C

OIU

WJP

*HSGGP

Tcd

BsadtnrerwUiwrdtpswnrrtdpcr

CLIN

ICA

L–A

LIMEN

TARY

TRA

CT

GASTROENTEROLOGY 2010;138:1286–1296

LINICAL—ALIMENTARY TRACT

nce-Daily Dosing of Delayed-Release Oral Mesalamine (400-mg Tablet)s as Effective as Twice-Daily Dosing for Maintenance of Remission oflcerative Colitis

ILLIAM J. SANDBORN,* JOSHUA KORZENIK,‡ BRET LASHNER,§ JONATHAN A. LEIGHTON,� UMA MAHADEVAN,¶

AMES F. MARION,# MICHAEL SAFDI,** CHARLES A. SNINSKY,‡‡ RAMAN M. PATEL,§§ KEITH A. FRIEDENBERG,� �

RESTON DUNNMON,¶¶ DAVID RAMSEY,¶¶ and SUNANDA KANE*

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; ‡Crohn’s & Colitis Center and Gastrointestinal Unit, Massachusetts Generalospital, Boston, Massachusetts; §Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio; �Division of Gastroenterology and Hepatology, Mayo Clinic Arizona,cottsdale, Arizona; ¶Center for Colitis and Crohn’s Disease, University of California, San Francisco, California; #Department of Medicine, Division ofastroenterology, Mt. Sinai School of Medicine, New York, New York; **Ohio Gastroenterology and Liver Institute, Cincinnati, Ohio; ‡‡Digestive Disease Associates,ainesville, Florida; §§High Desert Gastroenterology, Inc, Lancaster, California; � �Great Lakes Gastroenterology, Mentor, Ohio; and ¶¶Procter & Gambleharmaceuticals, Inc, Mason, Ohio

his article has an accompanying continuing medical education activity on page e11. Learning Objective: Uponompletion of reading this article, successful learners will become familiar with the comparative efficacy of once-daily

osing of delayed-release mesalamine as compared with divided dosing in patients with ulcerative colitis.

fheOdar

KC

Vo

DsTv1mwdcAO

MfS

See related articles, Langille M et al, on page322, and Vermeire S et al, on page 357 inCGH.

ACKGROUND & AIMS: The practice of dosing me-alamines in divided doses for the treatment of ulcer-tive colitis (UC) began with sulfasalazine and wasriven by sulfapyridine toxicity. This convention andhe assumption that dosing multiple times a day isecessary to treat UC had not been challenged untilecently. This study was conducted to determine thefficacy and safety of once-daily dosing of delayed-elease mesalamine (Asacol 400-mg tablets) comparedith twice-daily dosing for maintaining remission inC patients. METHODS: A multicenter, randomized,

nvestigator-blinded, 12-month, active-control trialas conducted to assess the noninferiority of delayed-

elease mesalamine 1.6 –2.4 g/day administered onceaily compared with twice daily in patients with mild-o-moderate UC currently in clinical remission. Therimary end point was maintenance of clinical remis-ion at month 6. RESULTS: A total of 1023 patientsere randomized and dosed. The primary objective ofoninferiority was met. At month 6, 90.5% of patientseceiving once-daily dosing had maintained clinicalemission, compared with 91.8% of patients receivingwice-daily dosing (95% confidence interval for twiceaily - once daily, -2.3 to 4.9). At month 12, 85.4% ofatients receiving once-daily dosing had maintainedlinical remission, compared with 85.4% of patients

eceiving twice-daily dosing (95% confidence interval

or twice daily - once daily, -4.6 to 4.7). Both regimensad low rates of withdrawals as a result of adversevents and serious adverse events. CONCLUSIONS:nce-daily dosing of delayed-release mesalamine atoses of 1.6 –2.4 g/day was shown to be as effectives twice-daily dosing for maintenance of clinicalemission in patients with UC.

eywords: Ulcerative Colitis; Mesalamine; Maintenance;ontrolled Trial.

iew this article’s video abstract at www.gastrojournal.rg.

rugs that deliver mesalamine to the gastrointestinaltract as treatment for ulcerative colitis (UC) include

ulfasalazine, olsalazine, balsalazide, and mesalamine.1,2

hese drugs historically have been administered in di-ided doses. The practice of divided dosing began in the940s with sulfasalazine3 and was driven by the need toinimize toxicity from sulfapyridine after sulfasalazineas cleaved to mesalamine and sulfapyridine.4 Dividedosing administration then was carried over into thelinical trial designs of olsalazine (twice-daily dosing),5,6

sacol (Procter & Gamble Pharmaceuticals, Inc, Mason,H) (divided or 3 times daily dosing),7–9 Pentasa (Shire

Abbreviations used in this paper: CI, confidence interval; MARS,edication Adherence Report Scale; QDIEM, QD Dosing Investigation

or Efficacy in UC Maintenance; SAE, serious adverse event; SCCAI,imple Clinical Colitis Activity Index.

© 2010 by the AGA Institute0016-5085/10/$36.00

doi:10.1053/j.gastro.2009.12.054

Uzopgstzmam(wr(wnErA

m(tgnccCIddShdirttca

Gdpptsawamd

tte

mgmwd

biAbg

1tACAmpphcdaohidcguarprhd(mithghwUif

ttme

CLI

NIC

AL–

ALI

MEN

TARY

TRA

CT

April 2010 ONCE–DAILY MESALAMINE FOR UC MAINTENANCE REMISSION 1287

S Inc, Wayne, PA) (4 times daily dosing),10 and balsala-ide (3 times daily dosing).11,12 Although the mechanismf action of mesalamine is not understood fully, it ap-ears to be topical rather than systemic. If mesalamine isiven without any modifications to its release it is ab-orbed rapidly from the proximal gastrointestinal tract,13

hus with little potential therapeutic benefit. Sulfasala-ine, olsalazine, and balsalazide are pro-drugs that releaseesalamine in the right colon after rapid cleavage of the

zo-bond by colonic bacteria.1 The first generation of oralesalamine formulations included the following: Asacol

Eudragit S-coated tablets, which dissolve at pH � 7),hich releases mesalamine in the terminal ileum and

ight colon (delayed-release mesalamine)14; and Pentasaethylcellulose-coated microgranules of mesalamine),hich releases mesalamine throughout the gastrointesti-al tract (prolonged or controlled-release mesalamine).15

ventually divided dosing of these agents was incorpo-ated into clinical practice based on Food and Drugdministration–approved labeling of these agents.In 2006 D’Haens et al16 reported the use of an oralesalamine formulation with the trade name Lialda

United States) and Mezavant or Mezavant XL (outsidehe United States), which is characterized by both aastro-resistant coating (which breaks down at pH � 7,ormally in the terminal ileum) and a tablet core thatontains mesalamine with hydrophilic and lipophilic ex-ipients that is reported to prolong release in the colon.16

linical trials showed that Lialda (Shire Pharmaceuticalsnc, Wayne, PA) (Mezavant) can be administered onceaily.17–19 Another oral mesalamine formulation also waseveloped with the trade name Apriso (Salofalk Granu-tix), which is characterized by mesalamine granules thatave both a gastric acid–resistant enteric coating (whichissolves at pH � 6) that delays release and has a retard-

ng polymer matrix in the granule core that extendselease throughout the colon.20 Clinical trials showedhat Apriso can be administered once daily.21–23 Clinicalrials also were performed with Pentasa (ethylcellulose-oated, prolonged, or controlled-release mesalamine),gain showing that it can be administered once daily.24,25

The finding that Lialda (Mezavant), Apriso (Salofalkranu-Stix), and Pentasa could be administered onceaily challenged the conventional understanding of theharmacokinetics of mesalamine, but potentially was ex-lained by the fact that all 3 formulations were designedo reportedly prolong, extend, or sustain release of me-alamine in the colon. The applicability of these data todelayed-release mesalamine formulation such as Asacolas uncertain. However, several pharmacokinetic studiesnd 2 pilot clinical trials raised the possibility that Asacolay be similarly effective when administered once

aily.26 –29

Here we present the results of the QD Dosing Inves-igation for Efficacy in UC Maintenance (QDIEM)rial, a 12-month noninferiority study to determine the

fficacy and assess the safety of Asacol 1.6 –2.4 g ad- o

inistered once daily compared with Asacol 1.6 –2.4/day administered as a divided twice-daily dose foraintenance of clinical remission in patients with UCho generally have experienced a mild-to-moderateisease course.

Materials and MethodsPatientsThis multicenter, randomized, investigator-

linded, active-control trial enrolled patients at 193 sitesn the United States, Puerto Rico, and Canada betweenugust 2007 and July 2009. The institutional reviewoard at each site approved the protocol, and all patientsave written informed consent.

