Aliment. Pharmacol. Ther. (1992) 6, 647-652.
Short report: comparison of two doses of balsalazide in maintaining ulcerative colitis in remission over 12 months
J. R. B. GREEN", C. H. J. SWAN*, A. ROWLINSON", J. A. GIBSONt, P. BROWN*, G. D. KERRS, E. T. SWARBRICKj & P. THORNTON"" " Norfh Sfaffs Hospital Centre, Stoke-on- Trent, t Stafford General Infirmary, Stafford, *Princess Royal Hospital, Telford, S Royal Shrewsbury Hospital, Shrewsbury, j New Cross Hospifal, W o l u e y h a ~ p f ~"*n ,Biorex Labovatovies Ltd, London Accepted for publication 14 May 1992
SUMMARY
In a four-centre prospective double-blind trial, 108 patients with ulcerative colitis in remission were randomized to receive balsalazide in doses of 3 g or 6 g/day for 12 months. The patients were assessed at 3monthly intervals clinically, sigmoidoscopically and with routine haematology and biochemistry. Remission rates of 77% ( 3 g/day) and 68% (6 g/day) at 12 months were not significantly different. Intolerance reactions leading to withdrawal from the study occurred in only 9 patients (8%), all occurring in the first 7 weeks of the study. Balsalazide is therefore both highly effective in maintaining remission in ulcerative colitis and well tolerated in both conventional and high dosage (the latter equivalent to 5.5 g/day of sulphasalazine).In this study no distinct advantage in maintenance of remission has been found for the higher dose of balsalazide.
Correspondence to : Dr J. R. B. Green, Department of Gastroenterology, City General Hospital, Newcastle Road, Stoke-on-Trent, Staffs ST4 6QG, UK 64 7
648
J. R. B. GREEN et al.
INTRODUCTION Sulphasalazine is widely used to maintain remission in patients with chronic ulcerative colitis and for treatment of mild/moderate relapses.’’ The therapeutic effect of sulphasalazine is attributed to the topical actions of 5-aminosalicylic acid (5-ASA) which is split from the sulphapyridine moiety by bacterial azo-red~ctase.~r About one-third of patients taking sulphasalazine develop dose-related side-effects which are attributed to the sulphapyridine which is readily absorbed from the C O ~ O ~ . ~ J
Replacement of the sulphapyridine moiety in the sulphasalazine molecule by an inert carrier molecule should reduce the incidence of side-effects and, by allowing ingestion of larger doses, allow the delivery of larger amounts of 5-ASA to the colonic mucosa. Balsalazide is 5-ASA linked to 4-aminobenzoyl-/3-alanine. Studies to date have shown that this is well tolerated in doses of 2 g/day for 6 months and of equal efficacy as the same dose of sulpha~alazine.~ The expected lack of sideeffects of balsalazide allow the test of a hypothesis that prolonged high dosage of 5-ASA might increase therapeutic benefit. This study was undertaken to test this hypo thesis.
