An Oral Preparation of Mesalamine as Long-Term MaintenanceTherapy for Ulcerative ColitisA Randomized, Placebo-Controlled TrialThe Mesalamine Study Group*

Objective: To compare the safety and efficacy of a pH-sensitive, polymer-coated oral formulation of mesalamine(Asacol, Procter & Gamble Pharmaceuticals, Cincinnati,Ohio) with those of placebo in maintaining remission inpatients with ulcerative colitis.Design: Muiticenter, double-blind, placebo-controlled,randomized clinical trial.Setting: Eight private practices, five university-basedmedical centers, and four hospitals or clinics.Patients: 264 patients with ulcerative colitis that hadbeen maintained in remission for at least 1 month whilethe patients were receiving stable doses of sulfasalazine orany oral mesalamine product.Intervention: Coated mesalamine at oral dosages of 0.8g/d or 1.6 g/d or matching placebo for 6 months.Measurements: Treatment success, defined as mainte-nance of remission after 6 months, and treatment failure,defined as relapse during the study (as indicated by proc-tosigmoidoseopy at 1, 3, or 6 months of treatment) orwithdrawal due to adverse events. Safety was assessed onthe basis of laboratory analyses and patient- and investi-gator-noted adverse events.Results: 189 patients were compliant with the protocolfor 6 months or stopped receiving therapy because ofrelapse or adverse events. Of these 189 patients, 25 of the63 patients (39.7%) in the placebo group had treatmentsuccess compared with 40 of the 68 patients (58.8% [95%Cl, 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% [Cl,52.4% to 78.6%]) in the group receiving mesalamine, 1.6g/d (P = 0.006). In the intention-to-treat analysis of allpatients, 42 of the 87 patients (48.3%) in the placebogroup had treatment success compared with 57 of the 90patients (63.3% [Cl, 52.8% to 73.8%]) in the group receiv-ing mesalamine, 0.8 g/d (P = 0.050) and 61 of the 87patients (70.1 % [Cl, 59.9% to 80.3%]) in the group receiv-ing mesalamine, 1.6 g/d (P = 0.005). Age, sex, and racewere not found to predict treatment success or failure. Themesalamine tablet was well tolerated, and no clinicallysignificant changes were seen in hematologic, hepatic, orrenal laboratory profiles.

Conclusion: Coated mesalamine at oral dosages of 0.8g/d and 1.6 g/d is safe and effective in maintaining remis-sion in patients with quiescent ulcerative colitis.

Ann Intern Med. 1996;124:204-211.

*For a listing of members of The Mesalamine Study Group, seethe Appendix.

204 © 1996 American College of Physicians

Sulfasalazine has been first-line therapy for mildlyto moderately aetive uleerative colitis and for

maintenance of remission in ulcerative colitis sinceit was introduced more than 50 years ago. It isclearly effective (1-5) but is associated with an ap-preciable incidence of dose-related side effects anda spectrum of serious idiosyncratic reactions (6, 7).Sulfasalazine is a pro-drug comprising mesalamine(5-aminosalicylic acid) and sulfapyridine joined byan azo bond. The oral use of free mesalamine, theprincipal active moiety of the drug (8-10), is com-promised by the instability of mesalamine in theacid environment of the stomach and by the absorp-tion of it in the proximal small intestine (11). Azo-bond linkage with the carrier molecule sulfapyridineenables mesalamine to reach the colon, where bac-terial enzymes split the azo bond, liberating the twocomponents (12).

The sulfapyridine moiety of sulfasalazine is aneflfective carrier molecule for mesalamine, but it isconsidered to be responsible for most cases of in-tolerance to sulfasalazine (13). Consequently, re-search has been directed toward developing a me-salamine formulation that would successfully delivermesalamine to the colon without toxic effects (14).One oral mesalamine formulation (Asacol, Procter& Gamble Pharmaceuticals, Cincinnati, Ohio) con-sists of a core of 400 mg of mesalamine (the sameamount contained in 1 g of sulfasalazine) envelopedby a pH-sensitive polymer coating. This coating pro-tects mesalamine from premature absorption in thesmall intestine and thus enables therapeutic quanti-ties of mesalamine to reach the colon.

