`Therapy for Ulcerative Colitis
`A Randomized, Placebo-Controlled Trial
`The Mesalamine Study Group*
`
`Objective: To compare the safety and efficacy of a pH-
`sensitivef polymer-coated oral formulation of mesalamine
`(Asacol, Procter & Gamble Pharmaceuticals, Cincinnati,
`Ohio) with those of placebo in maintaining remission in
`patients with ulcerative colitis.
`Design: Multicenter, double-blind, placebo-controlled,
`randomized clinical trial.
`Setting: Eight private practices, five university-based
`medical centers, and four hospitals or clinics.
`Patients: 264 patients with ulcerative colitis that had
`been maintained in remission for at least 1 month while
`the patients were receiving stable doses of sulfasalazine or
`any oral mesalamine product.
`Intervention: Coated mesalamine at oral dosages of 0.8
`g/d or 1.6 g/d or matching placebo for 6 months.
`Measurements: Treatment success, defined as mainte(cid:173)
`nance of remission after 6 months, and treatment failure,
`defined as relapse during the study (as indicated by proc(cid:173)
`tosigmoidoscopy at 1, 3, or 6 months of treatment) or
`withdrawal due to adverse events. Safety was assessed on
`the basis of laboratory analyses and patient- and investi(cid:173)
`gator-noted adverse events.
`Results: 189 patients were compliant with the protocol
`for 6 months or stopped receiving therapy because of
`relapse or adverse events. Of these 189 patients, 25 of the
`63 patients (39.7%) in the placebo group had treatment
`success compared with 40 of the 68 patients (58.8% [95%
`CI, 46.4% to 71.3%]) in the group receiving mesalamine,
`0.8 g/d (P = 0.036) and 38 of the 58 patients (65.5% [CI,
`52.4% to 78.6%]) in the group receiving mesalamine, 1.6
`g/d (P = 0.006). In the intention-to-treat analysis of all
`patients, 42 of the 87 patients (48.3%) in the placebo
`group had treatment success compared with 57 of the 90
`patients (63.3% [CI, 52.8% to 73.8%]) in the group receiv(cid:173)
`ing mesalamine, 0.8 g/d (P = 0.050) and 61 of the 87
`patients (70.1 % [CI, 59.9% to 80.3%]) in the group receiv(cid:173)
`ing mesalamine, 1.6 g/d (P = 0.005). Age, sex, and race
`were not found to predict treatment success or failure. The
`mesalamine tablet was well tolerated, and no clinically
`significant changes were seen in hematologic, hepatic, or
`renal laboratory profiles.
`Conclusion: Coated mesalamine at oral dosages of 0.8
`g/d and 1.6 g/d is safe and effective in maintaining remis(cid:173)
`sion in patients with quiescent ulcerative colitis.
`
`Ann Intern Med. 1996;124:204-211.
`
`*For a listing of members of The Mesalamine Study Group, see
`the Appendix.
`
`204 © 1996 American College of Physicians
`
`Sulfasalazine has been first-line therapy for mildly
`
`to moderately active ulcerative colitis and for
`maintenance of remission in ulcerative colitis since
`it was introduced more than 50 years ago. It is
`clearly effective (1-5) but is associated with an ap(cid:173)
`preciable incidence of dose-related side effects and
`a spectrum of serious idiosyncratic reactions (6, 7).
`Sulfasalazine is a pro-drug comprising mesalamine
`(5-aminosalicylic acid) and sulfapyridine joined by
`an azo bond. The oral use of free mesalamine, the
`principal active moiety of the drug (8-10), is com(cid:173)
`promised by the instability of mesalamine in the
`acid environment of the stomach and by the absorp(cid:173)
`tion of it in the proximal small intestine (11). Azo-
`bond linkage with the carrier molecule sulfapyridine
`enables mesalamine to reach the colon, where bac(cid:173)
`terial enzymes split the azo bond, liberating the two
`components (12).
`The sulfapyridine moiety of sulfasalazine is an
`effective carrier molecule for mesalamine, but it is
`considered to be responsible for most cases of in(cid:173)
`tolerance to sulfasalazine (13). Consequently, re(cid:173)
`search has been directed toward developing a me(cid:173)
`salamine formulation that would successfully deliver
`mesalamine to the colon without toxic effects (14).