METHODS The trial was a prospective, randomized, double-blind trial involving 108 patients from four centres with biopsy-proven chronic ulcerative colitis. All patients had a disease extent of 15 cm of more at some time in their illness. At entry all patients were in clinical and sigmoidoscopic remission and maintained on a 5-ASA preparation alone. A study of over 100 patients was deemed sufficient to detect a substantial difference in dose-related adverse events and would furthermore detect differences in remission in excess of 40%. At entry, patients were randomized to receive balsalazide (Colazide, Biorex Laboratories Ltd, London, UK) either 3 g/day or 6 g/day (equivalent to 2.7 and 5.5 g/day of sulphasalazine, respectively). There were 54 patients in each group. Dummy and active (750 mg) capsules were taken by those patients on the lower dose and active capsules by those on the higher dose. Patients were asked to record any unexpected symptoms. They were reviewed after 1,3,6, 9 and 12 months. At each review, patients were asked to record both specific symptoms (diarrhoea, bleeding, etc.) and also a global assessment of their overall health. Sigmoidoscopy was performed at 3-monthly intervals or on relapse or withdrawal from the trial for other reasons. Routine haematology and biochemistry were recorded at entry, 6 months and 12 months-or at relapse. Blood and urine samples were taken for analysis of balsalazide concentrations at 6 months and one year to test compliance. Relapse was diagnosed on symptomatic (7 days of increased stool frequency with or without blood and mucus), sigmoidoscopic (friable mucosa or spontaneous haemorrhage) and histological grounds (active disease) to distinguish it from non-
BALSALAZIDE IN ULCERATIVE COLITIS
649
Table 1. Patient details at entry Dose of balsalazide Number of patients
M:F
+
Age-mean ( range) years Smokers Disease extent: Total Left-sided colitis Proctosigmoiditis Previous 5-ASA medication Sulphasalazine Mesalazine Olsalazine Time since previous relapse ,< One year > One year
3 glday 54 29: 25 46 (21-78) 6
6 glday 54 25 :29 47 (19-77) 7
18 23 13
18 20
51 3
52 9 4
31 23
20 34
13
16
inflammatory diarrhoea. All patients entered into the trial were followed by a single clinical trial Nurse Co-ordinator who acted as a central point of contact for all centres and to ensure uniformity of record keeping. RESULTS One hundred and eight patients were entered into the trial and were randomized into two comparable groups of 54 patients. The main characteristics of the two groups are shown in Table 1. The two groups of patients were comparable in all respects. Importantly, there was equal gender distribution and similar age range. There were few smokers in either group (11% on 3 g/day, 13% on 6 g/day). The maximum recorded extent of colitis in both groups of patients was similar as was the time, before entry, since previous relapse. No patients were taking either topical or oral corticosteroid medication on entry by definition but the pre-entry exposure to medication with 5-ASA compounds was similar in both groups. Rather more patients allocated to balsalazide 6 g/day had experienced adverse reactions to previous sulphasalazine (30 of 52, 58%) than those allocated to receive 3 g/day (20 of 51, 39%). Of the 25 patients (23%) aged 60 years or over, there was no suggestion of age-related intolerance to balsalazide, adverse haematology or serum chemistry. Those elderly patients who had perturbed serum chemistry at entry to the study, did not show a further perturbation after one year’s treatment with balsalazide at either dose level.
RELAPSE RATES Relapses were seen at a slow and steady rate throughout the study period as shown
650
J. R. B. GREEN ef al.
Figure 1. Remission rates for two groups of 54 patients with ulcerative colitis maintained on 3 g or 6 g/&y balsalazide for 12 months.
Trea tment time (weeks)
Table 2. Patients withdrawn from the study, and defaulting Number of patients Reason for withdrawal Headache Nausea Diarrhoea and abdominal pain Rash Total Defaulters etc.
3 glday
6 glday
1
0 1 2 0 3 (6%) 4
2 2 1
6 (11%) 4
in Fig. 1.During the 12-month study, 10 patients (18.5%) receiving balsalazide 3 g/day relapsed while 15 patients (27.8%) on 6 g/day relapsed (not significantKaplan-Meier life table estimate). There was no difference in time from entry to relapse between the two groups. Furthermore, those patients who did relapse in either group could not be differentiated from those in the same group remaining in remission by criteria such as previous disease extent, age, gender, length of time (pre-entry) from previous relapse or type or dose of previous 5-ASA medication. Relapse rates seen at both doses were comparable with those previously reported for all other 5-ASA medication, (but superior to balsalazide 2 g/day) over comparable periods of time. W I T H D R A W A L S D U E T O SIDE-EFFECTS