This coated mesalamine formulation has beenshown to be effective in the treatment of mildly tomoderately active ulcerative colitis (15, 16) and tobe well tolerated by patients who had previouslyhad adverse reactions to sulfasalazine (17, 18). Inaddition, three randomized, double-blind studieshave shown that this formulation is as effective assulfasalazine in maintaining remission in patientswith quiescent ulcerative colitis (19-21). In onestudy. Dew and colleagues (19) showed that me-salamine at an average dosage of 1.4 g/d was similarto sulfasalazine at an average dosage of 2.4 g/d inmaintaining remission for 16 weeks in 72 patientswith quiescent ulcerative colitis. In a later study

(20), these authors showed that a higher dosage ofmesalamine (2.7 g/d) did not differ from sulfasala-zine at an average dosage of 2.3 g/d in maintainingremission for 24 weeks in 67 patients with quiescentulcerative colitis. Riley and coworkers (21) com-pared this same oral mesalamine formulation withsulfasalazine in 100 patients who had ulcerative co-litis in remission: The most common dosage of oralmesalamine was 0.8 g/d, and the most commondosage of sulfasalazine was 2.0 g/d. Again, no sta-tistically significant difference was found betweenthe two treatment groups with respect to the pro-portion of patients who had had relapse by 48 weeks.

The results of these three studies suggest thatthis oral mesalamine formulation is as effective assulfasalazine as maintenance therapy for ulcerativecolitis. However, these studies share the followingmethodologic flaws: Different dosages were used,but the studies do not indicate the relative efficacyof different dosages of mesalamine; and no placebocontrols were used to aid in the interpretation ofthe remission rates achieved or to provide reassur-ance that the patients recruited actually neededdrug therapy to maintain remission.

To further evaluate this pH-sensitive oral me-salamine formulation, we conducted a muiticenter,double-blind, placebo-controlled, randomized studyto compare the efficacy and safety of mesalamine,0.8 g/d and 1.6 g/d, with those of placebo in main-taining remission in patients with ulcerative colitis.A sulfasalazine arm was not included in order toreduce the sample size required for the study.

Methods

The study protocol was approved by the institu-tional review board of each study site, and eachpatient gave written, informed consent before studyentry.

PatientsWe recruited patients from 17 study sites: 8 pri-

vate practices, 5 university-based medical centers,and 4 hospitals or clinics. Recruiting was done usingprint and radio advertising, posters, and announce-ment letters to referring physicians and local sup-port groups. Each patient enrolled in the trial wasbetween 18 and 75 years of age and had a docu-mented diagnosis of ulcerative colitis. At the timethe study began, all patients had been in remissionfor at least 1 month as indicated by the endoscopicappearance of the bowel and by the passage of fiveor fewer bloodless stools per day. To qualify forstudy entry, patients were required to have a scoreof 0 on the proctosigmoidoscopic grading scale de-scribed below {see Evaluation Methods). The pres-

ence of colitis symptoms, such as loose stools orabdominal cramps, was not a reason for exclusionfrom the study, provided that endoscopic examina-tion showed remission of disease. All patients hadbeen treated previously with 2.0 to 4.0 g of sul-fasalazine per day or 0.8 to 1.6 g of any oral me-salamine product per day; the dosage of these drugshad been constant for at least 1 month before studyentry. No patient had received corticosteroid or top-ical rectal therapy within 1 month of study entry.

Female patients with child-bearing potential wererequired to practice a reliable method of birth con-trol throughout the study, and women who werepregnant or nursing were excluded from the study.Patients with a history of allergy or intolerance toaspirin or salicylates were also excluded, as werepatients with a history of extensive bowel resectioncausing the short-bowel syndrome and patients withlaboratory evidence of renal or hepatic dysfunction.

Throughout the study, patients were not allowedto use corticosteroids (except topically for dermato-logic reasons), sulfasalazine, antibiotics for morethan 10 consecutive days, topical rectal therapies, orinvestigational drugs other than mesalamine.

Study DesignIn this muiticenter, double-blind study, 264 pa-

tients were randomly assigned to receive one ofthree treatment regimens: placebo, 0.8 g of oralmesalamine per day, or 1.6 g of oral mesalamineper day. Randomization was done within centers bymeans of randomization codes using specific patientnumbers generated for each study site before thestudy began. Each patient number was randomlydistributed by computer to one of the three treat-ment groups. Patients were not stratified accordingto any clinical characteristic, such as disease loca-tion or previous treatment.

