Title: Once-Daily, High-Concentration MMX Mesalamine in Active Ulcerative Colitis
Abstract: Background & Aims: SPD476 (LIALDA™ in the US; MEZAVANT™ in the EU; otherwise known as MMX mesalamine; Shire Pharmaceuticals Inc., Wayne, PA, under license from Giuliani SpA, Milan, Italy) is a novel, once-daily, high-strength (1.2 g/tablet) formulation of mesalamine, utilizing MMX Multi Matrix System (MMX) technology designed to deliver the active drug throughout the colon. We performed a double-blind, multicenter study, comparing MMX mesalamine vs placebo for the treatment of active ulcerative colitis. A delayed-release oral mesalamine (ASACOL; Procter & Gamble, Cincinnati, OH) reference arm was included.Methods: Three hundred forty-three patients with active, mild-to-moderate ulcerative colitis received MMX mesalamine 2.4 g/day or 4.8 g/day given once daily, ASACOL 2.4 g/day given in 3 divided doses, or placebo for 8 weeks. The primary end point was the proportion of patients in clinical and endoscopic remission (modified ulcerative colitis disease activity index of ≤1 with rectal bleeding and stool frequency scores of 0, no mucosal friability, and a ≥1-point reduction in sigmoidoscopy score from baseline). Results: A significantly greater proportion of patients receiving MMX mesalamine 2.4 g/day given once daily (40.5%; P = .01) and 4.8 g/day given once daily (41.2%; P = .007) achieved clinical and endoscopic remission at week 8, vs placebo (22.1%). The clinical and endoscopic remission rate for ASACOL (32.6%; P = .124) was not significantly superior to placebo. All active treatments were well-tolerated. Conclusions: Once-daily MMX mesalamine was efficacious and well-tolerated for the induction of clinical and endoscopic remission. MMX mesalamine offers effective and convenient mesalamine therapy, potentially improving treatment compliance. Background & Aims: SPD476 (LIALDA™ in the US; MEZAVANT™ in the EU; otherwise known as MMX mesalamine; Shire Pharmaceuticals Inc., Wayne, PA, under license from Giuliani SpA, Milan, Italy) is a novel, once-daily, high-strength (1.2 g/tablet) formulation of mesalamine, utilizing MMX Multi Matrix System (MMX) technology designed to deliver the active drug throughout the colon. We performed a double-blind, multicenter study, comparing MMX mesalamine vs placebo for the treatment of active ulcerative colitis. A delayed-release oral mesalamine (ASACOL; Procter & Gamble, Cincinnati, OH) reference arm was included.Methods: Three hundred forty-three patients with active, mild-to-moderate ulcerative colitis received MMX mesalamine 2.4 g/day or 4.8 g/day given once daily, ASACOL 2.4 g/day given in 3 divided doses, or placebo for 8 weeks. The primary end point was the proportion of patients in clinical and endoscopic remission (modified ulcerative colitis disease activity index of ≤1 with rectal bleeding and stool frequency scores of 0, no mucosal friability, and a ≥1-point reduction in sigmoidoscopy score from baseline). Results: A significantly greater proportion of patients receiving MMX mesalamine 2.4 g/day given once daily (40.5%; P = .01) and 4.8 g/day given once daily (41.2%; P = .007) achieved clinical and endoscopic remission at week 8, vs placebo (22.1%). The clinical and endoscopic remission rate for ASACOL (32.6%; P = .124) was not significantly superior to placebo. All active treatments were well-tolerated. Conclusions: Once-daily MMX mesalamine was efficacious and well-tolerated for the induction of clinical and endoscopic remission. MMX mesalamine offers effective and convenient mesalamine therapy, potentially improving treatment compliance. CME quiz on page 432. CME quiz on page 432. See Turner D et al on page 103; and Lichtenstein GR et al on page 95 for companion articles in Clin Gastroenterol Hepatol. See Turner D et al on page 103; and Lichtenstein GR et al on page 95 for companion articles in Clin Gastroenterol Hepatol. The current standard of care for ulcerative colitis (UC) is 5-aminosalicylic acid (5-ASA). A variety of mechanisms for delivering 5-ASA to the colonic mucosa have been developed.1Qureshi A.I. Cohen R.D. Mesalamine delivery systems: do they really make much difference?.Adv Drug Deliv Rev. 2005; 57: 281-302Crossref PubMed Scopus (71) Google Scholar, 2Asacol (mesalazine) delayed-release tablets. 