The criteria for eligibility were male or female patients8 years of age or older with a diagnosis of UC main-ained in clinical remission for at least 3 months onsacol at a stable dose ranging from 1.6 to 2.4 g/day.linical remission was defined as a Simple Clinical Colitisctivity Index (SCCAI) score of 2 points or fewer. Patientsust have experienced at least one flare of UC in the

revious 18 months. Patients were excluded from studyarticipation if they had a history of or current renal orepatic disease or a history of co-existing acute orhronic organic or uncontrolled functional or mentalisease. Additional exclusion criteria were a history ofllergy or hypersensitivity to salicylates, aminosalicylates,r any component of the Asacol tablet; a history ofuman immunodeficiency virus infection or acquired

mmune deficiency syndrome; or a history of alcohol orrug abuse. Patients also were excluded if they had re-eived an oral mesalamine-containing product at a dosereater than 2.4 g/day within the past 3 months, hadsed rectal mesalamine therapy within 14 days, had takenny corticosteroid (oral, intravenous, intramuscular, orectal) within the past 90 days, had taken immunosup-ressive drugs (including azathioprine, 6-mercaptopu-ine, methotrexate, cyclosporine) within the past 90 days,ad received any antidiarrheal and/or antispasmodicrugs within the previous 1 month, had received aspirin

except for cardioprotective indications up to a maxi-um dose of 325 mg/day) or other nonsteroidal anti-

nflammatory drugs within the past week, had used an-ibiotics (other than topical antibiotics) within 1 month,ad received infliximab, adalimumab, certolizumab pe-ol, or other biologic treatment within the past 90 days,ad participated in any drug or device clinical studyithin the past 30 days, or had traveled outside thenited States and Canada within 2 weeks of the screen-

ng visit. Pregnant and/or lactating women were excludedrom study participation.

After randomization, patients were prohibited fromaking aspirin (for any indication other than cardiopro-ection, for which the maximum allowed dose was 325

g/day) or other nonsteroidal anti-inflammatory drugsxcept for occasional use, other medications containing

r metabolized to mesalamine (eg, sulfasalazine, olsala-

zattmiw

tmdgfasdwm

(wcbnbgbivbsw

aRayrt2ahPdPie

ia

rusmptwbpatfdmidyctdrmai

wtcwlfiaotl

metsidtpee

aawstei

CLIN

ICA

L–A

LIMEN

TARY

TRA

CT

1288 SANDBORN ET AL GASTROENTEROLOGY Vol. 138, No. 4

ine, balsalazide), corticosteroids, immunomodulatorygents, metronidazole, antibiotics (other than topical an-ibiotics) for more than 10 days throughout the study,opical rectal therapies, antidiarrheal and/or antispas-

odic medications (except for occasional use), or anynvestigational or marketed drug that might interfereith the evaluation of the study medication.

Study DesignEligible patients were randomized (in a 1:1 ratio)

o receive either a once-daily or twice-daily dosing regi-en of Asacol (400-mg tablet) at the same total daily

ose that the patients were receiving at baseline (1.6/day up to 2.4 g/day). The randomization was per-ormed centrally via an interactive voice response system,nd treatment allocation was stratified by prior me-alamine dose within a site. An investigator-blinded trialesign was used. The patients, who were not blinded,ere instructed not to share their dosing regimen treat-ent assignment with the investigator.

Patient Schedule and Efficacy/SafetyEvaluationsPatients were assessed at screening and months 0

baseline), 3, 6, 9 (via telephone), and 12. The SCCAI scoreas used for the assessment of disease severity and effi-

acy.30 The components of the SCCAI include the following:owel frequency (during the day), bowel frequency (atight), urgency of defecation, blood in stool, general welleing, and extracolonic features (arthritis, pyoderma gan-renosum, erythema nodosum, uveitis) (Supplementary Ta-le 1).30 These clinical assessments were completed by the

nvestigator at screening and at months 0, 3, 6, and 12/exitisit and were based on the patient’s recall over the 24 hoursefore the assessment. Relapse was defined as any SCCAIcore of 5 points or higher. Patients who had not relapsedere considered to be in remission.In addition, at months 6 and 12 patients completed via

n interactive voice response system the Patient-Definedemission Index consisting of one question (“Is your ulcer-tive colitis in remission?”) to which the patient answeredes or no.31 Patient adherence with a once- or twice-dailyegimen was assessed by patient completion of the Medica-ion Adherence Report Scale (MARS) (Supplementary Table)32 via interactive voice response system at months 0, 3, 6,nd 12/exit. The maximum MARS score is 45 points, andigher scores indicate higher levels of reported adherence.atient satisfaction and preference with a once- or twice-aily regimen were assessed by a Patient Satisfaction andreference Questionnaire (Supplementary Table 3) via an

nteractive voice response system at months 0, 6, and 12/xit.

At each visit, serious adverse events (SAEs) and concom-tant medications were recorded. Serum creatinine level was

ssessed at the screening and months 6 and 12/exit visits. t

Statistical AnalysisThe primary end point was maintenance of clinical

emission at month 6 in the primary efficacy analysis pop-lation (the intention-to-treat population for whom diseasetatus [remission or response] at month 6 could be deter-

ined and was available for analysis). The intention-to-treatopulation included all patients who were randomized andook one or more doses of study medication. For patientshose primary efficacy end point could not be calculatedecause of no or insufficient data the primary efficacy endoint was missing and excluded from the primary efficacynalysis. Three sensitivity analyses were performed to assesshe robustness of the primary efficacy result: (1) a set-to-ailure analysis in which outcome was set to relapse ifisease status [remission or relapse] could not be deter-ined; (2) a per-protocol analysis including patients in the

ntention-to-treat population who had no major protocoleviations; and (3) a last observation carried forward anal-sis in which the last posttreatment efficacy evaluation wasarried forward to month 6. Secondary end points includedhe following: the time to relapse measured from the firstosing date to diagnosis of relapse; maintenance of clinicalemission at months 3 and 12; patient-defined remission at

onths 6 and 12; MARS assessment at months 3, 6, and 12;nd patient satisfaction and preference with treatment reg-men at months 6 and 12.

The primary efficacy analysis was designed to assesshether the once-daily dosing regimen was noninferior

o the twice-daily dosing regimen for maintenance oflinical remission at month 6. The noninferiority marginas set at 10% with a 1-sided hypothesis test, with an �

evel of .025 indicating significance. A 2-sided 95% con-dence interval for the difference between the twice-dailynd the once-daily groups was computed. Noninferiorityf the once-daily dosing regimen would be established ifhe upper boundary of the 95% confidence interval wasess than 10%.

It was assumed that the true rate of clinical remission atonth 6 would be 70% and that there would be no differ-

nce in clinical remission rates between the once-daily andwice-daily dosing regimens. The noninferiority margin waset at 10%. Based on these assumptions, to establish non-nferiority for clinical remission at a 2-sided upper confi-ence interval of 95% with 90% power, 442 patients perreatment group were required to be analyzable for therimary end point. Assuming that approximately 10% ofnrolled patients would not be analyzable, we planned tonroll 500 patients per group, for a total of 1000 patients.

Total MARS scores at each visit were analyzed bynalysis of variance to examine the regimen effect afterdjusting for prior dose. Patient satisfaction at each visitas analyzed using the Cochran–Mantel–Haenszel chi-

quare test with prior dose as a stratum variable to assesshe dosing regimen difference. To assess patient prefer-nce at each visit a binomial proportion, exact confidencenterval, and exact P value were computed separately for

he regimens.

etugshhaqefnCd

ct

mtFtwgad

Fd

CLI

NIC

AL–

ALI

MEN

TARY

TRA

CT

April 2010 ONCE–DAILY MESALAMINE FOR UC MAINTENANCE REMISSION 1289

Subgroup analyses were conducted for the primarynd point of clinical remission to evaluate the consis-ency of treatment effects across various patient pop-lations. Predefined subgroup analyses included demo-raphic parameters (age, sex, race, weight, smokingtatus), prior maintenance regimen, prior dose, diseaseistory (anatomic extent of disease, length of diseaseistory, prior UC medication use, relapse frequency),nd baseline disease activity measures (bowel fre-uency [day], bowel frequency [night], urgency of def-cation, blood in stool, general well being, extracoloniceatures [arthritis, pyoderma gangrenosum, erythemaodosum, uveitis]). For all subgroup analyses theochran–Mantel–Haenszel chi-square test was used toetermine the overall treatment effect, and the 95%

igure 1. Patient disposition. A total of 1023 patients were randomiz

elayed-release mesalamine 1.6–2.4 g/day.

onfidence intervals for the treatment difference be-ween the treatment groups also were computed.