Patients were seen at baseline and at months 1,3, and 6 of treatment. They were also seen at anytime during the study if they felt that their diseasewas worsening or that they were having an adverseevent. At baseline, each patient had a screening atwhich medical history was recorded and physicalexamination, proctosigmoidoscopy or colonoscopy,laboratory analyses, and pregnancy testing were done.At each follow-up visit, physical examination, proc-tosigmoidoscopy or colonoscopy, laboratory analy-ses, and pregnancy testing were done. Throughoutthe study, patients maintained a daily diary in whichthey recorded their study medication dosing, theirsymptoms, and their concomitant medication dos-ing.

Study DrugThe mesalamine used in our study (Asacol) was

supplied in tablets that consisted of a 400-mg me-15 January 1996 • Annals of Intemal Medicine • Volume 124 • Number 2 205

salamine core enveloped by a pH-sensitive acrylicpolymer 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 reachesthe terminal ileum, where the pH is consistentlyhigher than 7. Radiologic studies have shown thatbarium-containing capsules coated with this resinbreak down in the terminal ileum and colon (22,23); thus, this resin makes it possible to providetopical application of mesalamine directly to theseareas (22). The placebo tablets were identical to themesalamine tablets in odor and appearance but con-tained no active ingredients.

Placebo was administered as four tablets daily.Mesalamine, 0.8 g/d, was administered as two activeand two placebo tablets daily, and mesalamine, 1.6g/d, was administered as four active tablets daily.Tablets were packaged in four bottles, each ofwhich was labeled with the time of day at whichpatients were to take the tablets in that bottle. Allpatients took one tablet at breakfast, one at lunch,one at dinner, and one at bedtime. Patients in themesalamine, 0.8 g/d group took the active tablets atbreakfast and at bedtime. The study treatment pe-riod was scheduled to last 6 months.

Compliance was monitored by tablet count andby review of patient diaries at each study visit. Non-compliance was defined as missing more than 15%of the study medication over the duration of treat-ment or more than 50% of the study medication for4 consecutive days (for reasons other than intoler-ance).

Evaluation MethodsAll patients were evaluated using proctosigmoid-

oseopy or eolonoscopy at baseline and at each visit.Findings were graded according to the followingscale: 0 (normal or mild granularity, edema, hypere-mia, or erythema; mildly diminished vascular mark-ings); 1 (mild granularity, edema, hyperemia, or er-ythema; mildly diminished vascular markings plusfriability); 2 (marked erythema or granularity; novascular markings; bleeding with minimal trauma;no ulcerations); and 3 (spontaneous bleeding; ulcer-ations). A score of 0 was required for study entry. Ifa patient was noted at baseline to have a score of 0with mild granularity, edema, hyperemia, or ery-thema or mildly diminished vascular markings, theinvestigator specifically commented on these factorsand clearly stated that the patient was consideredto be in endoscopic remission. The investigatorsagreed that these findings could be present in pa-tients with longstanding ulcerative colitis in remis-sion. Subsequently, a score of 1 or higher at anytime was considered indicative of relapse.

Safety was evaluated at each visit using physical

examination and laboratory analyses. Laboratoryanalyses consisted of routine biochemical and hema-tologic measurements and urinalyses done at eachvisit, plus creatinine clearance assays to monitorrenal function done at the baseline visit and thefinal visit. Patients were questioned at each visitabout any adverse events they may have had. Inaddition, any events noted in patient diaries thatwere considered to be possible adverse events weretabulated as adverse events.

Efficacy VariablesThe primary eflficacy variable was treatment out-

come. Treatment outcome could be either success,defined as maintenance of remission (as indicatedby endoscopic evaluation) at the 6-month studyvisit, or failure, defined as endoscopic relapse at anytime during the study or withdrawal due to an ad-verse event. Time to relapse was also evaluated.

Statistical AnalysisThe primary efficacy analysis included patients

who were compliant with the protocol until they hadcompleted 6 months of therapy or until they haddiscontinued treatment because of relapse or ad-verse events. In addition, an intention-to-treat anal-ysis, which included all patients exposed to treat-ment, was also done. In this analysis, treatmentsuccess was determined on the hasis of remission atthe patient's final visit, regardless of whether thepatient had completed 6 months of treatment.