2004Google Scholar, 3Forbes A. Al-Damluji A. Ashworth S. Bramble M. Herbert K. Ho J. Kang J.Y. Przemioslo R. Shetty A. Multicentre randomized-controlled clinical trial of Ipocol, a new enteric-coated form of mesalazine, in comparison with Asacol in the treatment of ulcerative colitis.Aliment Pharmacol Ther. 2005; 21: 1099-1104Crossref PubMed Scopus (19) Google Scholar, 4Marakhouski Y. Fixa B. Holoman J. Hulek P. Lukas M. Batovsky M. Rumyantsev V.G. Grigoryeva G. Stolte M. Vieth M. Greinwald R. A double-blind dose-escalating trial comparing novel mesalazine pellets with mesalazine tablets in active ulcerative colitis.Aliment Pharmacol Ther. 2005; 21: 133-140Crossref PubMed Scopus (45) Google Scholar Pharmacokinetic and placebo-controlled efficacy studies indicate that the variety of available oral 5-ASA formulations and prodrugs have similar systemic exposure and efficacy, although some studies in which different active drugs have been compared directly have highlighted possible differences in clinical efficacy between compounds.5Green J.R. Gibson J.A. Kerr G.D. Swarbrick E.T. Lobo A.J. Holdsworth C.D. Crowe J.P. Schofield K.J. Taylor M.D. ABACUS Investigator groupMaintenance of remission of ulcerative colitis: a comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months.Aliment Pharmacol Ther. 1998; 12: 1207-1216Crossref PubMed Scopus (78) Google Scholar, 6Green J.R. Lobo A.J. Holdsworth C.D. Leicester R.J. Gibson J.A. Kerr G.D. Hodgson H.J. Parkins K.J. Taylor M.D. The Abacus Investigator GroupBalsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis.Gastroenterology. 1998; 114: 15-22Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 7Green J.R. Mansfield J.C. Gibson J.A. Kerr G.D. Thornton P.C. A double-blind comparison of balsalazide, 6.75 g daily, and sulfasalazine, 3 g daily, in patients with newly diagnosed or relapsed active ulcerative colitis.Aliment Pharmacol Ther. 2002; 16: 61-68Crossref PubMed Scopus (72) Google Scholar, 8Courtney M.G. Nunes D.P. Bergin C.F. O’Driscoll M. Trimble V. Keeling P.W. Weir D.G. Randomised comparison of olsalazine and mesalazine in prevention of relapses in ulcerative colitis.Lancet. 1992; 339: 1279-1281Abstract PubMed Scopus (82) Google Scholar, 9Levine D.S. Riff D.S. Pruitt R. Wruble L. Koval G. Sales D. Bell J.K. Johnson L.K. 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 coltis.Am J Gastroenterol. 2002; 97: 1398-1407Crossref PubMed Scopus (125) Google Scholar, 10Pruitt R.E. Hanson J. Safdi M. Wruble L. Hardi R. Johannsson J.H. Koval G. Riff D. Winston B. Cross A. Doty P. Johnson L.K. Balsalazide is superior to mesalamine in the time to improvement in signs and symptoms of acute mild-to-moderate ulcerative colitis.Am J Gastroenterol. 2002; 97: 3078-3086Crossref PubMed Google Scholar However, currently available formulations vary in the amount of 5-ASA per tablet, thereby influencing the number of tablets that need to be ingested. In addition, current treatment regimens are based on 2- to 4-times daily administration. The number and frequency of tablets to be ingested on a daily basis (pill burden) is likely to have a major effect on compliance. For example, the proportion of patients adhering to complex 5-ASA dosing regimens has been shown to be as low as 40%.11Kane S.V. Cohen R.D. Aikens J.E. Hanauer S.B. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis.Am J Gastroenterol. 2001; 96: 2929-2933Crossref PubMed Google Scholar Compliance to recommended 5-ASA dosing schedules has been shown to have a major effect on relapse rates, and thus quality of life, in patients receiving maintenance therapy.12Kane S. Huo D. Aikens J. Hanauer S. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis.Am J Med. 2003; 114: 39-43Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar, 13van Hees P.A. van Tongeren J.H. Compliance to therapy in patients on a maintenance dose of sulfasalazine.J Clin Gastroenterol. 