A total of 9 patients (8%)were withdrawn due to reported side-effects over the 12-month study period. Only 3 of those 9 patients withdrawn were taking the higher dose. Reasons for withdrawal are shown in Table 2. All intolerance reactions leading to withdrawal from the study occurred in the first 7 weeks of the study with none recorded thereafter. Withdrawal due to diarrhoea was recorded when
BALSALAZIDE I N ULCERATIVE COLITIS
651
this symptom occurred in the absence of sigmoidoscopic or histological change. It is notable that of the small number of side-effects reported, more occurred on the lower rather than the higher dose. DISCUSSION The results of the first phase of a longer-term study of balsalazide confirmed that this new drug is very well tolerated in a high dose over a prolonged period of time. Withdrawals due to intolerance were similar in both groups of patients and were mainly known salicylate reactions. All intolerance reactions were seen in the first 7 weeks of the study. That there were fewer withdrawals due to intolerance at the high dose level does suggest a true inertness of the carrier molecule. The relapse rates during the 12 months of the study were similar in both patient groups with no significant difference at 6 or 12 months. Rates of remission at 12 months are similar to those reported, not only for sulphasalazine in comparable dosage (2-4 g/day),'f2 but also to other 5-ASA compounds. The I2-month remission rates achieved in this study suggest that a maintenance dose of 3 g/day of balsalazide may be optimal as the remission rate is higher than that achieved with 2 g/day but similar to that seen at 4 g/day (Giaffer ef al. Improved maintenance of remission in ulcerative colitis by balsalazide 4 g/day compared with 2 g/day. Aliment Pharmacol Ther 1992; 6: 479-486). That the higher dose of balsalazide had no advantage in this part of the study does not, however, preclude other possible advantages for high dose balsalazide administration, such as in more prolonged remission maintenance after 12 months. This study is currently in progress. In the search for a compound with the therapeutic efficacy of sulphasalazine but without the high proportion of dose-related side-effects, many new formulations have been tried. Alternative ways of delivering 5-ASA to the colonic mucosa are now well described but experience with these methods is limited compared to the extensive body of clinical experience obtained with sulphasalazine over 50 years. An ideal successor to sulphasalazine should have all the advantages with none or few of its disadvantages. Using the same well-proven 5-ASA delivery mode of sulphasalazine, balsalazide would seem to confer all the advantages of sulphasalazine in terms of efficacy, combined with a very low side-effect profile. Although further experience with balsalazide is clearly essential, it does look to be a most promising candidate to replace sulphasalazine in the future. ' r 9
ACKNOWLEDGEMENT
This study was supported by a grant from Biorex Laboratories Ltd, Enfield, UK.
652
J. R. B. G R E E N et al.
REFERENCES 1 Misiewicz J J, Lennard-Jones J E, Connell A M, Baron J H, Avery Jones F. Controlled trial of sulphasalazine in maintenance therapy in ulcerative colitis. Lancet 1965; : 185-8. 2 Dissanayake A S , Truelove S C. A controlled therapeutic trial of longterm maintenance treatment of ulcerative colitis with sulphasalazine (salazopyrin). Gut 1973; 14 : 923-6. 3 Peppercorn M A, Goldman P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J Pharmacol Exp Ther 1972; 181: 555-62. 4 Das K M, Eastwood M A, McManus J P A, Sircus W. The role of the colon in the metabolism of salicylazosulfapyridine. Scand J Gastroenterol 1974; 9 : 137-41. 5 Das K M, Eastwood M A, McManus J P A, Sircus W. Adverse reactions during salicylazosulfapyridine therapy and the relation
6
7
8
9
with drug metabolism and acetylate phenotype. N Eng J Med 1973; 289: 491-5. Taffet S L, Das K M. Desensitisation of patients with inflammatory bowel disease to sulphasalazine. Am J Med 1982; 73: 520-4. McIntyre P B, Rodrigues C A, LennardJones et al. Balsalazide in the maintenance treatment of patients with ulcerative colitis, a double-blind comparison with sulphasalazine. Aliment Pharmacol Ther 1988; 2: 237-43. Dew M J, Harries A D, Evans N, Evans B K, Rhodes J. Maintenance of remission in ulcerative colitis with 5-aminosalicylic acid in high doses by mouth. Brit Med J 1983; 287: 23-4. Ireland A, Mason C H, Jewel1 D P. Controlled trial comparing olsalazine and sulphasalazine for the maintenance treatment of ulcerative colitis. Gut 1988; 29: 835-7.