Before the study began, a sample size of 64 pa-tients per treatment group was determined to besufficient to detect a 25% difference in proportionsof patients having relapse, using a two-sided 0.05significance level with 0.80 power. Because morepatients than expected could not be analyzed, thenumber of patients per treatment group was in-creased during the course of the study before thestudy was unblinded.

The baseline characteristics of patients in the twomesalamine groups were compared with those ofpatients in the placebo group by using the f-test forcontinuous variables and the Fisher exact test forcategorical variables.

The treatment outcome of patients in the twomesalamine groups was compared with the treat-ment outcome of patients in the placebo group byusing the Fisher exact test. Treatment outcome wasalso analyzed by treatment group and age, sex, andrace by using categorical methods, log-linear model.

Time to relapse in the mesalamine groups wascompared with time to relapse in the placebo groupby survival analysis using the product-limit methodto compute estimates of the survival function (re-mission) and using the log-rank test to examinetreatment group differences. In this analysis, pa-

206 15 January 1996 • Annals of Intemal Medicine • Volume 124 • Number 2

Table 1. Baseline Demographic and Disease HistoryCharacteristics by Treatment Group

BaselineCharacteristic

Mean age ± SE, ySex, n(%)

MaieFemaie

Race, n(%)WhiteNonwhite

Duration of uicerativecoiitis, n(%)

<1 year1 ~5 years>5-10 years>10 yearsUnknown

Extent of disease, n(%)ProctitisProctosigmoiditisLeft-sided diseasePancoiitisUnknown

Previous medication forulcerative colitis, n(%)

SulfasaiazineAny oral mesaiamineOtinert

Stool frequency, n(%)One per dayTwo per dayThree per dayFour or more per dayMean number per day

± SE

Placeboin = 87)

4.2 ± 1.44

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)

2.08 ± 0.109

Mesaiamine,0.8 g/d(n = 90)

41.9 ± 1.37

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)

1.83 ±0.103

Mesaiamine,1.6 g/d

(n = 87)

42.1 ± 1.45

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)

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 tobe censored at the last date of study participation,and patients in whom treatment was discontinuedprematurely because of an adverse event were con-sidered to be censored at the date of discontinua-tion.

The distribution of the number of adverse eventsrecorded per patient in the mesalamine groups wascompared with that in the placebo group by contin-gency table analysis using the Pearson chi-squarestatistic with the number of adverse events per pa-tient categorized as 0, 1 to 5, 6 to 10, or more than10.

Results

PatientsTwo hundred sixty-four patients were randomly

assigned to receive either placebo, 0.8 g of me-salamine per day, or 1.6 g of mesalamine per day.Randomization was done at all 17 study sites. Thenumber of patients at each site ranged from 1 to 47(mean, 16 patients). The demographic and diseasehistory characteristics of the 264 patients are pre-

sented in Table 1. The characteristics of the me-salamine groups were similar to those of the pla-cebo group, except for the sex distribution: Theproportion of women in the mesalamine, 1.6 g/dgroup (57.5%) was greater than that in the placebogroup (38.9%) (P = 0.015). In general, there wasgood agreement between clinical and endoscopicremission at baseline.

Seventy-five patients were excluded from the pri-mary efficacy analysis for the following reasons:failure to meet study entry criteria (n = 36), non-compliance with study medication (n = 18), non-compliance with study procedures (n = 3), concom-itant medication violation (« = 10), loss to follow-up(n = 4), and voluntary withdrawal (n = 4). Thenumbers of patients excluded were similar in thethree groups.