1982; 4: 333-336Crossref PubMed Scopus (70) Google Scholar, 14Janke K.H. Klump B. Gregor M. Meisner C. Haeuser W. Determinants of life satisfaction in inflammatory bowel disease.Inflamm Bowel Dis. 2005; 11: 272-286Crossref PubMed Scopus (126) Google Scholar, 15Han S.W. McColl E. Barton J.R. James P. Steen I.N. Welfare M.R. Predictors of quality of life in ulcerative colitis: the importance of symptoms and illness representations.Inflamm Bowel Dis. 2005; 11: 24-34Crossref PubMed Scopus (108) Google Scholar Consequently, it would be advantageous for both the treatment of acute disease and the maintenance of remission if 5-ASA could be delivered in a formulation that reduced daily pill burden. MMX mesalamine (SPD476 marketed as Lialda® [US] and Mezavant® [EU]; Shire Pharmaceuticals Inc., Wayne, PA, under license from Giuliani SpA, Milan, Italy) is a novel, high-strength formulation of 5-ASA (mesalamine, 1.2 g per tablet), which uses MMX Multi Matrix System technology designed to release 5-ASA throughout the colon. This delivery system uses lipophilic and hydrophilic matrices enclosed within a gastro-resistant, pH-dependent coating to facilitate prolonged exposure of the colonic mucosa to 5-ASA.16Prantera C. Viscido A. Biancone L. Francavilla A. Giglio L. Campieri M. A new oral delivery system for 5-ASA: preliminary clinical findings for MMX.Inflamm Bowel Dis. 2005; 11: 421-427Crossref PubMed Scopus (130) Google Scholar The gastro-resistant film, covering the multimatrix core, delays initial release of the active drug until the tablet is exposed to a pH of 7.0 or higher, normally in the terminal ileum. As the gastro-resistant coating disintegrates, intestinal fluids interact with the hydrophilic matrix causing the tablet to swell (much like a sponge exposed to water) and form an outer, viscous gel mass. This viscous gel mass is expected to slow diffusion of the active drug from the tablet core into the colonic lumen. As the tablet core and its surrounding gel mass progress through the colon, pieces of the gel mass gradually break away from the core releasing 5-ASA. In addition, the hydrophilic matrix may adhere to the colonic mucosa,17Mohammadi-Samani S. Bahri-Najafi R. Yousefi G. Formulation and in vitro evaluation of prednisolone buccoadhesive tablets.Farmaco. 2005; 60: 339-344Crossref PubMed Scopus (49) Google Scholar, 18Ali J. Khar R.K. Ahuja A. Formulation and characterisation of a buccoadhesive erodible tablet for the treatment of oral lesions.Pharmazie. 1998; 53: 329-334PubMed Google Scholar further facilitating targeted drug delivery. The lipophilic matrix (together with 5-ASA) is interspersed within the hydrophilic matrix, creating a partially hydrophobic environment. This is expected to slow the penetration of aqueous fluids into the tablet core, reducing the rate of drug dissolution and thus prolonging therapeutic activity. The primary purpose of this study, SPD476-302, was to investigate the efficacy and safety of 2 doses of MMX mesalamine given once daily, in comparison with placebo, for the induction of clinical and endoscopic remission in patients with mild-to-moderately active UC. An active comparator group, using one of the most commonly prescribed delayed-release oral 5-ASA formulations (ASACOL; Procter & Gamble, Cincinnati, OH), was also included. Male and female patients aged ≥18 years who had newly diagnosed or relapsing (relapsed ≤6 weeks prior to baseline) active, mild-to-moderate UC (score of 4–10 on a modified UC-disease activity index [UC-DAI], with a sigmoidoscopy score ≥1 and a Physician’s Global Assessment [PGA] score ≤2) with compatible histology were eligible for enrollment in this study. The modified UC-DAI scoring system used in this study was based on that developed by Sutherland et al,19Sutherland L.R. Martin F. Greer S. Robinson M. Greenberger N. Saibil F. Martin T. Sparr J. Prokipchuk E. Borgen L. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.Gastroenterology. 