ResultsCharacteristics and Disposition of PatientsA total of 1027 patients were randomized to a treat-

ent regimen and 1023 were dosed (512 once daily and 511wice daily). A summary of patient disposition is provided inigure 1. The baseline characteristics were similar in the 2reatment groups (Table 1). At baseline, 28% of patientsere receiving 1.6 g/day, 2% of patients were receiving 2.0/day, and 70% of patients were receiving 2.4 g/day. Inddition, at baseline, 4% of patients were receiving a once-aily dosing regimen, 62% were receiving a twice-daily dos-

either a once-daily or twice-daily treatment regimen and dosed with

ed to

irmgptp5othbpmt

Ad9fi4cmi1nniddTarrw

T

M

S

R

S

D

P

P

L

R

P

D

T

B

B

1–3 25 (4.9%) 27 (5.3%)

T

B

B

B

B

CLIN

ICA

L–A

LIMEN

TARY

TRA

CT

1290 SANDBORN ET AL GASTROENTEROLOGY Vol. 138, No. 4

ng regimen, 33% were receiving a 3 times daily dosingegimen, and 1.0% were receiving an “other” dosing regi-

en. Baseline disease activity was similar in the 2 treatmentroups with the exception of the extracolonic features com-onent (note that all extracolonic features were arthritis);here were more cases in the once-daily regimen (15%) com-ared with the twice-daily regimen (10%) (P � .006). Almost0% of patients had baseline relapse frequency of less thannce per year, 22% of patients previously had received cor-icosteroid therapy, and less than 3% of patients previouslyad received immunosuppressive or biologic therapy. Theseaseline clinical characteristics are consistent with a patientopulation that generally could be described as havingild-to-moderate UC that was in clinical remission at the

ime of enrollment into the study.

EfficacyThe primary objective of noninferiority was met.

t month 6, 90.5% (428 of 473) of patients dosed onceaily had maintained clinical remission compared with1.8% (435 of 474) of those dosed twice daily (95% con-dence interval [CI] for twice daily - once daily, -2.3 to.9) (Figure 2A). The results of the sensitivity analysesonfirmed these results with point estimates for the treat-ent difference between twice daily and once daily, rang-

ng from 1.1 to 1.5, which was very consistent with the.3-point estimate observed in the primary analysis (dataot shown). Similar to the results at month 6, there wereo significant differences between the 2 dosing regimens

n the rates of clinical remission at months 3 (treatmentifference 0.8 with 95% CI, -1.8 to 3.5) and 12 (treatmentifference 0.0 with 95% CI, -4.6 to 4.7) (Figure 2A).ime-to-relapse also was similar between the once-dailynd twice-daily dosing regimens at month 6 (hazardatio, 1.17; 95% CI, 0.76, 1.80) and month 12 (hazardatio, 1.01; 95% CI, 0.71, 1.42) (Figure 2B and C). There

able 1. Continued

ParameterQD (N � 512),

nBID (N � 511),

n

aseline urgency of defecationNone 387 (75.7%) 367 (72.0%)Hurry 120 (23.5%) 141 (27.6%)Immediately 4 (0.8%) 2 (0.4%)

aseline blood in stoolNone 454 (88.8%) 470 (92.2%)Trace 52 (10.2%) 35 (6.9%)Occasionally frank 5 (1.0%) 5 (1.0%)

aseline general well beingVery well 449 (87.9%) 451 (88.4%)Slightly below par 62 (12.1%) 59 (11.6%)

aseline extracolonic features(arthritis, pyodermagangrenosum, erythemanodosum, uveitis)

0 433 (84.7%) 461 (90.4%)1 78 (15.3%) 49 (9.6%)

able 1. Baseline Characteristics of Patients with UC inRemission

ParameterQD (N � 512),

nBID (N � 511),

n

ean age, y (standard deviation) 50.4 (14.6) 50.2 (14.8)�65 409 (79.9%) 414 (81.0%)�65 103 (20.1%) 97 (19.0%)

exMale 251 (49.0%) 243 (47.6%)Female 261 (51.0%) 268 (52.4%)

aceCaucasian 462 (90.2%) 447 (87.5%)Black 31 (6.1%) 43 (8.4%)Other 19 (3.7%) 21 (4.1%)

moking historyCurrent smoker 48 (9.4%) 66 (12.9%)Current nonsmoker 464 (90.6%) 445 (87.1%)

isease extent at diagnosisProctosigmoiditis 108 (23.1%) 98 (20.7%)Left-sided colitis 158 (33.8%) 186 (39.2%)Pancolitis 202 (43.2%) 190 (40.1%)

rior maintenance dose1.6 g/day 145 (28.3%) 145 (28.4%)2.0 g/day 15 (2.9%) 5 (1.0%)2.4 g/day 352 (68.8%) 361 (70.6%)

rior maintenance regimenBID 331 (64.6%) 304 (59.5%)TID 158 (30.9%) 184 (36.0%)QD 20 (3.9%) 17 (3.3%)Other 3 (0.6%) 6 (1.2%)

ength of disease history, y�1 66 (12.9%) 61 (11.9%)1–5 161 (31.5%) 150 (29.4%)�5–10 104 (20.4%) 135 (26.4%)�10 180 (35.2%) 165 (32.3%)

elapse frequencyMore than once a month 5 (1.0%) 1 (0.2%)Once every 6 months 70 (13.7%) 84 (16.4%)Once every 6–12 months 140 (27.4%) 149 (29.2%)Less than once a year 245 (47.9%) 233 (45.6%)Newly diagnosed 51 (10.0%) 44 (8.6%)

rior treatmentSteroids (oral or intravenous) 117 (22.9%) 109 (21.5%)Immunomodulators 12 (2.4%) 8 (1.6%)Biologics 3 (0.6%) 0 (0.0%)Sulfasalazine 27 (5.3%) 18 (3.5%)Rectal therapies 41 (8.0%) 44 (8.6%)

uration in days from onset ofmost recent flare to firstdose

Mean (standard deviation) 252 (128.5) 242 (127.0)Median 215 201Minimum/maximum 16/550 2/548

otal SCCAI scores at baseline0 245 (47.9%) 244 (47.8%)1 148 (29.0%) 178 (34.9%)2 116 (22.7%) 88 (17.3%)3 1 (0.2%) 0 (0.0%)4 1 (0.2%) 0 (0.0%)

aseline bowel frequency duringthe day

1–3 479 (93.7%) 481 (94.3%)4–6 32 (6.3%) 29 (5.7%)

aseline bowel frequency at night0 486 (95.1%) 483 (94.7%)

ere no significant differences in Patient-Defined Remis-

s8dt8dt

ewMte

(htmidp(mopoP

aoSfsa

s

FTr6w(At

Ftd(

T

M

M

CLI

NIC

AL–

ALI

MEN

TARY

TRA

CT

April 2010 ONCE–DAILY MESALAMINE FOR UC MAINTENANCE REMISSION 1291

ion between the 2 dosing regimens at month 6 with3.1% (343 of 413) and 86.6% (356 of 411) of patientsosed once daily and twice daily, respectively (95% CI forwice daily - once daily, -1.3 to 8.5) or at month 12 with3.4% (286 of 343) and 85.4% (280 of 328) of patientsosed once daily and twice daily, respectively (95% CI forwice daily - once daily, -3.5 to 7.5).

Based on the MARS questionnaire, medication adher-nce was high in both treatment groups (Figure 3). Thereere minor, but statistically significant, differences inARS questionnaire scores between the once-daily and

wice-daily dosing regimens at month 3 (P � .04); differ-

igure 2. (A) Maintenance of clinical remission at months 3, 6, and 12.he once-daily dosing regimen was noninferior to the twice-daily dosingegimen for the end point of maintaining clinical remission at months 3,, and 12. (B) Time to relapse (month 6). At month 6 the time to relapseas similar between the once-daily and twice-daily dosing regimens

hazard ratio, 1.17; 95% CI, 0.76, 1.80). (C) Time to relapse (month 12).t month 12 the time to relapse was similar between the once-daily and

wice-daily dosing regimens (hazard ratio, 1.01; 95% CI, 0.71, 1.42).

nces were not statistically significant at months 6 or 12

P � .18 and P � .12) (Figure 3). Patients who relapsedad similar MARS questionnaire scores as compared withhose who did not relapse (Supplementary Table 4). At

onth 6, there was no statistically significant differencen patient satisfaction between the once-daily and twice-aily dosing regimens (P � .08); however, at month 12atients were more satisfied with the once-daily regimen

P � .01) (Table 2). Overall, patients preferred takingedication fewer times a day with twice daily preferred

ver 3 times daily (P � .0001 and P � .0001), once dailyreferred over twice daily (P � .0001 and P � .0001), andnce daily preferred over 3 times daily (P � .0001 and� .0001) at months 6 and 12, respectively.Treatment outcomes at month 6 (primary end point)

nd month 12 were consistent among subgroups withnly one subgroup (baseline trace blood in stool onCCAI, P � .02 at month 6 and P � .04 at month 12 inavor of the twice-daily regimen) showing a statisticallyignificant difference between regimens (Figure 4A–C,nd Supplementary Table 5).