Treatment OutcomeAnalyses of data from patients who completed 6

months of treatment or who withdrew because ofrelapse or adverse events (primary efficacy analyses)showed that the criteria for treatment success weremet in 25 of 63 patients (39.7%) in the placebogroup compared with 40 of 68 patients (58.8% [95%CI, 46.4% to 71.3%]) in the group receiving me-salamine, 0.8 g/d, and 38 of 58 patients (65.5%[CI, 52.4% to 78.6%]) in the group receiving me-salamine, 1.6 g/d (Table 2). The percentage of pa-tients who met the criteria for treatment successwas greater in both the group receiving mesalamine,0.8 g/d {f = 0.036) and the group receiving me-salamine, 1.6 g/d (P = 0.006) than in the placebogroup. In the intention-to-treat analysis of all pa-tients, the differences between the placebo and themesalamine groups were also significant: The crite-ria for treatment success were met in 42 of 87patients (48.3%) in the placebo group comparedwith 57 of 90 patients (63.3% [CI, 52.8% to 73.8%])in the group receiving mesalamine, 0.8 g/d (F =0.050) and 61 of 87 patients (70.1% [CI, 59.9% to80.3%]) in the group receiving mesalamine, 1.6 g/d(P = 0.005). Subgroup analyses of treatment out-

Table 2. Treatment Outcome of Patients Who Completed6 Months of Therapy or Who Withdrew from theStudy because of Relapse or Adverse Events

Treatment Group Success* Faiiure*

Piacebo (n = 63)Mesalamine, 0.8 /gd (n = 68)Mesalamine, 1.6 g/d (n = 58)

25 (39.7)40 (58.8)t38 (65.5)*

38 (60.3)28(41.2)20 (34.5)

* Success - maintenance of remission (as indicated by endoscopic evaiuation) at the6-month study visit; faiiure = endoscopic relapse at any time during the study orwithdrawai due to an adverse event.

t P - 0.036 compared with placebo group (Fisher exact test, two-tailed).t P = 0.006 compared with placebo group (Fisher exact test, two-tailed).

15 January 1996 • Annals of Intemal Medicine • Volume 124 • Number 2 207

Table 3. Time to Relapse in Patients Who Combed 6iwonins OT inerapiy or wno wnnorew Trom ineStucfy because of Relapse or Adverse Events

Time toRelapse (weeks)

Placebo

0-45-89-1213-1617-2021-24>24Censored t

(n = 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 1

Mesalamine, 0.8 g/d*(n = 68)

4(5.9)7(10.3)3 (4.4)2 (2.9)3 (4.4)2 (2.9)3 (4.4)

44 (64.7)

Relapse

Mesalamine, 1.6 g/dt(n = 58)

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-ciation between these baseline factors and treatmentoutcome {F > 0.05). Throughout the study, agree-ment was generally good between symptomatic andendoscopic relapse in all groups. Treatment wasdiscontinued in two patients, one in the placebogroup and one in the group receiving mesalamine,1.6 g/d, because of the appearance of symptoms ofulcerative colitis, despite normal proctosigmoido-scopic findings.

Time to RelapseTable 3 and Figure 1 show that in the primary

efficacy analysis of compliant patients who com-pleted 6 months of therapy or who withdrew be-cause of relapse or adverse events, both of themesalamine groups differed from the placebo groupwith respect to time to relapse (P = 0.026 for thegroup receiving mesalamine, 0.8 g/d; P = 0.011 forthe group receiving mesalamine, 1.6 g/d). The sur-vival plots of the patients who received placebo andthe patients who received mesalamine diverge afterapproximately 30 days; patients who received me-salamine showed a greater probability of maintain-ing remission throughout the rest of the study. Inthe intention-to-treat analysis of all patients, a sta-tistically significant difference in survival distributionwas seen between the group receiving mesalamine,1.6 g/d and the placebo group {P = 0.008) but notbetween the group receiving mesalamine, 0.8 g/dand the placebo group {P = 0.074).

In a supplemental analysis, in which patientswere stratified according to extent of disease (pan-colitis, left-sided disease, proctosigmoiditis, proctitis,and unspecified), the distributions of time to relapsewere similar in the five groups {P = 0.907).

ComplianceSix of 87 patients (6.9%) in the placebo group,

11 of 90 patients (12.2%) in the group receivingmesalamine, 0.8 g/d, and 4 of 87 patients (4.6%) inthe group receiving mesalamine, 1.6 g/d, met thecriteria for study drug noncompliance. All 21 ofthese patients were dropped from the study, somebecause of dosing noncompliance alone and othersfor this reason plus others.