Short report: comparison of two doses of balsalazide in maintaining ulcerative colitis in remission over 12 months
J. R. B. GREEN", C. H. J. SWAN*, A. ROWLINSON", J. A. GIBSONt, P. BROWN*, G. D. KERRS, E. T. SWARBRICKj & P. THORNTON"" " Norfh Sfaffs Hospital Centre, Stoke-on- Trent, t Stafford General Infirmary, Stafford, *Princess Royal Hospital, Telford, S Royal Shrewsbury Hospital, Shrewsbury, j New Cross Hospifal, W o l u e y h a ~ p f ~"*n ,Biorex Labovatovies Ltd, London Accepted for publication 14 May 1992
SUMMARY
In a four-centre prospective double-blind trial, 108 patients with ulcerative colitis in remission were randomized to receive balsalazide in doses of 3 g or 6 g/day for 12 months. The patients were assessed at 3monthly intervals clinically, sigmoidoscopically and with routine haematology and biochemistry. Remission rates of 77% ( 3 g/day) and 68% (6 g/day) at 12 months were not significantly different. Intolerance reactions leading to withdrawal from the study occurred in only 9 patients (8%), all occurring in the first 7 weeks of the study. Balsalazide is therefore both highly effective in maintaining remission in ulcerative colitis and well tolerated in both conventional and high dosage (the latter equivalent to 5.5 g/day of sulphasalazine).In this study no distinct advantage in maintenance of remission has been found for the higher dose of balsalazide.
Correspondence to : Dr J. R. B. Green, Department of Gastroenterology, City General Hospital, Newcastle Road, Stoke-on-Trent, Staffs ST4 6QG, UK 64 7
648
J. R. B. GREEN et al.
INTRODUCTION Sulphasalazine is widely used to maintain remission in patients with chronic ulcerative colitis and for treatment of mild/moderate relapses.’’ The therapeutic effect of sulphasalazine is attributed to the topical actions of 5-aminosalicylic acid (5-ASA) which is split from the sulphapyridine moiety by bacterial azo-red~ctase.~r About one-third of patients taking sulphasalazine develop dose-related side-effects which are attributed to the sulphapyridine which is readily absorbed from the C O ~ O ~ . ~ J
Replacement of the sulphapyridine moiety in the sulphasalazine molecule by an inert carrier molecule should reduce the incidence of side-effects and, by allowing ingestion of larger doses, allow the delivery of larger amounts of 5-ASA to the colonic mucosa. Balsalazide is 5-ASA linked to 4-aminobenzoyl-/3-alanine. Studies to date have shown that this is well tolerated in doses of 2 g/day for 6 months and of equal efficacy as the same dose of sulpha~alazine.~ The expected lack of sideeffects of balsalazide allow the test of a hypothesis that prolonged high dosage of 5-ASA might increase therapeutic benefit. This study was undertaken to test this hypo thesis.