SafetyThe incidence of withdrawals as a result of AEs was

lightly higher in the twice-daily group whereas the inci-

igure 3. MARS (months 3, 6, and 12) medication adherence be-ween the once-daily and twice-daily dosing regimens was significantlyifferent at month 3 (P � .04) but not at month 6 (P � .18) or month 12

P � .12).

able 2. Patient Satisfaction by Visit

Visit outcomeQD (N � 512)

n (%)BID (N � 511)

n (%) P value

onth 6Extremely satisfied 227 (55.0%) 185 (45.0%)Very satisfied 133 (32.2%) 174 (42.3%)Somewhat satisfied 36 (8.7%) 31 (7.5%)Somewhat dissatisfied 9 (2.2%) 13 (3.2%)Not satisfied at all 8 (1.9%) 8 (1.9%)Total 413 411 .0791onth 12Extremely satisfied 200 (58.3%) 149 (45.4%)Very satisfied 94 (27.4%) 125 (38.1%)Somewhat satisfied 35 (10.2%) 35 (10.7%)Somewhat dissatisfied 7 (2.0%) 9 (2.7%)Not satisfied at all 7 (2.0%) 10 (3.0%)

Total 343 328 .0117

d(boasgmo

dogacpod

Fo

CLIN

ICA

L–A

LIMEN

TARY

TRA

CT

1292 SANDBORN ET AL GASTROENTEROLOGY Vol. 138, No. 4

ence of SAEs was slightly higher in the once-daily groupTables 3 and 4). All SAEs were judged by the investigator toe doubtfully related to the study drug with the exceptionf one patient in the twice-daily group who experiencedcute renal failure. Nine patients were withdrawn from thetudy because of AEs (2 patients [0.4%] in the once-dailyroup and 7 patients [1.4%] in the twice-daily group). Theost common AEs reported as reason for withdrawal were

igure 4. Treatment outcome by subgroups at month 12. The maintennce-daily and twice-daily dosing regimens.

f gastrointestinal nature (3 patients [0.6%] in the twice- c

aily group). There were 18 patients (3.5%) with SAEs in thence-daily group and 9 patients (1.8%) in the twice-dailyroup. The only SAEs reported by more than 1 patient werecute renal failure (2 patients in the twice-daily group),holelithiasis (2 patients in the once-daily group), and ap-endicitis (2 patients in the once-daily group). One deathccurred in the study (myocardial infarction judged to beoubtfully drug related). Overall, there were no significant

of clinical remission rate was consistent among most subgroups for the

ance

hanges in serum creatinine level in either treatment group.

asmtsdSdawDft

fsBpilcrmclepmodqmLobmd

obsi

zstmaneottt

T

OFACNOPRFM

Mpcg

T

O

Mpc

CLI

NIC

AL–

ALI

MEN

TARY

TRA

CT

April 2010 ONCE–DAILY MESALAMINE FOR UC MAINTENANCE REMISSION 1293

DiscussionIn this study, delayed-release mesalamine (Asacol)

dministered once daily at doses of 1.6 –2.4 g/day washown to be as effective as twice-daily dosing for the

aintenance of clinical remission in patients with a his-ory of mild-to-moderate UC. Specifically, the trialhowed that once-daily dosing is noninferior to twice-aily dosing for the end point of clinical remission.ubgroup analyses showed consistent efficacy for once-aily dosing in a wide range of subgroups. The resultslso were consistent whether maintenance of remissionas measured by either the SCCAI or by the Patient-efined Remission Index. There were no significant dif-

erences in withdrawals owing to AEs or SAEs betweenhe 2 dosing regimens.

Previous studies with Lialda (Mezavant), Apriso (Salo-alk Granu-Stix), and Pentasa have shown that me-alamine can be administered once daily.17–19,21–23,25

ecause these 3 mesalamine formulations reportedlyrolong, extend, or sustain release throughout the colon,

t was speculated that successful once-daily dosing wasinked to the characteristics of the delivery systems. Inontrast to these 3 formulations, Asacol is a delayed-elease formulation that releases mesalamine in the ter-

inal ileum and right colon; however, clinical trialslearly have shown that it is effective in patients regard-ess of anatomic extent of UC (proctitis, left-sided dis-ase, and pancolitis). The results of our study (a large,rospective, controlled UC study) show that Asacol ad-inistered once daily was effective for the maintenance

f clinical remission of UC, thus indicating that preciseelivery of mesalamine throughout the colon is not re-uired for successful once-daily dosing. A previous phar-acokinetic study in healthy volunteers showed that

ialda administered once daily and Asacol administerednce daily had similar pharmacokinetic profiles and thatoth drugs administered once daily had a different phar-acokinetic profile from Asacol administered 3 times a

able 3. Adverse Events Leading to Withdrawal

MedDRA preferredterm

QD (N � 512)n (%)

BID (N � 511)n (%)

verall 2 (0.4) 7 (1.4)latulence 0 (0.0) 2 (0.4)bdominal distension 0 (0.0) 1 (0.2)ardiomyopathy 0 (0.0) 1 (0.2)ausea 0 (0.0) 1 (0.2)esophageal carcinoma 0 (0.0) 1 (0.2)lantar fasciitis 0 (0.0) 1 (0.2)enal failure 0 (0.0) 1 (0.2)atigue 1 (0.2) 0 (0.0)yocardial infarction 1 (0.2) 0 (0.0)

edDRA, Medical Dictionary for Regulatory Activities; N, number ofatients within specified treatment; n, number of patients withinategory and treatment group; %, percentage of patients within cate-ory and treatment group: (n/N)*100.

ay.27 The totality of these data suggests that the success g

f once-daily dosing for all of these compounds maye owing to the pharmacodynamic properties of me-alamine and may not depend on the specific character-stics of the formulation determining drug delivery.

Previous maintenance of remission trials with olsala-ine, Asacol, and Pentasa recruited patients with endo-copic remission, and the primary end point was main-enance of endoscopic remission.5,6,9,33 More recent

aintenance trials with Lialda and Apriso used diseasectivity indexes that included an endoscopic compo-ent.19,22,23 In contrast, the instruments used to assessfficacy in the QDIEM trial did not include endosc-py.30,31 Higgins et al34 have shown that the SCCAI andhe Patient-Defined Remission Index have good correla-ion with the UC Disease Activity Index, suggesting thathese clinical instruments are clinically meaningful and

able 4. Serious Adverse Events

MedDRA preferred termQD (N � 512)

n (%)BID (N � 511)

n (%)

verall 18 (3.5) 9 (1.8)Renal failure acute 0 (0.0) 2 (0.4)Abdominal pain 0 (0.0) 1 (0.2)Ascites 0 (0.0) 1 (0.2)Breast cancer 0 (0.0) 1 (0.2)Cardiomyopathy 0 (0.0) 1 (0.2)Constipation 0 (0.0) 1 (0.2)Coronary artery disease 0 (0.0) 1 (0.2)Deep vein thrombosis 0 (0.0) 1 (0.2)Dehydration 0 (0.0) 1 (0.2)Oesophageal carcinoma 0 (0.0) 1 (0.2)Pulmonary embolism 0 (0.0) 1 (0.2)Rectal haemorrhage 0 (0.0) 1 (0.2)Small cell lung cancer metastatic 0 (0.0) 1 (0.2)Altered state of consciousness 1 (0.2) 0 (0.0)Appendicitis 2 (0.4) 0 (0.0)Anal fistula 1 (0.2) 0 (0.0)Atrial fibrillation 1 (0.2) 0 (0.0)Cardiac failure congestive 1 (0.2) 0 (0.0)Chest pain 1 (0.2) 0 (0.0)Cholangitis 1 (0.2) 0 (0.0)Cholelithiasis 2 (0.4) 0 (0.0)Clavicle fracture 1 (0.2) 0 (0.0)Convulsion 1 (0.2) 0 (0.0)Diverticulitis 1 (0.2) 0 (0.0)Haemothorax 1 (0.2) 0 (0.0)Hypertension 1 (0.2) 0 (0.0)Hyponatremia 1 (0.2) 0 (0.0)Jaundice cholestatic 1 (0.2) 0 (0.0)Myocardial infarction 1 (0.2) 0 (0.0)Renal cancer 1 (0.2) 0 (0.0)Rib fracture 1 (0.2) 0 (0.0)Spinal compression fracture 1 (0.2) 0 (0.0)Thrombophlebitis 1 (0.2) 0 (0.0)Thyroid neoplasm 1 (0.2) 0 (0.0)Transient ischemic attack 1 (0.2) 0 (0.0)Uterine leiomyoma 1 (0.2) 0 (0.0)

edDRA, Medical Dictionary for Regulatory Activities; N, number ofatients within specified treatment; n, number of patients withinategory and treatment group; %, percentage of patients within cate-

ory and treatment group: (n/N)*100.