Adverse Reactions to TherapyThe number of investigator-recorded adverse

events and the percentage of patients who reportedadverse events were similar among the three treat-ment groups. Thirty-four of 87 patients (39.1%) inthe placebo group reported 81 events; 29 of 90patients (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/dreported 106 events. The adverse events recordedmost frequently by the investigators were headache,fiu syndrome, diarrhea, rhinitis, and abdominal pain.When potential adverse events noted in patient di-aries were combined with investigator-recorded ad-verse events, statistical analysis of the distribution ofthe number of adverse events reported per person(0, 1 to 5, 6 to 10, or more than 10) showed nosignificant differences between the placebo groupand the group receiving mesalamine, 0.8 g/d {P =0.922) or between the placebo group and the groupreceiving mesalamine, 1.6 g/d {P = 0.236).

Most adverse events were mild to moderate inseverity and were not serious. Three patients, onefrom each treatment group, had serious adverseevents: One patient in the placebo group had chestpain, hypertension, and dyspnea that were consid-

1.0

0.8

0.6

•e 0.4

0.2n=63

0.8 g/day n=68"Mesalamine 1.6 g/day n=58

60 90 120 150 1800.0

Days of Til. 30# at RiskPlacebo 540.8 g/day 651.6 g/day 52

Figure 1. Pereantage of patiants writh uimatlve caUtis vyho re-mained in ramistion during traiA«wnt w M ptacobo: wMh me-salwnine, 0.8 g/d; or M W I mwalMMM, 1.6 g/d. P values are forcomparisons between treatment and placebo

435447

385044

314744

304541

142121

208 15 January 1996 • Annals of Intemal Medicine • Volume 124 • Number 2

ered to be unrelated to treatment; one patient re-ceiving mesalamine, 0.8 g/d, had a questionabletransient ischemic attack and migraine, the relationof which to treatment was considered doubtful; andone patient receiving mesalamine, 1.6 g/d, had amiscarriage that was considered to be unrelated totreatment. Treatment was discontinued because ofan adverse event in 4 of 87 patients (4.6%) in theplacebo group, 4 of 90 patients (4.4%) in the groupreceiving 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 differentfor each patient, with the exception of headacheand paresthesia. Headache was the reason for dis-continuation in one patient in the placebo groupand one patient in the group receiving mesalamine,0.8 g/d, and paresthesia was the reason for discon-tinuation in two patients in the placebo group.None of these adverse events was considered seri-ous.

We detected no clinically significant trends in anyof the laboratory test results, no treatment-relatedabnormalities in the results of biochemical or he-matologic tests or urinalyses, and no changes increatinine clearance. No patient was dropped fromthe study prematurely because of laboratory abnor-malities.

Discussion

In our study, daily dosages of 0.8 and 1.6 g of thepH-sensitive, polymer-coated oral mesalamine prep-aration were safe and effective in maintaining re-mission in patients with quiescent ulcerative colitis.After 6 njonths of treatment, 58.8% of the patientsreceiving mesalamine, 0.8 g/d, and 65.5% of thepatients receiving mesalamine, 1.6 g/d remained inremission, compared with 39.7% of patients receiv-ing placebo. Sex, age, and race were not found topredict treatment success or failure.

Relapse rates for patients with quiescent ulcer-ative colitis may depend on the length of follow-upand, probably, on the dose of the maintenance drug,although further studies are indicated. In addition,comparisons of the results of clinical trials of main-tenance treatments for ulcerative colitis are con-founded by the different definitions of relapse andthe different measures of treatment success used inthe various studies. Recognizing that these factorsmake direct comparisons between studies problem-atic, we present relapse rates reported in other com-parative trials of sulfasalazine and mesalamineproducts {see Table 4) to provide a context for ourfindings. In our study, the rates of relapse over 6months (excluding patients who were withdrawn be-cause of adverse events) were 35.3% for patientsreceiving 0.8 g of mesalamine per day, 31.0% for

Table 4. Relapse Rates Reported in Studies of Patientswith Quiescent Uicerative Coiitis Treated withSulfasalazine or Mesalamine Products

Study (Reference)

Dew etal. (19)

Rileyetal. (21)

Dew et al. (20)

Rutgeerts (24)

Bianchi Porro et al.(25)

Mulder et al. (26)

Gionchettietal.(27)

Misiewicz et al. (4)

Riis et al. (28)

DIssanayakeetal.(3)

Azad Khan et al. (5)