`One oral mesalamine formulation (Asacol, Procter
`& Gamble Pharmaceuticals, Cincinnati, Ohio) con(cid:173)
`sists of a core of 400 mg of mesalamine (the same
`amount contained in 1 g of sulfasalazine) enveloped
`by a pH-sensitive polymer coating. This coating pro(cid:173)
`tects mesalamine from premature absorption in the
`small intestine and thus enables therapeutic quanti(cid:173)
`ties of mesalamine to reach the colon.
`This coated mesalamine formulation has been
`shown to be effective in the treatment of mildly to
`moderately active ulcerative colitis (15, 16) and to
`be well tolerated by patients who had previously
`had adverse reactions to sulfasalazine (17, 18). In
`addition, three randomized, double-blind studies
`have shown that this formulation is as effective as
`sulfasalazine in maintaining remission in patients
`with quiescent ulcerative colitis (19-21). In one
`study, Dew and colleagues (19) showed that me(cid:173)
`salamine at an average dosage of 1.4 g/d was similar
`to sulfasalazine at an average dosage of 2.4 g/d in
`maintaining remission for 16 weeks in 72 patients
`with quiescent ulcerative colitis. In a later study
`
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`
`GeneriCo, Flat Line Capital
`Exhibit 1064 Page 1
`
`
`
`(20), these authors showed that a higher dosage of
`mesalamine (2.7 g/d) did not differ from sulfasala(cid:173)
`zine at an average dosage of 2.3 g/d in maintaining
`remission for 24 weeks in 67 patients with quiescent
`ulcerative colitis. Riley and coworkers (21) com(cid:173)
`pared this same oral mesalamine formulation with
`sulfasalazine in 100 patients who had ulcerative co(cid:173)
`litis in remission: The most common dosage of oral
`mesalamine was 0.8 g/d, and the most common
`dosage of sulfasalazine was 2.0 g/d. Again, no sta(cid:173)
`tistically significant difference was found between
`the two treatment groups with respect to the pro(cid:173)
`portion of patients who had had relapse by 48 weeks.
`The results of these three studies suggest that
`this oral mesalamine formulation is as effective as
`sulfasalazine as maintenance therapy for ulcerative
`colitis. However, these studies share the following
`methodologic flaws: Different dosages were used,
`but the studies do not indicate the relative efficacy
`of different dosages of mesalamine; and no placebo
`controls were used to aid in the interpretation of
`the remission rates achieved or to provide reassur(cid:173)
`ance that the patients recruited actually needed
`drug therapy to maintain remission.
`To further evaluate this pH-sensitive oral me(cid:173)
`salamine formulation, we conducted a multicenter,
`double-blind, placebo-controlled, randomized study
`to compare the efficacy and safety of mesalamine,
`0.8 g/d and 1.6 g/d, with those of placebo in main(cid:173)
`taining remission in patients with ulcerative colitis.
`A sulfasalazine arm was not included in order to
`reduce the sample size required for the study.
`
`Methods
`
`The study protocol was approved by the institu(cid:173)
`tional review board of each study site, and each
`patient gave written, informed consent before study
`entry.
`
`Patients
`We recruited patients from 17 study sites: 8 pri(cid:173)
`vate practices, 5 university-based medical centers,
`and 4 hospitals or clinics. Recruiting was done using
`print and radio advertising, posters, and announce(cid:173)
`ment letters to referring physicians and local sup(cid:173)
`port groups. Each patient enrolled in the trial was
`between 18 and 75 years of age and had a docu(cid:173)
`mented diagnosis of ulcerative colitis. At the time
`the study began, all patients had been in remission
`for at least 1 month as indicated by the endoscopic
`appearance of the bowel and by the passage of five
`or fewer bloodless stools per day. To qualify for
`study entry, patients were required to have a score
`of 0 on the proctosigmoidoscopic grading scale de(cid:173)
`scribed below {see Evaluation Methods). The pres(cid:173)
`
`ence of colitis symptoms, such as loose stools or
`abdominal cramps, was not a reason for exclusion
`from the study, provided that endoscopic examina(cid:173)
`tion showed remission of disease. All patients had
`been treated previously with 2.0 to 4.0 g of sul(cid:173)
`fasalazine per day or 0.8 to 1.6 g of any oral me(cid:173)
`salamine product per day; the dosage of these drugs
`had been constant for at least 1 month before study
`entry. No patient had received corticosteroid or top(cid:173)
`ical rectal therapy within 1 month of study entry.