csra

isbdttMIwmprwtiiatua

cwtfptpcm2

d3psbteb(ppstao

(er

aG1

1

1

1

1

1

1

1

1

CLIN

ICA

L–A

LIMEN

TARY

TRA

CT

1294 SANDBORN ET AL GASTROENTEROLOGY Vol. 138, No. 4

an be used as a basis for clinical practice. Another recenttudy reported that the SCCAI is a valid, reliable, andesponsive noninvasive index to assess disease activity indult patients with UC.35

Nonadherence to medication is associated with anncreased risk of relapse in patients with UC.36 Our studyhowed significant differences in adherence as measuredy the MARS questionnaire in favor of the once-dailyosing group at 3 months but not at 6 or 12 months,hus reinforcing the complicated and multifactorial na-ure of adherence. Patients who relapsed had similar

ARS questionnaire scores as those who did not relapse.t should be noted, however, that the adherence ratesere very high (MARS questionnaire scores of approxi-ately 42 points out of a possible 45 points at all time

oints) in both dosing groups. Similar findings wereeported with other mesalamine products.19 However,hen patients in our study were asked their preference,

hey preferred dosing regimens that required taking med-cation fewer times per day. There are data to show thatt is at 3 months when patients diverge, and either remaindherent or stop their maintenance medications.37 Ithus would be important in a real-world setting to followp with patients at this time period to ensure continueddherence.

The patient population recruited in this trial generallyould be described as having mild-to-moderate UC thatas in clinical remission at the time of enrollment into

he study. Almost 50% of patients had a baseline relapserequency of less than once per year, 22% of patientsreviously had received corticosteroid therapy, and lesshan 3% of patients previously had received immunosup-ressive or biologic therapy. The results of this studyannot necessarily be generalized to patients receivingaintenance therapy with mesalamine doses greater than

.4 g/day or to those with more severe UC.Both dosing regimens of Asacol had low rates of with-

rawals as a result of AEs and SAEs. SAEs occurred in.5% of patients in the once-daily group and 1.8% ofatients in the twice-daily group (difference was notignificant). All SAEs were judged by the investigators toe doubtfully related to the study drug with the excep-ion of 1 patient in the twice-daily dosing group whoxperienced acute renal failure. The only SAEs reportedy more than 1 patient were as follows: acute renal failure2 patients in the twice-daily group), cholelithiasis (2atients in the once-daily group), and appendicitis (2atients in the once-daily group). There were no clinicallyignificant changes in serum creatinine level in eitherreatment group or between the treatment groups. Over-ll, these findings show a similar safety profile in thence-daily and twice-daily treatment groups.

Once-daily dosing of delayed-release mesalamineAsacol) at doses of 1.6 –2.4 g/day was shown to be asffective as twice-daily dosing for maintenance of clinical

emission in patients with UC.

Supplementary Material

Note: To access the supplementary materialccompanying this article, visit the online version ofastroenterology at www.gastrojournal.org, and at doi:0.1053/j.gastro.2009.12.054.

References

1. Sandborn WJ, Hanauer SB. Systematic review: the pharmacoki-netic profiles of oral mesalazine formulations and mesalazinepro-drugs used in the management of ulcerative colitis. AlimentPharmacol Ther 2003;17:29–42.

2. Sandborn WJ. Oral 5-ASA therapy in ulcerative colitis: what arethe implications of the new formulations? J Clin Gastroenterol2008;42:338–344.

3. Svartz N. Salazopyrin, a new sulfanilamide preparation. Acta MedScand 1942;110:577–598.

4. Das KM, Eastwood MA, McManus JP, et al. Adverse reactionsduring salicylazosulfapyridine therapy and the relation with drugmetabolism and acetylator phenotype. N Engl J Med 1973;289:491–495.

5. Sandberg-Gertzen H, Jarnerot G, Kraaz W. Azodisal sodium in thetreatment of ulcerative colitis. A study of tolerance and relapse-prevention properties. Gastroenterology 1986;90:1024–1030.

6. Ireland A, Mason CH, Jewell DP. Controlled trial comparing olsala-zine and sulphasalazine for the maintenance treatment of ulcer-ative colitis. Gut 1988;29:835–837.

7. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosal-icylic acid therapy for mildly to moderately active ulcerative colitis.A randomized study. N Engl J Med 1987;317:1625–1629.

8. Sninsky CA, Cort DH, Shanahan F, et al. Oral mesalamine(Asacol) for mildly to moderately active ulcerative colitis. A mul-ticenter study. Ann Intern Med 1991;115:350–355.

9. The Mesalamine Study Group. An oral preparation of mesalamineas long-term maintenance therapy for ulcerative colitis. A random-ized, placebo-controlled trial. Ann Intern Med 1996;124:204–211.

0. Hanauer S, Schwartz J, Robinson M, et al. Mesalamine capsulesfor treatment of active ulcerative colitis: results of a controlledtrial. Pentasa Study Group. Am J Gastroenterol 1993;88:1188–1197.

1. Green JR, Lobo AJ, Holdsworth CD, et al. Balsalazide is moreeffective and better tolerated than mesalamine in the treatmentof acute ulcerative colitis. The Abacus Investigator Group. Gas-troenterology 1998;114:15–22.

2. Levine DS, Riff DS, Pruitt R, et al. A randomized, double-blind,dose-response comparison of balsalazide (6.75 g), balsalazide(2.25 g), and mesalamine (2.4 g) in the treatment of active,mild-to-moderate ulcerative colitis. Am J Gastroenterol 2002;97:1398–1407.

3. Myers B, Evans DN, Rhodes J, et al. Metabolism and urinaryexcretion of 5-amino salicylic acid in healthy volunteers whengiven intravenously or released for absorption at different sites inthe gastrointestinal tract. Gut 1987;28:196–200.

4. Dew MJ, Hughes PJ, Lee MG, et al. An oral preparation to releasedrugs in the human colon. Br J Clin Pharmacol 1982;14:405–408.

5. Rasmussen SN, Bondesen S, Hvidberg EF, et al. 5-aminosalicylicacid in a slow-release preparation: bioavailability, plasma level, andexcretion in humans. Gastroenterology 1982;83:1062–1070.

6. D’Haens G, Hommes D, Engels L, et al. Once daily MMX mesala-zine for the treatment of mild-to-moderate ulcerative colitis: aphase II, dose-ranging study. Aliment Pharmacol Ther 2006;24:1087–1097.

7. Kamm MA, Sandborn WJ, Gassull M, et al. Once-daily high con-centration MMX mesalamine in active ulcerative colitis. Gastro-

enterology 2007;132:66–75.

1

1

2

2

2

2

2

2

2

2

2

2

3

3

3

3

3

3

3

3

R

IH5

A

UaNA((PINBBBHVBC((FMC(K(RFG(((IDFGSHJGEHKHH(C(CTK((H(C(((O

CLI

NIC

AL–

ALI

MEN

TARY

TRA

CT

April 2010 ONCE–DAILY MESALAMINE FOR UC MAINTENANCE REMISSION 1295

8. Lichtenstein GR, Kamm MA, Boddu P, et al. Effect of once- ortwice-daily MMX mesalamine (SPD476) for the induction of re-mission of mild to moderately active ulcerative colitis. Clin Gas-troenterol Hepatol 2007;5:95–102.

9. Kamm MA, Lichtenstein GR, Sandborn WJ, et al. Randomized trialof once- or twice-daily MMX™ mesalazine for maintenance ofremission in ulcerative colitis. Gut 2008;57:893–902.

0. Brunner M, Greinwald R, Kletter K, et al. Gastrointestinal transitand release of 5-aminosalicylic acid from 153Sm-labelled me-salazine pellets vs. tablets in male healthy volunteers. AlimentPharmacol Ther 2003;17:1163–1169.