METHODS The trial was a prospective, randomized, double-blind trial involving 108 patients from four centres with biopsy-proven chronic ulcerative colitis. All patients had a disease extent of 15 cm of more at some time in their illness. At entry all patients were in clinical and sigmoidoscopic remission and maintained on a 5-ASA preparation alone. A study of over 100 patients was deemed sufficient to detect a substantial difference in dose-related adverse events and would furthermore detect differences in remission in excess of 40%. At entry, patients were randomized to receive balsalazide (Colazide, Biorex Laboratories Ltd, London, UK) either 3 g/day or 6 g/day (equivalent to 2.7 and 5.5 g/day of sulphasalazine, respectively). There were 54 patients in each group. Dummy and active (750 mg) capsules were taken by those patients on the lower dose and active capsules by those on the higher dose. Patients were asked to record any unexpected symptoms. They were reviewed after 1,3,6, 9 and 12 months. At each review, patients were asked to record both specific symptoms (diarrhoea, bleeding, etc.) and also a global assessment of their overall health. Sigmoidoscopy was performed at 3-monthly intervals or on relapse or withdrawal from the trial for other reasons. Routine haematology and biochemistry were recorded at entry, 6 months and 12 months-or at relapse. Blood and urine samples were taken for analysis of balsalazide concentrations at 6 months and one year to test compliance. Relapse was diagnosed on symptomatic (7 days of increased stool frequency with or without blood and mucus), sigmoidoscopic (friable mucosa or spontaneous haemorrhage) and histological grounds (active disease) to distinguish it from non-
BALSALAZIDE IN ULCERATIVE COLITIS
649
Table 1. Patient details at entry Dose of balsalazide Number of patients
M:F
+
Age-mean ( range) years Smokers Disease extent: Total Left-sided colitis Proctosigmoiditis Previous 5-ASA medication Sulphasalazine Mesalazine Olsalazine Time since previous relapse ,< One year > One year
3 glday 54 29: 25 46 (21-78) 6
6 glday 54 25 :29 47 (19-77) 7
18 23 13
18 20
51 3
52 9 4
31 23
20 34
13
16
inflammatory diarrhoea. All patients entered into the trial were followed by a single clinical trial Nurse Co-ordinator who acted as a central point of contact for all centres and to ensure uniformity of record keeping. RESULTS One hundred and eight patients were entered into the trial and were randomized into two comparable groups of 54 patients. The main characteristics of the two groups are shown in Table 1. The two groups of patients were comparable in all respects. Importantly, there was equal gender distribution and similar age range. There were few smokers in either group (11% on 3 g/day, 13% on 6 g/day). The maximum recorded extent of colitis in both groups of patients was similar as was the time, before entry, since previous relapse. No patients were taking either topical or oral corticosteroid medication on entry by definition but the pre-entry exposure to medication with 5-ASA compounds was similar in both groups. Rather more patients allocated to balsalazide 6 g/day had experienced adverse reactions to previous sulphasalazine (30 of 52, 58%) than those allocated to receive 3 g/day (20 of 51, 39%). Of the 25 patients (23%) aged 60 years or over, there was no suggestion of age-related intolerance to balsalazide, adverse haematology or serum chemistry. Those elderly patients who had perturbed serum chemistry at entry to the study, did not show a further perturbation after one year’s treatment with balsalazide at either dose level.
RELAPSE RATES Relapses were seen at a slow and steady rate throughout the study period as shown
650
J. R. B. GREEN ef al.
Figure 1. Remission rates for two groups of 54 patients with ulcerative colitis maintained on 3 g or 6 g/&y balsalazide for 12 months.
Trea tment time (weeks)
Table 2. Patients withdrawn from the study, and defaulting Number of patients Reason for withdrawal Headache Nausea Diarrhoea and abdominal pain Rash Total Defaulters etc.
3 glday
6 glday
1
0 1 2 0 3 (6%) 4
2 2 1
6 (11%) 4
in Fig. 1.During the 12-month study, 10 patients (18.5%) receiving balsalazide 3 g/day relapsed while 15 patients (27.8%) on 6 g/day relapsed (not significantKaplan-Meier life table estimate). There was no difference in time from entry to relapse between the two groups. Furthermore, those patients who did relapse in either group could not be differentiated from those in the same group remaining in remission by criteria such as previous disease extent, age, gender, length of time (pre-entry) from previous relapse or type or dose of previous 5-ASA medication. Relapse rates seen at both doses were comparable with those previously reported for all other 5-ASA medication, (but superior to balsalazide 2 g/day) over comparable periods of time. W I T H D R A W A L S D U E T O SIDE-EFFECTS
