treatment. This may be Effects of Sulphapyridine, 5-aminosalicylic acid and explained by previous physiological studies which placebo in patients with idiopathic proctitis; a study to showed that olsalazine increases ileostomy output2" determine therapeutic moiety of Sulphasalazine. Gut and reduces intestinal transit time," both of which 1980; 21: 632-5. 3 Klotz U, Maier K, Fischer C, Heinkel K. Therapeutic could affect stool consistency whereas sulphasalazine efficacy of Sulphasalazine and its metabolites in patients does not cause any such effects.""'2 In spite of this with ulcerative colitis and Crohn's disease. N EnglJ Med on September 29, 2021 by guest. Protected copyright. effect on stool consistency, there was a significant and 1980; 303: 1499-502. comparable reduction in stool frequency. When 4 Dew MJ, Hughes P, Harries AD, et al. Maintenance of assessed for clinical and overall improvement, a remission in ulcerative colitis with oral preparations of 5- relatively higher proportion of patients taking aminosalicylic acid. Br Med J 1982; 285: 1012. olsalazine appeared to improve compared with sul- 5 Sharon P, Ligumsky M, Rachmilewitz D, Zor U. Role phasalazine (Table 2), but this difference was not of prostaglandins in ulcerative colitis. Gastroenterology significant. 1978; 75: 638-4). 6 Sircar JC, Schwender CF, Carethers ME. Inhibition of In our preliminary study we compared the two soya bean lipoxygenase by sulfasalazine and 5- drugs using doses which released approximately aminosalicylic acid: a possible mode of action in ulcera- equal amounts of 5-aminosalicylic acid in the colon. tive colitis. Biochlem Pharmacol 1983; 32: 170-2. This study was terminated as many patients in the 7 Campieri M, Lanfranchi GA, Bazzocchi G, et al. sulphasalazine group experienced intolerable Treatment of ulcerative colitis with high dose 5- adverse effects after receiving a daily dose of 4 g aminosalicylic acid enemas. Lancet 1981; ii: 270-1. enteric coated sulphasalazine. A dose of 4-6 g sulpha- 8 Miyachi Y, Yoshioka A, Imamura S, Niwa Y. Effect of salazine would have been required to produce sulphasalazine and its metabolites on the generation of equivalence in terms of 5-aminosalicylic acid release, reactive oxygen species. Gut 1987; 28: 190-5. to 2 9 Willoughby CP, Aronsson JK, Agback H, Bodin NO, g olsalazine. Moreover, even when prescribed a Truelove SC. Distribution and metabolism in healthy lower dose of sulphasalazine (3 g/day), a lower volunteers of disodium azodisalicylate in healthy sub- proportion of patients tolerated this drug. Thus, jects. A potential therapeutic agent for ulcerative colitis. olsalazine was certainly better tolerated than sulpha- Gut 1982; 23: 1081-7. salazine when given in comparable dosage, although 10 Lauritsen K, Hansen J, Ryde M, Rask-Madsen J. Gut: first published as 10.1136/gut.30.5.675 on 1 May 1989. Downloaded from

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