1. Kruis W, Kiudelis G, Racz I, et al. Once daily versus three timesdaily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial. Gut 2009;58:233–240.

2. Kruis W, Jonaitis L, Pokrotnieks J, et al. Once daily 3 g mesalamineis the optimal dose for maintaining clinical remission in ulcerativecolitis: a double-blind, double-dummy, randomized, controlled, dose-ranging study. Gastroenterology 2008;134(Suppl 1):A489.

3. Prescribing information for Apriso (extended release mesala-mine). Morrisville, NC: Salix Pharmaceuticals, Inc; 2009.

4. Gandia P, Idier I, Houin G. Is once-daily mesalazine equivalent tothe currently used twice-daily regimen? A study performed in 30healthy volunteers. J Clin Pharmacol 2007;47:334–342.

5. Dignass AU, Bokemeyer B, Adamek H, et al. Mesalamine oncedaily is more effective than twice daily in patients with quies-cent ulcerative colitis. Clin Gastroenterol Hepatol 2009;7:762–769.

6. Hussain FN, Ajjan RA, Kapur K, et al. Once versus divided dailydosing with delayed-release mesalazine: a study of tissue drugconcentrations and standard pharmacokinetic parameters. Ali-ment Pharmacol Ther 2001;15:53–62.

7. Sandborn WJ, Balan G, Kuzmak B, et al. Comparable pharmaco-kinetics (PK) of two delayed release formulations of oral me-salamine. Am J Gastroenterol 2007;102:S465.

8. Kane S, Huo D, Magnanti K. A pilot feasibility study of once dailydosing versus conventional dosing mesalamine for maintenance ofulcerative colitis. Clin Gastroenterol Hepatol 2003;1:170–173.

9. Kane S, Holderman W, Jacques P, et al. Once daily versusconventional dosing of pH-dependent mesalamine long-term tomaintain quiescent ulcerative colitis: preliminary results from arandomized trial. Patient Prefer Adherence 2008;2:253–258.

0. Walmsley RS, Ayres RC, Pounder RE, et al. A simple clinicalcolitis activity index. Gut 1998;43:29–32.

1. Higgins PDR, Schwartz M, Mapili J, et al. Patient defined dichot-omous end points for remission and clinical improvement inulcerative colitis. Gut 2005;54:782–788.

2. Horne R, Weinman J. Self-regulation and self-management inasthma: exploring the role of illness perceptions and treatmentbeliefs in explaining non-adherence to preventer medication. Psy-chol Health 2002;17:17–32.

3. Miner P, Hanauer S, Robinson M, et al. Safety and efficacy ofcontrolled-release mesalamine for maintenance of remission inulcerative colitis. Pentasa UC Maintenance Study Group. Dig DisSci 1995;40:296–304.

4. Higgins PD, Schwartz M, Mapili J, et al. Is endoscopy necessaryfor the measurement of disease activity in ulcerative colitis? Am JGastroenterol 2005;100:355–361.

5. Turner D, Seow CH, Greenberg GR, et al. A systematic prospec-tive comparison of non-invasive disease activity indices in ulcer-ative colitis. Clin Gastroenterol Hepatol 2009;7:1081–1088.

6. Kane S, Huo D, Aikens J, et al. Medication nonadherence and theoutcomes of patients with quiescent ulcerative colitis. Am J Med2003;114:39–43.

7. Kane SV, Accortt NA, Magowan S, et al. Predictors of persistencewith 5-aminosalicylic acid therapy for ulcerative colitis. Aliment

Pharmacol Ther 2009;29:855–862. L

Received October 14, 2009. Accepted December 28, 2009.

eprint requestsAddress requests for reprints to: William J. Sandborn, MD,

nflammatory Bowel Disease Clinic, Division of Gastroenterology andepatology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota5905. e-mail: sandborn.william@mayo.edu; fax: (507) 266-0335.

cknowledgmentsThe authors wish to thank the QD Dosing Investigation for Efficacy in

C Maintenance (QDIEM) Investigators who participated in this study,s listed below in alphabetical order: Charles Adelmann (Norwalk, CT),isar Ahmed (Houston, TX), Naeem Akhtar (Madera, CA), Robertlbares (Dothan, AL), Stephen Amann (Tupelo, MS), Shirish Amin

Indiana, PA), Leonard Baidoo (Pittsburgh, PA), Arthur BaluyutIndianapolis, IN), Leslie Bank (Binghamton, NY), Alpha Banks (Collegeark, MD), Alfonso Barbati (Clairton, PA), Michael Basista (Toledo, OH),

saac Bassan (North Miami Beach, FL), Clint Behrend (Idaho Falls, ID),icholas Bellicini (Pittsburgh, PA), Arthur Berman (Largo, FL), Crystalernstein (Seattle, WA), Magued Beshay (Mission Hills, CA), Jitenderhandari (Bloomington, IN), Sudhir Bhaskar (Orlando, FL), Philipowden (Memphis, TN), Jack Bragg (Columbia, MO), Myron Brand (Newaven, CT), Edward Brettholz (New York, NY), Whitney Brooks (Norfolk,A), Michael Brown (Athen, AL), Paul Brown (Louisville, KY), Mushtaqukhari (Morganton, NC), Charles Calabrese (Uniontown, PA), Josephappa (Hartford, CT), Victor Carlo (San Juan, PR), George CatinisMetairie, LA), Anthony Celifarco (Lake Success, NY), Maurice CerulliBrooklyn, NY), Shekhar Challa (Topeka, KS), Tawfik Chami (Zephyrhills,L), Adam Cheifetz (Boston, MA), Naoki Chiba (Guelph, ON, Canada),ihnea Chiorean (Indianapolis, IN), Allan Coates (Wyoming, MI), Albertohen (Montreal, QC), James Corkum (Reisterstown, MD), Dale CoyLake Barrington, IL), Israel Crespo (Trinity, FL), John Dalena (Cedarnolls, NJ), Chrystian Dallaire (Quebec, QC, Canada), Yvette David

Mission Hills, CA), Carleton Davis (Monroe, WI), Glenn Davis (Littleock, AR), Fadi Deeb (Wichita, KS), Rajiv Dhingra (New Port Richey,L), James Dimitroff (St. Louis, MO), James DiSario (Monterey, CA),erald Dryden (Louisville, KY), Ben Echols (Houston, TX), Craig Ennis

Orange, CA), William Essilfie (Long Beach, CA), William EubanksTampa, FL), Peter Eweje (Jacksonville, NC), Abraham FallahHomewood, IL), Steven Fein (Pasadena, TX), Bernard Feldman (Clive,A), Nelson Ferreira (Hagerstown, MD), Brian First (San Diego, CA),avid Flavin (Somersworth, NH), Ronald Fogel (Chesterfield, MI), Keithriedenberg (Mentor, OH), William Futch (Newbern, NC), Burnettallman (Columbia, SC), Franco Gallo (Port Jefferson Station, NY),ubhas Ganguli (Hamilton, ON, Canada), David Gatof (Lafayette, CO),oward Gogel (Albuquerque, NM), Richard Golding (Hackensack, NJ),effrey Goldstein (Rochester, NY), Michael Goldstein (Great Neck, NY),lenn Gordon (Mexico, MO), Bruce Greenberg (Arlington Heights, IL),ugene Greenberg (Urbana, IL), Suryakanth Gurudu (Scottsdale, AZ),oward Guss (Ocean, NJ), Alexandra Gutierrez (Birmingham, AL),umar Gutta (Fort Worth, TX), Flavio Habal (Toronto, ON, Canada),oward Hamat (Houston, TX), Stephen Hanauer (Chicago, IL), Richardansen (Golden, CO), Robert Hardi (Chevy Chase, MD), Raouf Hilal

Maitland, FL), William Holderman (Tacoma, WA), Ken Holt (Torrance,A), John Hong (Murrieta, CA), CT Hung (Upland, CA), Michael IbachJackson, TN), Ike Ibegbu (Kinston, NC), Gilles Jobin (Montreal, QC,anada), Jerry Jones (Charlotte, NC), Ronald Joseph (Salt Lake City, UT),homas Judge (Camden, NJ), Mirza Kajani (Newnan, GA), Rokayamyar (La Mesa, CA), Carl Kanun (Tucson, AZ), Robert Kaplan

Greensboro, NC), Steven Kaster (Wenatchee, WA), Mustafa KathawalaBismarck, ND), Seymour Katz (Great Neck, NY), Barry Kaufman (Eggarbor Township, NJ), Michael Kestell (Spokane, WA), Noor Khaiser