`Female patients with child-bearing potential were
`required to practice a reliable method of birth con(cid:173)
`trol throughout the study, and women who were
`pregnant or nursing were excluded from the study.
`Patients with a history of allergy or intolerance to
`aspirin or salicylates were also excluded, as were
`patients with a history of extensive bowel resection
`causing the short-bowel syndrome and patients with
`laboratory evidence of renal or hepatic dysfunction.
`Throughout the study, patients were not allowed
`to use corticosteroids (except topically for dermato-
`logic reasons), sulfasalazine, antibiotics for more
`than 10 consecutive days, topical rectal therapies, or
`investigational drugs other than mesalamine.
`
`Study Design
`In this multicenter, double-blind study, 264 pa(cid:173)
`tients were randomly assigned to receive one of
`three treatment regimens: placebo, 0.8 g of oral
`mesalamine per day, or 1.6 g of oral mesalamine
`per day. Randomization was done within centers by
`means of randomization codes using specific patient
`numbers generated for each study site before the
`study began. Each patient number was randomly
`distributed by computer to one of the three treat(cid:173)
`ment groups. Patients were not stratified according
`to any clinical characteristic, such as disease loca(cid:173)
`tion or previous treatment.
`Patients were seen at baseline and at months 1,
`3, and 6 of treatment. They were also seen at any
`time during the study if they felt that their disease
`was worsening or that they were having an adverse
`event. At baseline, each patient had a screening at
`which medical history was recorded and physical
`examination, proctosigmoidoscopy or colonoscopy,
`laboratory analyses, and pregnancy testing were done.
`At each follow-up visit, physical examination, proc(cid:173)
`tosigmoidoscopy or colonoscopy, laboratory analy(cid:173)
`ses, and pregnancy testing were done. Throughout
`the study, patients maintained a daily diary in which
`they recorded their study medication dosing, their
`symptoms, and their concomitant medication dos(cid:173)
`ing.
`
`Study Drug
`The mesalamine used in our study (Asacol) was
`supplied in tablets that consisted of a 400-mg me-
`
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`
`205
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`GeneriCo, Flat Line Capital
`Exhibit 1064 Page 2
`
`
`
`salamine core enveloped by a pH-sensitive acrylic
`polymer coating (Eudragit-S, Rohm Pharma GmbH,
`Weiterstadt, West Germany). Because the pH-sen-
`sitive resin breaks down only at a pH of 7 or more,
`the coating remains intact until the tablet reaches
`the terminal ileum, where the pH is consistently
`higher than 7. Radiologic studies have shown that
`barium-containing capsules coated with this resin
`break down in the terminal ileum and colon (22,
`23); thus, this resin makes it possible to provide
`topical application of mesalamine directly to these
`areas (22). The placebo tablets were identical to the
`mesalamine tablets in odor and appearance but con(cid:173)
`tained no active ingredients.
`Placebo was administered as four tablets daily.
`Mesalamine, 0.8 g/d, was administered as two active
`and two placebo tablets daily, and mesalamine, 1.6
`g/d, was administered as four active tablets daily.
`Tablets were packaged
`in four bottles, each of
`which was labeled with the time of day at which
`patients were to take the tablets in that bottle. All
`patients took one tablet at breakfast, one at lunch,
`one at dinner, and one at bedtime. Patients in the
`mesalamine, 0.8 g/d group took the active tablets at
`breakfast and at bedtime. The study treatment pe(cid:173)
`riod was scheduled to last 6 months.
`Compliance was monitored by tablet count and
`by review of patient diaries at each study visit. Non(cid:173)
`compliance was defined as missing more than 15%
`of the study medication over the duration of treat(cid:173)
`ment or more than 50% of the study medication for
`4 consecutive days (for reasons other than intoler(cid:173)
`ance).
`
`Evaluation Methods
`All patients were evaluated using proctosigmoid(cid:173)
`oscopy or colonoscopy at baseline and at each visit.