Drug

Mesalamine (Asacol)*SulfasalazineMesalamine (Asacol)*SulfasalazineMesalamine (Asacol)*SulfasalazineMesalamine (Claversal)tSulfasalazineMesalamine (Claversal)tSulfasalazineMesalamine (Pentasa)*SulfasalazineMesalamine (Pentasa)tSulfasalazinePlaceboSulfasalazinePlaceboSulfasalazinePlaceboSulfasalazineSulfasalazine

Dose, g

1.22

0.8-1.62-4

2.4-4.42-40.75

1.5-2.012

1.53

1.53-2_2-2421

StudyDuration,

mo

4

12

6

12

12

12

4

12

6

6

6

RelapseRate,

%

26183839222028235053465420167629242955129

1433

* Proctor & Gamble Pharmaceuticals, Cincinnati, Ohio.t SmithKline Beecham, Philadelphia, Pennsylvania.+ Ferring Pharmaceuticals, Denmark.

patients receiving 1.6 g of mesalamine per day, and54.0% for patients receiving placebo. These rateswere within the range of those reported by otherinvestigators.

We used the proctosigmoidoscopic appearance ofthe bowel as the indicator of whether relapse hadoccurred. Because of the spectrum of normal bowelhabits and their overlap with "irritable bowel"symptoms in patients with ulcerative colitis and withoccasional blood from benign anal conditions, webelieve that proctosigmoidoscopy is the most objec-tive way to determine the level of disease activity.Proctosigmoidoscopic findings generally correlatewell with the level of symptoms the patient is hav-ing, but we used them to clarify discrepancies be-tween subjective symptoms (bowel frequency or li-quidity) and to assess hematochezia not related toactive colitis. Clearly, an effective maintenance ther-apy for ulcerative colitis should control symptoms inaddition to maintaining the integrity of the bowelmucosa. Our study design did not include the anal-ysis of ulcerative colitis symptoms over the course oftreatment. During the study, only two patients wereconsidered to have had a symptomatic relapse notaccompanied by proctosigmoidoscopic changes. Thisprovides reassurance that proctosigmoidoscopic re-mission was accompanied by control of symptoms inalmost all cases.

The dropout rate in our study was high, largelybecause patients failed to meet strict entry criteria.When the study began, patients who had been en-

15 January 1996 • Annals of Intemal Medicine • Volume 124 • Number 2 209

tered were dropped if their baseline proctosigmoid-oscopic examinations showed even mild granularityor erythema or mildly diminished vascular markings.As a result, many patients considered to be in clin-ical remission were excluded from the study on thebasis of minor proctosigmoidoscopic findings. Dur-ing the course of the study, the proctosigmoido-scopic grading scale was changed to allow entry ofpatients with these mild findings, because the inves-tigators agreed that patients with longstanding ul-cerative colitis in remission may have had mildgranularity, edema, hyperemia, or erythema or mild-ly diminished vascular markings on endoscopy.

The polymer-coated oral mesalamine preparationwas well tolerated; most adverse events were mildor moderate in severity. The percentages of patientshaving adverse events and the number of adverseevents that patients had were similar in the placebogroup and the mesalamine groups. This suggeststhat the adverse events reported may have beenrelated to the symptoms of ulcerative colitis ratherthan to any eifects of the active treatment. Further-more, no cHnically meaningful dose-response rela-tion was apparent for any of the adverse eventsreported. The adverse events seen in our study weresimilar to those reported in other studies of me-salamine as maintenance therapy for ulcerative co-litis (19, 2t) and to those most frequently reportedby patients receiving sulfasalazine (29). In previousstudies done in rats (30), the intravenous adminis-tration of mesalamine was associated with renal tox-icity. Careful monitoring of renal function in ourpatients showed no clinically significant untowardchanges in any of the renal function variables stud-ied. This finding is consistent with the findings ofother clinical trials of treatment of ulcerative colitiswith mesalamine (t5, 16, 21).

Our results indicate that coated mesalamine atdosages of 0.8 g/d and t.6 g/d is safe and effective inmaintaining remission in patients with quiescent ul-cerative colitis.