Peoria, IL), Sardar Khan (Houston, TX), Richard Kim (Sewickley, PA),hung Kim (Pittsford, NY), Joshua Korzenik (Boston, MA), Tarun KothariRochester, NY), Ravindranath Kottoor (Jacksonville, FL), Louis KouoCape Girardeau, MO), George Koval (Portland, OR), Piyush KumarEncinitas, CA), Mark Lamet (Hollywood, FL), Bret Lashner (Cleveland,H), Thomas Lee (Elgin, IL), Leonard Leichus (Tallahassee, FL), Bernard

eman (Clive, IA), Scott Levenson (San Carlos, CA), Michael LeVine

(ST((((((AKMM(TDP(((JRAJBR((OCAFMWRFF((((((S((((DJSBTH(PRLC(W

(S

GP

SMSimefiDddPoWQhd

C

sPaJPrBPPPfScFPPhCEBshPsGPsPaGn

F

CLIN

ICA

L–A

LIMEN

TARY

TRA

CT

1296 SANDBORN ET AL GASTROENTEROLOGY Vol. 138, No. 4

Marietta, GA), Simon Lichtiger (New York, NY), Mark Lijewski (Greer,C), Robert Lindenberg (Torrington, CT), Neil Lobo (Babylon, NY),homas Loludice (Akron, OH), John Lowe (Ogden, UT), Joseph LowneyWarwick, RI), Ramesh Luther (Cheektowaga, NY), William LylesAlexandria, LA), Uma Mahadevan (San Francisco, CA), Pramod MalikChesapeake, VA), Robert Manning (Pueblo, CO), Siva MaranMorristown, TN), Stefano Marcuard (Greenville, NC), James MarionNew York, NY), Michael Mastrangelo (Wilmington, NC), Elizabeth MayDetroit, MI), Paul McRae (St Petersburg, FL), Peter Miller (Birmingham,L), Douglas Miller (Meriden, CT), Perry Milman (Lake Success, NY),enneth Mirkin (Fairfax, VA), Morry Moskovitz (Beaver Falls, PA), Samoskowitz (Brooklyn, NY), Sam Moussa (Tucson, AZ), Sivakumarunnangi (Merced, CA), Tobin Naidorf (Alexandria, VA), Partha Nandi

Troy, MI), Frank Nemec (Las Vegas, NV), Jacque Noel (Lafayette, LA),homas Nowak (Anderson, IN), Frederick Nunes (Philadelphia, PA),avid Oelsner (West Valley City, UT), Terry Ortego (Lowell, AR), Pierreare (Quebec, QC, Canada), Nimisha Parekh (Orange, CA), Mehul Patel

Indianapolis, IN), Devang Patel (South Plainfield, NJ), Pankaj PatelSouth Bend, IN), Ramanbhai Patel (Lancaster, CA), Teressa PatrickDayton, OH), Stephen Pearce (Chico, CA), Allan Peck (Cincinnati, OH),ack Peicher (Fort Lauderdale, FL), Glenn Pfitzner (Mt. Airy, NC),aymond Phillips (Naples, FL), Henryk Pluta (Abbotsford, BC, Canada),rthur Poch (Shreveport, LA), Vijayalakshmi Pratha (San Diego, CA),effrey Pressman (San Diego, CA), Nazir Rahim (Folsom, CA), Bal Rajhandari (Monroe, LA), Charles Randall (San Antonio, TX), Rawelandhawa (Phoenix, AZ), Udipi Rao (Odessa, TX), Prakash U Rau

Braintree, MA), Donald Rauh (Bowling Green, KY), Suresh ReddyWaterloo, IA), Alvaro Reymunde (Ponce, PR), Donato Ricci (Portrange, FL), Dean Rider (San Francisco, CA ), Dennis Riff (Anaheim,A), Elizabeth Rock (Phoenixville, PA), Richard Roman (Englewood, CO),llen Rosenbaum (Berwyn, IL), Andrew Rosenberg (Garden City, NY),red Rosenberg (Highland Park, IL), Soraya Ross (Beverly Hills, CA),ichael Safdi (Cincinnati, OH), Fred Saibil (Toronto, ON, Canada),illiam Sandborn (Rochester, MN), Barry Sanders (Lewisville, TX),aymond Sandler (Aventura, FL), Sheldon Scheinert (St. Petersburg,L), Ronald Schwarz (Raleigh, NC), Richard Sears (Winchester, VA),ayez Seif (Greenville, TX), Ira Shafran (Winter Park, FL), Gaurang ShahJacksonville, FL), Mushtaq Shah (Greenbelt, MD), Umedchandra ShahHollywood, MD), Bradley Shapiro (Hoffman Estates, IL), Tarun SharmaKalamazoo, MI), Aasim Sheikh (Marietta, GA), Roland ShepardTampa, FL), Alex Sherman (New York, NY), Bavikatte ShivakumarDavenport, IA), Vasanth Siddalingaiah (Milwaukee, WI), Ann SilvermanWest Bloomfield, MI), Timothy Simmons (Los Angeles, CA), Rolandoineneng (Dayton, OH), Shayne Skarda (Longview, TX), Duane SmootWashington, DC), Charles Sninsky (Gainesville, FL), Bob SouderJackson, TN), John Stagias (Southbridge, MA), William SteinbergRockville, MD), Michael Steinbook (Columbus, GA), William SternRockville, MD), Mark Stern (Decatur, GA), Scott Stern (Bangor, ME),avid Stockwell (Virginia Beach, VA), Neil Stollman (Oakland, CA),

ames Strohecker (Columbia, SC), Daniel Suiter (Pratt, KS), Thomaswantkowski (Pinehurst, NC), Richmond Sy (Ottawa, ON, Canada),iswarup Syam (Cortland, NY), Mousab Tabbaa (Westlake, OH), Ikeanabe (Boise, ID), Harvey Tatum (Tulsa, OK), Jawahar Taunk (Palmarbor, FL), Abdul Thannoun (Amarillo, TX), James Thornton

Souderton, PA), Douglas Trate (Boone, NC), Michael Ufberg (Allentown,A), Michael Van Ness (Canton, OH), Rajeer Vasudeva (Columbia, SC),avikumar Vemuru (Odessa, TX), Subramanian Venkataraman (Oakawn, IL), Bruce Waldholtz (Chesapeake, VA), Joseph Wang (Jeffersonity, MO), Frederick Weber (Savannah, GA), Joseph WebsterTallahassee, FL), Zelman Weingarten (Los Angeles, CA), Michael

eisberg (Plano, TX), Dale Whitebloom (Lancaster, PA), Douglas Wolf M

Atlanta, GA), Robert Yin (Lutherville, MD), Homan Zadeh (Palmprings, CA), and Oren Zaidel (Torrance, CA).Editorial and writing support were provided by Judith M. Pepin, Terri

affney, and Christi A. Messer, employees of Procter & Gambleharmaceuticals.The QDIEM Steering Committee of academic investigators (William

andborn, Joshua Korzenik, Bret Lashner, Jonathan Leighton, Umaahadevan, James Marion, Michael Safdi, Charles Sninsky, andunanda Kane) were involved in the design and execution of the study,

nterpretation of the results, and drafting and final approval of theanuscript; Raman Patel and Keith Friedenberg were involved in the

xecution of the study, interpretation of the results, and drafting andnal approval of the manuscript; Procter & Gamble scientists (Prestonunnmon and David Ramsey) were involved with the conception andesign of the study, assembly, analysis, and interpretation of data, andrafting and final approval of the manuscript; data were collected byrocter & Gamble Pharmaceuticals and a clinical researchrganization, and analyzed by Procter & Gamble Pharmaceuticals;illiam Sandborn wrote the first draft of the manuscript and theDIEM Steering Committee made the decision to publish; the authorsad full access to and vouch for the veracity and completeness of theata and data analyses.