A total of 9 patients (8%)were withdrawn due to reported side-effects over the 12-month study period. Only 3 of those 9 patients withdrawn were taking the higher dose. Reasons for withdrawal are shown in Table 2. All intolerance reactions leading to withdrawal from the study occurred in the first 7 weeks of the study with none recorded thereafter. Withdrawal due to diarrhoea was recorded when
BALSALAZIDE I N ULCERATIVE COLITIS
651
this symptom occurred in the absence of sigmoidoscopic or histological change. It is notable that of the small number of side-effects reported, more occurred on the lower rather than the higher dose. DISCUSSION The results of the first phase of a longer-term study of balsalazide confirmed that this new drug is very well tolerated in a high dose over a prolonged period of time. Withdrawals due to intolerance were similar in both groups of patients and were mainly known salicylate reactions. All intolerance reactions were seen in the first 7 weeks of the study. That there were fewer withdrawals due to intolerance at the high dose level does suggest a true inertness of the carrier molecule. The relapse rates during the 12 months of the study were similar in both patient groups with no significant difference at 6 or 12 months. Rates of remission at 12 months are similar to those reported, not only for sulphasalazine in comparable dosage (2-4 g/day),'f2 but also to other 5-ASA compounds. The I2-month remission rates achieved in this study suggest that a maintenance dose of 3 g/day of balsalazide may be optimal as the remission rate is higher than that achieved with 2 g/day but similar to that seen at 4 g/day (Giaffer ef al. Improved maintenance of remission in ulcerative colitis by balsalazide 4 g/day compared with 2 g/day. Aliment Pharmacol Ther 1992; 6: 479-486). That the higher dose of balsalazide had no advantage in this part of the study does not, however, preclude other possible advantages for high dose balsalazide administration, such as in more prolonged remission maintenance after 12 months. This study is currently in progress. In the search for a compound with the therapeutic efficacy of sulphasalazine but without the high proportion of dose-related side-effects, many new formulations have been tried. Alternative ways of delivering 5-ASA to the colonic mucosa are now well described but experience with these methods is limited compared to the extensive body of clinical experience obtained with sulphasalazine over 50 years. An ideal successor to sulphasalazine should have all the advantages with none or few of its disadvantages. Using the same well-proven 5-ASA delivery mode of sulphasalazine, balsalazide would seem to confer all the advantages of sulphasalazine in terms of efficacy, combined with a very low side-effect profile. Although further experience with balsalazide is clearly essential, it does look to be a most promising candidate to replace sulphasalazine in the future. ' r 9
ACKNOWLEDGEMENT
This study was supported by a grant from Biorex Laboratories Ltd, Enfield, UK.
652
J. R. B. G R E E N et al.
REFERENCES 1 Misiewicz J J, Lennard-Jones J E, Connell A M, Baron J H, Avery Jones F. Controlled trial of sulphasalazine in maintenance therapy in ulcerative colitis. Lancet 1965; : 185-8. 2 Dissanayake A S , Truelove S C. A controlled therapeutic trial of longterm maintenance treatment of ulcerative colitis with sulphasalazine (salazopyrin). Gut 1973; 14 : 923-6. 3 Peppercorn M A, Goldman P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J Pharmacol Exp Ther 1972; 181: 555-62. 4 Das K M, Eastwood M A, McManus J P A, Sircus W. The role of the colon in the metabolism of salicylazosulfapyridine. Scand J Gastroenterol 1974; 9 : 137-41. 5 Das K M, Eastwood M A, McManus J P A, Sircus W. Adverse reactions during salicylazosulfapyridine therapy and the relation
6
7
8
9
with drug metabolism and acetylate phenotype. N Eng J Med 1973; 289: 491-5. Taffet S L, Das K M. Desensitisation of patients with inflammatory bowel disease to sulphasalazine. Am J Med 1982; 73: 520-4. McIntyre P B, Rodrigues C A, LennardJones et al. Balsalazide in the maintenance treatment of patients with ulcerative colitis, a double-blind comparison with sulphasalazine. Aliment Pharmacol Ther 1988; 2: 237-43. Dew M J, Harries A D, Evans N, Evans B K, Rhodes J. Maintenance of remission in ulcerative colitis with 5-aminosalicylic acid in high doses by mouth. Brit Med J 1983; 287: 23-4. Ireland A, Mason C H, Jewel1 D P. Controlled trial comparing olsalazine and sulphasalazine for the maintenance treatment of ulcerative colitis. Gut 1988; 29: 835-7.