Appendix

The following are members of The MesalamineStudy Group: Stephen B. Hanauer, MD, Universityof Chicago Hospital, Chicago, Illinois; Charles A.Sninsky, MD, University of Florida, Gainesville,Florida; Malcolm Robinson, MD, University of Okla-homa College of Medicine, Oklahoma City, Okla-homa; Bernard J. Powers, MD, Arapahoe Gastroen-terology, Englewood, Colorado; James D. McHattie,MD, Pasqua Hospital, Regina, Saskatchewan, Can-ada; James E. Mayle, MD, Michigan State Uni-versity, Lansing, Michigan; Charles O. Elson, MD,University of Alabama at Birmingham, Birmingham,

Alabama; Michael P. DeMicco, MD, AssociatedGastroenterology Medical Group, Anaheim, Cali-fornia; James H. Butt, MD, University of MissouriSchool of Medicine, Columbia, Missouri; Ronald E.Pruitt, MD, Nashville Medical Research Institute,Nashville, Tennessee; John M. Bozdech, MD, TheCleveland Qinic, Cleveland, Ohio; Michael A. Safdi,MD, Greater Cincinnati Gastroenterological Asso-ciates, Cincinnati, Ohio; Michael S. Gurney, MD,The Portland Chnic, Portland, Oregon; Alan M.Fixelle, MD, Atlanta, Georgia; Arnold I. Levin,MD, Eastside Digestive Disease Clinic, Kirkland,Washington; John Smoots, MD, The WesternClinic, Tacoma, Washington; and Douglas C. Wolf,MD, Emory University, Atlanta, Georgia.

Acknowledgments: The authors thank Mary G. Royer for assis-tance in preparing the manuscript.

Grant Support: In part by a clinical grant from Procter & GamblePharmaceuticals, Cincinnati, Ohio.

Requests for Reprints: Stephen B. Hanauer, MD, Division ofGastroenterology, University of Chicago Hospital, 584] SouthMaryland Avenue, Box 400, Chicago, IL 60637.

Current Author Addresses: Dr. Hanauer: Division of Gastroenter-ology, University of Chicago Hospital, 5841 South Maryland Av-enue, Box 400, Chicago, IL 60637.Dr. Sninsky: Division of Gastroenterology, Gainesville VeteransAdministration Center, Section 111 C, Room E 330, 1600 ArcherRoad, Gainesville, FL 32608.Dr. Robinson: Oklahoma Foundation for Digestive Research,711 SL Young Boulevard, Suite 501, Oklahoma City, OK 73104.Dr. Powers: Arapahoe Gastroenterology, 950 East Harvard, Suite540, Englewood, CO 80210.Dr. McHattie: Gastrointestinal Unit, Pasqua Hospital, 4101 Dew-dney Avenue, Regina, Saskatchewan, S4T 1A5, Canada.Dr. Mayle: Michigan State University Gastroenterological Ser-vices, Ingham Medical Professional Center, 405 West GreenlawnAvenue, Suite 130, Lansing, MI 48910.Dr. Elson: Division of Gastroenterology, University of Alabamaat Birmingham, 701 South 19th Street, Birmingham, AL 35294.Dr. DeMicco: Associated Gastroenterology Medical Group, 1222West La Palma, Suite 306, Anaheim, CA 92801.Dr. Butt: University of Missouri School of Medicine, TrumanVeterans Administration Hospital, 800 Hospital Drive, Columbia,MO 65201.Dr. Pruitt: Nashville Medical Research Institute, 4230 HardingRoad, Suite 309, Nashville, TN 37205.Dr. Bozdech: QPS Clinic, 14th and Main Streets, Quincy, IL62301.Dr. Safdi: Greater Cincinnati Gastroenterologieal Associates,2925 Vernon Place, Suite 100, Cincinnati, OH 45219.Dr. Gurney: West Hills Gastroenterology Association, 9155South West Barnes Road, Suite 636, Portland, OR 97225-6652.Dr. Fixelle: 4470 North Shallowford Road, Suite 203, Atlanta,GA 30338.Dr. Levin: Eastside Digestive Disease Clinic, 13030 121st WayNE, Suite 201, Kirkland, WA 98034.Dr. Smoots: Franciscan Family Care, 1708 South Yakima, Ta-coma, WA 98405.Dr. Wolf: 5671 Peachtree-Dunwoody Road, Suite 550, Atlanta,GA 30342.

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