onflicts of interestThese authors disclose the following: William Sandborn has

erved as a consultant for and received research funding fromrocter & Gamble Pharmaceuticals, Inc, and Shire Pharmaceuticals,nd has served as a consultant for Salix Pharmaceuticals, Inc;oshua Korzenik has served as a consultant for Procter & Gambleharmaceuticals, Shire, CytokinePharma, Eurand, Zyogenetics, andeceived research funding from Procter & Gamble Pharmaceuticals;ret Lashner has served on the Advisory Board/Speakers Bureau forrocter & Gamble Pharmaceuticals, Salix, Shire, UCB, Abbott, andrometheus; Jonathan Leighton has served as a consultant forrocter & Gamble Pharmaceuticals and received research funding

rom Procter & Gamble Pharmaceuticals, Abbott, Bristol Myersquibb, Otsuka, and Centocor; Uma Mahadevan has served as aonsultant for Procter & Gamble Pharmaceuticals and Shire; James. Marion has served as a consultant for Procter & Gambleharmaceuticals and has served on the Speakers Bureau forrocter & Gamble Pharmaceuticals, Shire, and UCB; Michael Safdias received research funding from Forest Research Institute,onatus, Shire, Tibotec, Millennium, Cosmo, Abbott, Centocor, Pfizer,lan, Procter & Gamble Pharmaceuticals, Salix Pharmaceuticals,iolex, Gilead, Roche, Vertex, Celltech, Eisai, BMS, and Lexicon, haserved as a consultant for Procter & Gamble Pharmaceuticals, andas served on the Speakers Bureau for Procter & Gambleharmaceuticals, Shire, and Centocor; Charles A. Sninsky haserved on Advisory Boards and Speakers Bureau for Procter &amble Pharmaceuticals, Shire, Centocor, Abbott, UCB, andrometheus; Keith A. Friedenberg owns shares of Procter & Gambletock; Preston Dunnmon and David Ramsey are employees ofrocter & Gamble Pharmaceuticals; and Sunanda Kane has serveds a consultant for and received research funding from Procter &amble Pharmaceuticals and Shire. The remaining authors discloseo conflicts: Raman M. Patel.

undingThis study was funded by Procter & Gamble Pharmaceuticals, Inc,

ason, Ohio. ClinicalTrials.gov Identifier NCT00505778.

S

B

B

U

B

G

E

NdiDuG

S

T

P

a

Mman.32

April 2010 ONCE–DAILY MESALAMINE FOR UC MAINTENANCE REMISSION 1296.e1

upplementary Table 1. SCCAI

Symptom Score

owel frequency during the day1–3 04–6 17–9 2�9 3

owel frequency at night0 01–3 14–6 2

rgency of defecationNone 0Hurry 1Immediately 2Incontinence 3

lood in stoolNone 0Trace 1Occasionally frank 2Usually frank 3

eneral well beingVery well 0Slightly below par 1Poor 2Very poor 3Terrible 4

xtracolonic features (arthritis, pyodermagangrenosum, erythema nodosum,uveitis)

1 per manifestation

OTE. There is a possible maximum score of 19. A score of 5 or moreefines relapse/flare with 92% sensitivity, 91% specificity, 85% pos-

tive predictive value, and 89% negative predictive value.ata from Walmsley et al,30 and Jowett et al (“Defining relapse oflcerative colitis using a symptom-based activity index.” Scand J

astroenterol 2003;38:164–171)

upplementary Table 2. MARS Questionnaire

he questionnaire is prefaced by the following statement: “Manypeople find different ways of taking their study medicines to suittheir needs. This may differ from the instructions listed on thelabel or from the instructions given to them by their doctor. Youwill hear some of the ways in which people have said they havetaken their study medicines. Please indicate if you have takenyour study medication this way in the last week.”

atients were provided with the following scale for their responses:5 � never, 4 � rarely, 3 � sometimes, 2 � often, and 1 � veryoften.a. I have changed how many times per day I take my medicineb. I forgot to use itc. I stopped taking it for a whiled. I only used it when I had active symptomse. I decided to skip a dosef. I took less medicine than instructedg. I took more medicine than instructedh. I avoided using it if I couldi. I used it regularly every daya

Reverse scored.ARS questionnaire modified with approval from Horne and Wein-

S

A

A

F

S

Q

Q

B

Na

b

c

1296.e2 SANDBORN ET AL GASTROENTEROLOGY Vol. 138, No. 4

upplementary Table 3. Patient Satisfaction and Preference Questionnaire

t baseline:Please rate on the scale below your current level of satisfaction with the regimen you use to treat your Ulcerative Colitis. Considereverything about your regimen, drug product, dosing, frequency, etc.

Extremelysatisfied

Verysatisfied

Somewhatsatisfied

Somewhatdissatisfied

Not satisfiedat all

[ ] [ ] [ ] [ ] [ ]t 6 and 12 months:Considering only the treatment regimen you have been using to treat your Ulcerative Colitis as part of your participation in this clinicalstudy, how Satisfied would you say you are with this treatment regimen?

Extremelysatisfied

Verysatisfied

Somewhatsatisfied

Somewhatdissatisfied

Not satisfiedat all

[ ] [ ] [ ] [ ] [ ]

Considering the treatment regimen you have been using throughout the clinical study, and the treatment regimen you used prior toentering the clinical study to treat your Ulcerative Colitis, which if either of these treatment regimens would you say you Prefer?

[ ] Prefer my old treatment regimen (the therapy I used before participation in the clinical study)[ ] Prefer the new treatment regimen (the therapy I’ve been using during the clinical study)[ ] I don’t have a preference between the 2 regimens, my old one or the one I’ve been using during the study[ ] Don’t Know

orced preference:For any patients who indicate No Preference or Don’t Know, ask the following question:

Although you indicated that you don’t have a preference for either treatment regimen, or don’t Know, please think about your overallexperiences with your old regimen and the one you used in this study, and if you were forced to choose only one treatment to use totreat your Ulcerative Colitis from now on, which would you prefer?

[ ] Prefer my old treatment regimen (the regimen I used prior to participation in the clinical study)[ ] Prefer the new treatment regimen (the regimen I’ve been using during the clinical study)

[ ] No preference because the old treatment regimen and the new treatment regimen were the same

upplementary Table 4. MARS Questionnaire Scores by Treatment Group and Visit

Treatmentgroup and

visit

Relapse

Relapse yes vs no comparisonYes No

N Mean SE n Mean SE P valuea Difference in least square meanb Confidence intervalsc

D � BIDBaseline 123 40.7 0.53 837 40.1 0.20 .3829 �0.49 �1.60 to 0.62Month 3 95 42.5 0.42 800 42.1 0.18 .6558 �0.24 �1.31 to 0.83Month 6 78 42.3 0.48 762 42.0 0.18 .7368 �0.19 �1.31 to 0.93Month 12 47 41.6 0.71 639 41.9 0.20 .6129 0.39 �1.13 to 1.91

DBaseline 64 40.3 0.74 421 40.1 0.28 .8777 �0.12 �1.65 to 1.41Month 3 45 43.1 0.41 403 42.4 0.25 .3919 �0.64 �2.09 to 0.82Month 6 40 41.7 0.78 380 42.3 0.24 .4033 0.64 �0.87 to 2.15Month 12 25 41.9 0.80 325 42.2 0.26 .7263 0.34 �1.57 to 2.26

IDBaseline 59 41.2 0.75 416 40.2 0.29 .2573 �0.94 �2.56 to 0.69Month 3 50 42.0 0.70 397 41.8 0.27 .9047 0.10 �1.47 to 1.66Month 6 38 42.9 0.55 382 41.7 0.26 .2146 �1.05 �2.70 to 0.61Month 12 22 41.2 1.24 314 41.6 0.31 .6959 0.48 �1.92 to 2.88

, number of patients in given categories; n, number of patients in given categories with nonmissing MARS scores; SE, standard error of mean.P value from relapse yes vs no comparison using analysis of variance with prior dose category as factor.Difference in least square mean.

95% CI for the difference in relapse with prior dose category as stratification.

S

B

B

T

na

b

c

April 2010 ONCE–DAILY MESALAMINE FOR UC MAINTENANCE REMISSION 1296.e3

upplementary Table 5. Month 12 Remission Status for Patients With Prior Dosing Regimen and Prior Dose

Prior dosing regimenand prior dose QD n (%) BID n (%) Total n (%) P valuea

BID-QD difference inremission ratesb

95% CI forBID-QDc

ID 1.6 g/dayYes 103 (88.0%) 106 (91.4%) 209 (89.7%)No 14 (12.0%) 10 (8.6%) 24 (10.3%)Total 117 116 233 .4010 3.3 �4.4 to 11.1

ID 2.4 g/dayYes 137 (81.5%) 127 (81.9%) 264 (81.7%)No 31 (18.5%) 28 (18.1%) 59 (18.3%)Total 168 155 323 .9282 0.4 �8.0 to 8.8

ID 2.4 g/dayYes 112 (87.5%) 125 (82.8%) 237 (84.9%)No 16 (12.5%) 26 (17.2%) 42 (15.1%)Total 128 151 279 .2721 �4.7 �13.0 to 3.6

(%), number and percentage (n/total � 100) of patients in treatment with specified outcome.QD compared with BID using the chi-square test.Risk difference between QD and BID.

CI for the risk difference in response rates between QD and BID.