1987; 92: 1894-1898Abstract PubMed Google Scholar in which patients found to have mild friability of the colonic mucosa were given a sigmoidoscopy score of at least 1. In this study, to increase stringency, patients showing any mucosal friability were given a sigmoidoscopy score of at least 2. This modified scoring system is detailed in Table 1. During the 3- to 7-day screening period, patients were permitted to continue on a stable dose of mesalamine (≤2.0 g/day) if they were receiving this therapy prior to screening. This was withdrawn at baseline if the patient was found to be eligible for study inclusion.Table 1Modified UC Disease Activity Index Scoring SystemMild (score = 1)Moderate (score = 2)Severe (score = 3)Rectal bleedingStreaks of bloodObvious bloodMostly bloodStool frequency1–2/day > normal3–4/day > normal>4/day > normalMucosal appearanceErythemaDecreased vascular patternMinimal granularityMarked erythemaFriabilityGranularityAbsent vascular patternBleeding minimal traumaNo ulcerationsUlcerationSpontaneous bleedingPhysician’s Global AssessmentMildModerateSevereNOTE. Modified from Sutherland et al 1987.19Sutherland L.R. Martin F. Greer S. Robinson M. Greenberger N. Saibil F. Martin T. Sparr J. Prokipchuk E. Borgen L. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.Gastroenterology. 1987; 92: 1894-1898Abstract PubMed Google Scholar Open table in a new tab NOTE. Modified from Sutherland et al 1987.19Sutherland L.R. Martin F. Greer S. Robinson M. Greenberger N. Saibil F. Martin T. Sparr J. Prokipchuk E. Borgen L. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis.Gastroenterology. 1987; 92: 1894-1898Abstract PubMed Google Scholar Patients were excluded if they had severe UC (defined by PGA score >2); had previously experienced an inadequate or failed response to steroids or a mesalamine dose of >2.0 g/day; had a current relapse lasting >6 weeks; had relapsed while on maintenance therapy with doses of 5-ASA >2.0 g/day; or had relapsed within 2 weeks of dose reduction from >2.0 g/day to ≤2.0 g/day 5-ASA. Patients were also excluded if they had received systemic or rectal steroids within the 4 weeks prior to baseline; immunosuppressants within the previous 6 weeks; antibiotics within the previous 7 days; or repeated treatment (>3 days of use at doses that exceed those available without prescription) with anti-inflammatory drugs within 7 days prior to baseline (with the exception of prophylactic aspirin at doses of ≤325 mg/day for cardiac disease). Patients with the following conditions were also excluded: proctitis (inflammation confined to ≤15 cm from the anus); previous colonic surgery; Crohn’s disease; bleeding disorders; active peptic ulcer; immediate or significant risk of toxic megacolon; stools positive for enteric pathogens; hypersensitivity to salicylates or aspirin; or moderate-to-severe renal impairment. We conducted a randomized, phase III, double-blind, double-dummy, parallel-group, placebo-controlled, multicenter study with an ASACOL reference arm, which was conducted in patients with active mild-to-moderate UC. Forty-nine centers in Germany, Spain, France, Poland, Hungary, Russia, Israel, Latvia, Lithuania, and Estonia participated (Appendix). This study was conducted in accordance with current applicable regulations and International Conference on Harmonization and local ethical and legal requirements. The study complied with the principles of the 18th World Medical Assembly (Helsinki, 1964) and its subsequent amendments. Patients signed an informed consent form prior to any study procedure being conducted. Eligible patients were randomized equally among MMX mesalamine 2.4 g/day given once daily (QD), MMX mesalamine 4.8 g/day given QD, ASACOL 2.4 g/day given in 3 divided doses (0.8 g, 3 times daily [TID]) according to its approved dosing indication, and placebo. Treatment lasted for 8 weeks. Each MMX mesalamine tablet contained 1.2 g mesalamine. ASACOL tablets contained 400 mg mesalamine and were enclosed in a capsule for blinding purposes. Because of the double-dummy design of the study, patients received placebo tablets (for MMX mesalamine) and placebo capsules (for ASACOL). Therefore, all patients received 4 tablets and 2 capsules in the morning, 2 capsules at lunchtime, and 2 capsules in the evening. All tablets and capsules were taken with food. Patients visited the clinic on 5 occasions (screening visit at week −1; baseline visit at week 0; and at weeks 2, 4, and 8 (or early withdrawal). A stool sample for culture was taken at screening, and blood tests were carried out at the screening, week 4, and week 