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
`"* Biorex Labovatovies Ltd, London
`Cross Hospifal, W o l u e y h a ~ p f ~ n ,
`
`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 3-
`monthly 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
`
`GeneriCo, Flat Line Capital
`Exhibit 1069 Page 1
`
`

`
`648
`
`J. R. B. GREEN et al.
`
`I N T R O D U C T I O N
`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 side-
`effects 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 prep-
`aration 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
`at relapse. Blood and urine samples were taken for
`months and 12 months-or
`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-
`
`GeneriCo, Flat Line Capital
`Exhibit 1069 Page 2
`
`

`
`BALSALAZIDE IN ULCERATIVE COLITIS 649
`
`Table 1. Patient details at entry
`
`( + range) years
`
`Dose of balsalazide
`Number of patients
`M:F
`Age-mean
`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
`
`51
`13
`3
`
`31
`23
`
`18
`20
`16
`
`52
`9
`4
`
`20
`34
`
`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
`
`GeneriCo, Flat Line Capital
`Exhibit 1069 Page 3
`
`

`
`650
`
`J. R. B. GREEN ef al.
`
`Trea tment time (weeks)
`
`Table 2. Patients withdrawn from the study, and defaulting
`
`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.
`
`Reason for withdrawal
`
`Headache
`Nausea
`Diarrhoea and abdominal pain
`Rash
`Total
`Defaulters etc.
`
`Number of patients
`
`3 glday
`
`1
`2
`2
`1
`6 (11%)
`4
`
`6 glday
`
`0
`1
`2
`0
`3 (6%)
`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 significant-
`Kaplan-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 com-
`parable periods of time.
`
`WITHDRAWALS DUE 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
`
`GeneriCo, Flat Line Capital
`Exhibit 1069 Page 4
`
`

`
`BALSALAZIDE IN 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. ' r 9 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 main-
`tenance 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 formu-
`lations 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.
`
`ACKNOWLEDGEMENT
`This study was supported by a grant from Biorex Laboratories Ltd, Enfield, UK.
`
`GeneriCo, Flat Line Capital
`Exhibit 1069 Page 5
`
`

`
`652
`
`J. R. B. GREEN et al.
`
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`
`GeneriCo, Flat Line Capital
`Exhibit 1069 Page 6