`Findings were graded according to the following
`scale: 0 (normal or mild granularity, edema, hypere(cid:173)
`mia, or erythema; mildly diminished vascular mark(cid:173)
`ings); 1 (mild granularity, edema, hyperemia, or er(cid:173)
`ythema; mildly diminished vascular markings plus
`friability); 2 (marked erythema or granularity; no
`vascular markings; bleeding with minimal trauma;
`no ulcerations); and 3 (spontaneous bleeding; ulcer(cid:173)
`ations). A score of 0 was required for study entry. If
`a patient was noted at baseline to have a score of 0
`with mild granularity, edema, hyperemia, or ery(cid:173)
`thema or mildly diminished vascular markings, the
`investigator specifically commented on these factors
`and clearly stated that the patient was considered
`to be in endoscopic remission. The
`investigators
`agreed that these findings could be present in pa(cid:173)
`tients with longstanding ulcerative colitis in remis(cid:173)
`sion. Subsequently, a score of 1 or higher at any
`time was considered indicative of relapse.
`Safety was evaluated at each visit using physical
`
`laboratory analyses. Laboratory
`examination and
`analyses consisted of routine biochemical and hema(cid:173)
`tologic measurements and urinalyses done at each
`visit, plus creatinine clearance assays to monitor
`renal function done at the baseline visit and the
`final visit. Patients were questioned at each visit
`about any adverse events they may have had. In
`addition, any events noted in patient diaries that
`were considered to be possible adverse events were
`tabulated as adverse events.
`
`Efficacy Variables
`The primary efficacy variable was treatment out(cid:173)
`come. Treatment outcome could be either success,
`defined as maintenance of remission (as indicated
`by endoscopic evaluation) at the 6-month study
`visit, or failure, defined as endoscopic relapse at any
`time during the study or withdrawal due to an ad(cid:173)
`verse event. Time to relapse was also evaluated.
`
`Statistical Analysis
`The primary efficacy analysis included patients
`who were compliant with the protocol until they had
`completed 6 months of therapy or until they had
`discontinued treatment because of relapse or ad(cid:173)
`verse events. In addition, an intention-to-treat anal(cid:173)
`ysis, which included all patients exposed to treat(cid:173)
`ment, was also done. In this analysis, treatment
`success was determined on the basis of remission at
`the patient's final visit, regardless of whether the
`patient had completed 6 months of treatment.
`Before the study began, a sample size of 64 pa(cid:173)
`tients per treatment group was determined to be
`sufficient to detect a 25% difference in proportions
`of patients having relapse, using a two-sided 0.05
`significance level with 0.80 power. Because more
`patients than expected could not be analyzed, the
`number of patients per treatment group was in(cid:173)
`creased during the course of the study before the
`study was unblinded.
`The baseline characteristics of patients in the two
`mesalamine groups were compared with those of
`patients in the placebo group by using the Mest for
`continuous variables and the Fisher exact test for
`categorical variables.
`The treatment outcome of patients in the two
`mesalamine groups was compared with the treat(cid:173)
`ment outcome of patients in the placebo group by
`using the Fisher exact test. Treatment outcome was
`also analyzed by treatment group and age, sex, and
`race by using categorical methods, log-linear model.
`Time to relapse in the mesalamine groups was
`compared with time to relapse in the placebo group
`by survival analysis using the product-limit method
`to compute estimates of the survival function (re(cid:173)
`mission) and using the log-rank test to examine
`treatment group differences. In this analysis, pa-
`
`206
`
`15 January 1996 • Annals of Internal Medicine • Volume 124 • Number 2
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`
`GeneriCo, Flat Line Capital
`Exhibit 1064 Page 3
`
`
`
`Table 1. Baseline Demographic and Disease History
`Characteristics by Treatment Group
`
`Baseline
`Characteristic
`
`Mean age ± SE, y
`Sex, n(%)
`Male
`Female
`Race, n(%)
`White
`Nonwhite
`Duration of ulcerative
`colitis, n(%)
`<1 year
`1-5 years
`>5-10 years
`>10 years
`Unknown
`Extent of disease, n(%)
`Proctitis
`Proctosigmoiditis
`Left-sided disease