8 (or early withdrawal) visits. At all visits, vital signs were taken, adverse events (AEs) were recorded, and patients reported their UC symptoms (rectal bleeding and stool frequency) via an interactive voice response system. The scores for symptoms of rectal bleeding and stool frequency were calculated by averaging the total score over the last available 3 days prior to the study visit. Data that were recorded more than 5 days prior to the study visit were not used. At the baseline and week 8 or early withdrawal visits, a PGA score assessment was performed by the same investigator for individual patients. Sigmoidoscopy was also performed at these time points and by the same investigator. At screening and week 8 or early withdrawal, a urinalysis and a physical examination were carried out. Patients were not allowed to take alternative UC treatment after the screening period, and compliance was assessed throughout by pill counts. The primary objective for this study was to compare the percentage of patients in clinical and endoscopic remission at the end of the 8-week treatment period for the 2 MMX mesalamine dose groups vs placebo. Stringent criteria were used to define this end point: a modified UC-DAI score of ≤1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction from baseline in sigmoidoscopy score. As described previously, to increase stringency further, a modified sigmoidoscopy scoring system was utilized. The standard UC-DAI scoring system allows patients with mild mucosal friability to be given a sigmoidoscopy score of 1. However, in this study, patients with any mucosal friability were given a sigmoidoscopy score of at least 2 and were therefore not considered to have achieved the primary end point. In addition, exploratory analyses to evaluate remission rates (clinical and endoscopic combined) in subgroups of the intent-to-treat (ITT) population (patients with either mild disease [modified UC-DAI score of 4 to <6] or moderate disease at baseline [modified UC-DAI score of 6 to 10] and patients with either left-sided [below the splenic flexure] or extensive disease [involvement of the transverse colon or pancolitis]) were performed. Secondary objectives included the proportion of patients achieving clinical remission (a score of 0 points for stool frequency and rectal bleeding); the proportion of patients achieving clinical improvement (defined as a decrease of ≥3 points from baseline in the total modified UC-DAI score); the changes in modified UC-DAI score (baseline to week 8); the changes in sigmoidoscopic (mucosal) appearance (baseline to week 8); and the changes in rectal bleeding and stool frequency (from baseline to any study visit). Other secondary objectives included an analysis of treatment failure rate (defined as an unchanged, worsened, missing, or incomplete modified UC-DAI score); a comparison of the time to withdrawal; and an assessment of the safety and tolerability of MMX mesalamine compared with placebo or ASACOL. Patients were randomized centrally via an interactive voice response system. In the event of the assigned treatment group being unavailable at the site on randomization (eg, because of a delay in medication arrival at the site), patients were allocated to the next treatment in the randomization (forced randomization). The modified UC-DAI total score was calculated as the sum of scores of rectal bleeding, stool frequency, mucosal appearance (sigmoidoscopy), and PGA. This was assessed at baseline and week 8 or early withdrawal visit. Remission (both clinical and endoscopic; the primary end point) and clinical remission, as defined above, were evaluated. Time to initial clinical remission was defined as the time between the first dose of study medication and the first day of 3 consecutive symptom-free days. For sustained clinical remission, no residual symptoms were allowed unless they were preceded and followed by 3 consecutive symptom-free days. Safety and tolerability were assessed throughout via AE reporting, laboratory testing (hematology, biochemistry, and urinalysis), physical examination, and vital signs. Treatment-emergent AEs were defined as events that occurred after the first dose of medication and up to 30 days posttreatment. A serious AE (SAE) was defined as any AE that caused incapacity/disability, was life threatening or fatal, or required hospitalization. Time to withdrawal was also assessed. The ITT and safety populations were defined as all randomized patients who received at least 1 dose of study medication. The per protocol (PP) population was defined as all patients in the ITT population who were not major protocol violators. Taking the placebo clinical and endoscopic remission rate to be 15% and considering a clinical and endoscopic remission rate of 40% in the MMX mesalamine treatment arm to be a clinically worthwhile improvement, it was calculated that 85 patients per treatment arm would enable a 90% probability of detecting this improvement, assuming a 2-sided .025 significance level. The primary analysis was performed on the ITT population to compare the MMX mesalamine groups with placebo. The proportion of patients in clinical and endoscopic remission at week 8 was compared with placebo for both active treatment groups using the χ2 test. The odds ratio (OR) between MMX mesalamine active treatment and placebo, together with the associated confidence interval (CI), were calculated. The study-wise false-positive error rate from performing 2 primary comparisons was controlled using the Bonferroni–Holm method. The lower of the 2 P values was tested at the .025 significance level. If this was found to be significant, the higher P value was then tested at the .05 significance level. Therefore, CIs reported for the ORs in this study are analogous to the significance level utilized for each test. An exploratory secondary analysis of the primary efficacy variable was performed using the Cochran–Mantel–Haenszel test, with stratification by center on the ITT and PP populations. An additional supportive analysis of the primary efficacy variable (termed “endpoint”) was performed, using data from the ITT population at week 8 combined with the last observation carried forward (LOCF) for patients who had withdrawn early. Similarly, a LOCF analysis of the primary efficacy variable was completed using the PP population. All other analyses were carried out on both the ITT and PP populations. For the secondary endpoint analyses, hypothesis tests at the .05 significance level and 2-sided 95% CIs were used throughout as described for the primary efficacy analysis. For all 4 treatment groups, remission rates (clinical and endoscopic combined), clinical improvement, and treatment failure were analyzed as per the primary end point. Change from baseline in modified UC-DAI score was assessed at week 8 and endpoint (which included data for patients that withdrew early) using an analysis of covariance adjusted for baseline modified UC-DAI score and pooled center. Change from baseline in sigmoidoscopy score was compared with placebo at week 8 and endpoint for both active treatment arms using the Cochran–Mantel–Haenszel χ2 test. Time to initial and sustained clinical remission or withdrawal from the study was compared between the treatment groups by plotting Kaplan–Meier curves annotated with P values from a log-rank test. Descriptive summaries are presented for AEs, laboratory safety variables, and vital signs. The study was conducted between December 4, 2003 and October 20, 2004 and 343 patients were randomized to treatment (Figure 1). Thirty-five patients underwent forced randomization; this affected treatment groups similarly (MMX mesalamine 2.4 g/day given QD, n = 10; MMX mesalamine 4.8 g/day given QD, n = 8; ASACOL, n = 8; placebo, n = 9). Two patients were randomized in error and excluded from the study. Both of these patients were found to have a positive stool culture. Neither patient received study medication. Therefore, a total of 341 patients were included in the ITT population. Protocol violations were infrequent (n = 20), and most, with the exception of noncompliance (see below), were similar between the 4 arms: severity of UC at baseline, prior relapse, Crohn’s disease, proctitis or failure to establish original diagnosis. Three hundred twenty-one patients were included in the PP population. As shown in Figure 1, the