`Pancolitis
`Unknown
`Previous medication for
`ulcerative colitis, n(%)
`Sulfasalazine
`Any oral mesalamine
`Othert
`Stool frequency, n(%)
`One per day
`Two per day
`Three per day
`Four or more per day
`Mean number per day
`±SE
`
`Placebo
`(n = 87)
`
`Mesalamine, Mesalamine,
`0.8 g/d
`1.6 g/d
`(n = 90)
`(n = 87)
`
`4.2 ± 1.44
`
`41.9 ± 1.37
`
`42.1 ± 1.45
`
`54(62.1)
`33 (37.9)
`
`86 (98.9)
`1(1.1)
`
`9(10.3)
`23 (26.4)
`22 (25.3)
`33 (37.9)
`0
`
`13(14.9)
`20 (23.0)
`13(14.9)
`24 (27.6)
`17(19.5)
`
`48 (55.2)
`37 (42.5)
`2 (2.3)
`
`27(31.0)
`37 (42.5)
`14(16.1)
`9(10.3)
`
`55(61.1)
`35 (38.9)
`
`86 (95.6)
`4 (4.4)
`
`13(14.4)
`23 (25.6)
`22 (24.4)
`31 (34.4)
`1(1.1)
`
`10(11.1)
`28(31.1)
`18(20.0)
`26 (28.9)
`8 (8.9)
`
`58 (64.4)
`31 (34.4)
`1(1.1)
`
`41 (45.6)
`31 (34.4)
`12(13.3)
`6 (6.6)
`
`37 (42.5)
`50 (57.5)*
`
`84 (96.6)
`3 (3.4)
`
`13(14.9)
`22 (25.3)
`23 (26.4)
`29 (33.3)
`0
`
`16(18.4)
`15(17.2)
`17(19.5)
`23 (26.4)
`16(18.4)
`
`54(62.1)
`32 (36.8)
`1(1.1)
`
`30 (34.5)
`40 (46.0)
`10(11.5)
`7 (8.0)
`
`2.08 ± 0.109 1.83 ±0.103 1.95 ±0.102
`
`* P = 0.015 compared with placebo group (Fisher exact test, two-tailed),
`t Any patient who had previously received a medication for ulcerative colitis other than
`sulfasalazine or any oral mesalamine was excluded from the primary efficacy analysis.
`
`tients who did not have relapse were considered to
`be censored at the last date of study participation,
`and patients in whom treatment was discontinued
`prematurely because of an adverse event were con(cid:173)
`sidered to be censored at the date of discontinua(cid:173)
`tion.
`The distribution of the number of adverse events
`recorded per patient in the mesalamine groups was
`compared with that in the placebo group by contin(cid:173)
`gency table analysis using the Pearson chi-square
`statistic with the number of adverse events per pa(cid:173)
`tient categorized as 0, 1 to 5, 6 to 10, or more than
`10.
`
`sented in Table 1. The characteristics of the me(cid:173)
`salamine groups were similar to those of the pla(cid:173)
`cebo group, except for the sex distribution: The
`proportion of women in the mesalamine, 1.6 g/d
`group (57.5%) was greater than that in the placebo
`group (38.9%) (P = 0.015). In general, there was
`good agreement between clinical and endoscopic
`remission at baseline.
`Seventy-five patients were excluded from the pri(cid:173)
`mary efficacy analysis for the following reasons:
`failure to meet study entry criteria (n = 36), non(cid:173)
`compliance with study medication (n = 18), non(cid:173)
`compliance with study procedures (n = 3), concom(cid:173)
`itant medication violation (n = 10), loss to follow-up
`(n = 4), and voluntary withdrawal (n = 4). The
`numbers of patients excluded were similar in the
`three groups.
`
`Treatment Outcome
`Analyses of data from patients who completed 6
`months of treatment or who withdrew because of
`relapse or adverse events (primary efficacy analyses)
`showed that the criteria for treatment success were
`met in 25 of 63 patients (39.7%) in the placebo
`group compared with 40 of 68 patients (58.8% [95%
`CI, 46.4% to 71.3%]) in the group receiving me(cid:173)
`salamine, 0.8 g/d, and 38 of 58 patients (65.5%
`[CI, 52.4% to 78.6%]) in the group receiving me(cid:173)
`salamine, 1.6 g/d (Table 2). The percentage of pa(cid:173)
`tients who met the criteria for treatment success
`was greater in both the group receiving mesalamine,
`0.8 g/d (P = 0.036) and the group receiving me(cid:173)
`salamine, 1.6 g/d (P = 0.006) than in the placebo
`group. In the intention-to-treat analysis of all pa(cid:173)
`tients, the differences between the placebo and the
`mesalamine groups were also significant: The crite(cid:173)
`ria for treatment success were met in 42 of 87
`patients (48.3%) in the placebo group compared
`with 57 of 90 patients (63.3% [CI, 52.8% to 73.8%])
`in the group receiving mesalamine, 0.8 g/d (P =
`0.050) and 61 of 87 patients (70.1% [CI, 59.9% to
`80.3%]) in the group receiving mesalamine, 1.6 g/d
`(P = 0.005). Subgroup analyses of treatment out-
`
`Results
`
`Table 2. Treatment Outcome of Patients Who Completed
`6 Months of Therapy or Who Withdrew from the
`Study because of Relapse or Adverse Events
`
`Patients
`Two hundred sixty-four patients were randomly
`assigned to receive either placebo, 0.8 g of me(cid:173)
`salamine per day, or 1.6 g of mesalamine per day.
`Randomization was done at all 17 study sites. The
`number of patients at each site ranged from 1 to 47
`(mean, 16 patients). The demographic and disease
`history characteristics of the 264 patients are pre(cid:173)
`
`Treatment Group
`
`Success*
`
`Failure*
`
`n(%)
`
`Placebo (n = 63)
`= 68)
`Mesalamine, 0.8 /gd (n =
`
`Mesalamine, 1.6 g/d (n = = 58)
`
`25 (39.7)
`40 (58.8)t
`38(65.5)*
`
`38 (60.3)
`28(41.2)
`20(34.5)
`
`* Success = maintenance of remission (as indicated by endoscopic evaluation) at the
`6-month study visit; failure = endoscopic relapse at any time during the study or
`withdrawal due to an adverse event.
`t P = 0.036 compared with placebo group (Fisher exact test, two-tailed).
`$ P = 0.006 compared with placebo group (Fisher exact test, two-tailed).
`
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`GeneriCo, Flat Line Capital
`Exhibit 1064 Page 4
`
`
`
`Table 3. Time to Relapse in Patients Who Completed 6
`Months of Therapy or W ho Withdrew from the
`Study because of Relapse or Adverse Events
`
`Time to
`Relapse (weeks)
`
`0-4
`5-8
`9-12
`13-16
`17-20
`21-24
`>24
`Censored*
`
`in = 63)
`<
`
`6 (9.5)
`10(15.9)
`5 (7.9)
`4 (6.3)
`3 (4.8)
`1(1.6)
`4 (6.3)
`30 (47.6)
`
`Patients Who Had Relapse
`
`Mesalamine, 0.8 g/d* Mesalamine, 1.6 g/dt
`(n = 68)
`(n = 58)
`
`n(%)
`
`-
`
`»
`
`4(5.9)
`7(10.3)
`3 (4.4)
`2 (2.9)
`3 (4.4)
`2 (2.9)
`3 (4.4)
`44 (64.7)
`
`6(10.3)
`5 (8.6)
`3 (5.2)
`0(0)
`2 (3.4)
`0(0)
`2 (3.4)
`40 (69.0)
`
`* P = 0.026 compared with placebo group (log-rank test),
`t P = 0.011 compared with placebo group (log-rank test).
`* Censored patients were those who did not have relapse during study treatment or who
`were dropped from the study prematurely because of an adverse event.
`
`come by age, sex, and race did not show any asso(cid:173)
`ciation between these baseline factors and treatment
`outcome (P > 0.05). Throughout the study, agree(cid:173)
`ment was generally good between symptomatic and
`endoscopic relapse in all groups. Treatment was
`discontinued in two patients, one in the placebo
`group and one in the group receiving mesalamine,
`1.6 g/d, because of the appearance of symptoms of
`ulcerative colitis, despite normal proctosigmoido(cid:173)
`scopy findings.
`
`Time to Relapse
`Table 3 and Figure 1 show that in the primary
`efficacy analysis of compliant patients who com(cid:173)
`pleted 6 months of therapy or who withdrew be(cid:173)
`cause of relapse or adverse events, both of the
`mesalamine groups differed from the placebo group
`with respect to time to relapse (P = 0.026 for the
`group receiving mesalamine, 0.8 g/d; P = 0.011 for
`the group receiving mesalamine, 1.6 g/d). The sur(cid:173)
`vival plots of the patients who received placebo and
`the patients who received mesalamine diverge after
`approximately 30 days; patients who received me(cid:173)
`salamine showed a greater probability of maintain(cid:173)
`ing remission throughout the rest of the study. In
`the intention-to-treat analysis of all patients, a sta(cid:173)
`tistically significant difference in survival distribution
`was seen between the group receiving mesalamine,
`1.6 g/d and the placebo group (P = 0.008) but not
`between the group receiving mesalamine, 0.8 g/d
`and the placebo group (P = 0.074).