most frequent reason for premature discontinuation was lack of efficacy. Premature discontinuation was greatest in the placebo group (39.5% vs 15.3% in the MMX mesalamine 4.8 g/day given QD group and 18.6% in both the MMX mesalamine 2.4 g/day given QD and ASACOL 2.4 g/day given TID groups). Patient demographics were comparable among treatment groups, as shown in Table 2. The majority of concomitant medications was taken by a similar proportion of patients in each treatment group. The most frequent concomitant medications taken during the treatment period were aminosalicylic acids and similar agents (13.2% of patients overall); however, for all but 2 patients, these medications were stopped on study day 1. One patient in the MMX mesalamine 4.8 g/day given QD group received sulfasalazine until study day 7 (this patient completed the study and was included in the PP population). Other common concomitant medications were angiotensin-converting enzyme inhibitors (9.4% of patients overall) and benzodiazepine derivatives (7.3% of patients overall). Prior corticosteroid and immunomodulatory medications were taken by no more than 2 subjects in any treatment group (Table 2).Table 2Patient Demographics at BaselinePlacebo (n = 86)MMX mesalamine 2.4 g/day given QD (n = 84)MMX mesalamine 4.8 g/day given QD (n = 85)ASACOL 2.4 g/day given TID (n = 86)Sex Male, n (%)43 (50)39 (46.4)39 (45.9)41 (47.7) Female, n (%)43 (50)45 (53.6)46 (54.1)45 (52.3)Age (y), mean (SD)43.2 (14.06)43.3 (13.30)44.6 (13.13)41.9 (13.34)Weight (kg), mean (SD)68.7 (14.36)73.3 (14.87)73.0 (14.33)72.6 (15.65)Time since diagnosis (weeks), mean (SD)293.1 (324.5)290.4 (333.9)282.7 (380.9)244.4 (260.3)Relapses in last 2 years, n (%) 08 (9.3)8 (9.5)8 (9.4)6 (7.0) 1−252 (60.5)39 (46.4)40 (47.1)44 (51.2) 3−421 (24.4)27 (32.1)28 (32.9)20 (23.3) 5−61 (1.2)6 (7.1)4 (4.7)8 (9.3) ≥72 (2.3)1 (1.2)1 (1.2)2 (2.3)Duration of current episode (days), mean (SD)22.4 (11.61)21.3 (9.10)20.7 (8.46)21.5 (10.65)Classification, n (%) Left-sided63 (73.3)59 (70.2)67 (78.8)69 (80.2) Transverse colon involvement6 (7.0)7 (8.3)4 (4.7)2 (2.3) Pancolitis17 (19.8)18 (21.4)14 (16.5)15 (17.4)Diagnosis, n (%) Newly diagnosed10 (11.6)11 (13.1)12 (14.1)13 (15.1) History of UC76 (88.4)73 (86.9)73 (85.9)73 (84.9)Prior medication, n (%) Corticosteroids1 (1.2)2 (2.4)1 (1.2)2 (2.3) Immunomodulators01 (1.2)00NOTE. Intent-to-treat population, n = 341.UC, ulcerative colitis; QD, once daily; TID, 3 times daily. Open table in a new tab NOTE. Intent-to-treat population, n = 341. UC, ulcerative colitis; QD, once daily; TID, 3 times daily. The mean duration of current episode was similar in all groups. In terms of baseline disease severity, approximately two-thirds of patients in each treatment arm had moderate disease. Noncompliance with study drug (took <80% or >120% of tablets/capsules including double-dummy placebo) occurred in 6 patients in the MMX mesalamine 4.8 g/day given QD arm and 2 patients in each of the other 3 study arms. For the primary analysis, the LOCF approach was not used; patients who withdrew prematurely or who provided no baseline data were considered not to have achieved the primary end point. The primary end point was comparison of remission rates (clinical and endoscopic combined; MMX mesalamine vs placebo) achieved at week 8. In the ITT population, a statistically significantly greater proportion of patients receiving MMX mesalamine 2.4 g/day given QD (40.5%; P = .010; OR, 2.40 [95% CI: 1.23–4.69]; relative risk [RR], 1.83 [95% CI: 1.14–2.94]) or 4.8 g/day given QD (41.2%; P = .007; OR, 2.47 [97.5% CI: 1.15–5.3]; RR, 1.86 [95% CI: 1.09–3.19]) achieved clinical and endoscopic remission compared with placebo (22.1% [Figure 2]). The proportion of patients receiving ASACOL 2.4 g/day given TID who achieved clinical and endoscopic remission was not statistically significantly greater than placebo (32.6% vs 22.1%, respectively; P = .124; OR, 1.70 [95% CI: 0.86–3.36]; RR, 1.47 [95% CI: 0.89–2.43]). There were no notable differences with regard to primary end point data at week 8 between the ITT and PP populations; there were also no differences in the primary efficacy variable using the LOCF approach in analys