`In a supplemental analysis, in which patients
`were stratified according to extent of disease (pan(cid:173)
`colitis, left-sided disease, proctosigmoiditis, proctitis,
`and unspecified), the distributions of time to relapse
`were similar in the five groups (P = 0.907).
`
`Compliance
`Six of 87 patients (6.9%) in the placebo group,
`11 of 90 patients (12.2%) in the group receiving
`mesalamine, 0.8 g/d, and 4 of 87 patients (4.6%) in
`the group receiving mesalamine, 1.6 g/d, met the
`criteria for study drug noncompliance. All 21 of
`these patients were dropped from the study, some
`because of dosing noncompliance alone and others
`for this reason plus others.
`
`Adverse Reactions to Therapy
`The number of
`investigator-recorded adverse
`events and the percentage of patients who reported
`adverse events were similar among the three treat(cid:173)
`ment groups. Thirty-four of 87 patients (39.1%) in
`the placebo group reported 81 events; 29 of 90
`patients (32.2%) in the group receiving mesalamine,
`0.8 g/d, reported 72 events; and 36 of 87 patients
`(41.4%) in the group receiving mesalamine, 1.6 g/d
`reported 106 events. The adverse events recorded
`most frequently by the investigators were headache,
`flu syndrome, diarrhea, rhinitis, and abdominal pain.
`When potential adverse events noted in patient di(cid:173)
`aries were combined with investigator-recorded ad(cid:173)
`verse events, statistical analysis of the distribution of
`the number of adverse events reported per person
`(0, 1 to 5, 6 to 10, or more than 10) showed no
`significant differences between the placebo group
`and the group receiving mesalamine, 0.8 g/d (P =
`0.922) or between the placebo group and the group
`receiving mesalamine, 1.6 g/d (P = 0.236).
`Most adverse events were mild to moderate in
`severity and were not serious. Three patients, one
`from each treatment group, had serious adverse
`events: One patient in the placebo group had chest
`pain, hypertension, and dyspnea that were consid-
`
`Figure 1. Percentage of patients with ulcerative colitis who re(cid:173)
`mained in remission during treatment with placebo; with me-
`salamine, 0.8 g/d; or with mesalamine, 1.6 g/d. P values are for
`comparisons between treatment and placebo
`
`208
`
`15 January 1996 • Annals of Internal Medicine • Volume 124 • Number 2
`
`Downloaded From: http://annals.org/ by a University of Cincinnati User on 08/25/2016
`
`GeneriCo, Flat Line Capital
`Exhibit 1064 Page 5
`
`
`
`Table 4. Relapse Rates Reported in Studies of Patients
`with Quiescent Ulcerative Colitis Treated with
`Sulfasalazine or Mesalamine Products
`
`Study (Reference)
`
`Drug
`
`Dose, g Study
`Duration,
`mo
`
`Relapse
`Rate,
`%
`
`Dewetal. (19)
`
`Riley etal. (21)
`
`Dew et al. (20)
`
`Mesalamine (Asacol)*
`Sulfasalazine
`Mesalamine (Asacol)*
`Sulfasalazine
`Mesalamine (Asacol)*
`Sulfasalazine
`Mesalamine (Claversal)t
`Sulfasalazine
`Bianchi Porro et al. Mesalamine (Claversal)t
`Sulfasalazine
`(25)
`Mulder et al. (26)
`Mesalamine (Pentasa)t
`Sulfasalazine
`Gionchetti et al. (27) ' Mesalamine (Pentasa)*
`Sulfasalazine
`Misiewicz et al. (4) Placebo
`Sulfasalazine
`Placebo
`Sulfasalazine
`Placebo
`Dissanayake et al.
`Sulfasalazine
`(3)
`Azad Khan et al. (5) Sulfasalazine
`
`Rutgeerts (24)
`
`Riis et al. (28)
`
`4
`
`12
`
`6
`
`12
`
`12
`
`12
`
`4
`
`12
`
`6
`
`6
`
`6
`
`1.2
`2
`0.8-1.6
`2-4
`2.4-4.4
`2-4
`0.75
`1.5-2.0
`1
`2
`1.5
`3
`1.5
`3
`-
`2
`-
`2
`-
`2
`4
`2
`1
`
`26
`18
`38
`39
`22
`20
`28
`23
`50
`53
`46
`54
`20
`16
`76
`29
`24
`29
`55
`12
`9
`14
`33
`
`ered to be unrelated to treatment; one patient re(cid:173)
`ceiving mesalamine, 0.8 g/d, had a questionable
`transient ischemic attack and migraine, the relation
`of which to treatment was considered doubtful; and
`one patient receiving mesalamine, 1.6 g/d, had a
`miscarriage that was considered to be unrelated to
`treatment. Treatment was discontinued because of
`an adverse event in 4 of 87 patients (4.6%) in the
`placebo group, 4 of 90 patients (4.4%) in the group
`receiving mesalamine, 0.8 g/d, and 2 of 87 patients
`(2.3%) in the group receiving mesalamine, 1.6 g/d.
`The events leading to discontinuation were different
`for each patient, with the exception of headache
`and paresthesia. Headache was the reason for dis(cid:173)
`continuation in one patient in the placebo group
`and one patient in the group receiving mesalamine,
`0.8 g/d, and paresthesia was the reason for discon(cid:173)
`tinuation in two patients in the placebo group.
`None of these adverse events was considered seri(cid:173)
`ous.
`We detected no clinically significant trends in any
`of the laboratory test results, no treatment-related
`abnormalities in the results of biochemical or he(cid:173)
`matologic tests or urinalyses, and no changes in
`creatinine clearance. No patient was dropped from
`the study prematurely because of laboratory abnor(cid:173)
`malities.
`
`Discussion
`
`In our study, daily dosages of 0.8 and 1.6 g of the
`pH-sensitive, polymer-coated oral mesalamine prep(cid:173)
`aration were safe and effective in maintaining re(cid:173)
`mission in patients with quiescent ulcerative colitis.
`After 6 months of treatment, 58.8% of the patients
`receiving mesalamine, 0.8 g/d, and 65.5% of the
`patients receiving mesalamine, 1.6 g/d remained in
`remission, compared with 39.7% of patients receiv(cid:173)
`ing placebo. Sex, age, and race were not found to
`predict treatment success or failure.
`Relapse rates for patients with quiescent ulcer(cid:173)
`ative colitis may depend on the length of follow-up
`and, probably, on the dose of the maintenance drug,
`although further studies are indicated. In addition,
`comparisons of the results of clinical trials of main(cid:173)
`tenance treatments for ulcerative colitis are con(cid:173)
`founded by the different definitions of relapse and
`the different measures of treatment success used in
`the various studies. Recognizing that these factors
`make direct comparisons between studies problem(cid:173)
`atic, we present relapse rates reported in other com(cid:173)
`parative
`trials of sulfasalazine and mesalamine
`products {see Table 4) to provide a context for our
`findings. In our study, the rates of relapse over 6
`months (excluding patients who were withdrawn be(cid:173)
`cause of adverse events) were 35.3% for patients
`receiving 0.8 g of mesalamine per day, 31.0% for
`
`* Proctor & Gamble Pharmaceuticals, Cincinnati, Ohio
`t SmithKline Beecham, Philadelphia, Pennsylvania.
`* Ferring Pharmaceuticals, Denmark.
`
`patients receiving 1.6 g of mesalamine per day, and
`54.0% for patients receiving placebo. These rates
`were within the range of those reported by other
`investigators.
`We used the proctosigmoidoscopic appearance of
`the bowel as the indicator of whether relapse had
`occurred. Because of the spectrum of normal bowel
`habits and their overlap with "irritable bowel"
`symptoms in patients with ulcerative colitis and with
`occasional blood from benign anal conditions, we
`believe that proctosigmoidoscopy is the most objec(cid:173)
`tive way to determine the level of disease activity.
`Proctosigmoidoscopic findings generally correlate
`well with the level of symptoms the patient is hav(cid:173)
`ing, but we used them to clarify discrepancies be(cid:173)
`tween subjective symptoms (bowel frequency or li(cid:173)
`quidity) and to assess hematochezia not related to
`active colitis. Clearly, an effective maintenance ther(cid:173)
`apy for ulcerative colitis should control symptoms in
`addition to maintaining the integrity of the bowel
`mucosa. Our study design did not include the anal(cid:173)
`ysis of ulcerative colitis symptoms over the course of
`treatment. During the study, only two patients were
`considered to have had a symptomatic relapse not
`accompanied by proctosigmoidoscopic changes. This
`provides reassurance that proctosigmoidoscopic re(cid:173)
`mission was acco
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