Once-Daily Dosing of Delayed-Release Oral Mesalamine (400-mg Tablet) Is as Effective as Twice-Daily Dosing for Maintenance of Remission of Ulcerative Colitis

Article Outline

• Abstract
• Materials and Methods
  • Patients
  • Study Design
  • Patient Schedule and Efficacy/Safety Evaluations
  • Statistical Analysis
• Results
  • Characteristics and Disposition of Patients
  • Efficacy
  • Safety
• Discussion
• Acknowledgments
• Supplementary material
• References
• Copyright

Background & Aims

The practice of dosing mesalamines in divided doses for the treatment of ulcerative colitis (UC) began with sulfasalazine and was driven by sulfapyridine toxicity. This convention and the assumption that dosing multiple times a day is necessary to treat UC had not been challenged until recently. This study was conducted to determine the efficacy and safety of once-daily dosing of delayed-release mesalamine (Asacol 400-mg tablets) compared with twice-daily dosing for maintaining remission in UC patients.

Methods

A multicenter, randomized, investigator-blinded, 12-month, active-control trial was conducted to assess the noninferiority of delayed-release mesalamine 1.6–2.4 g/day administered once daily compared with twice daily in patients with mild-to-moderate UC currently in clinical remission. The primary end point was maintenance of clinical remission at month 6.

Results

A total of 1023 patients were randomized and dosed. The primary objective of noninferiority was met. At month 6, 90.5% of patients receiving once-daily dosing had maintained clinical remission, compared with 91.8% of patients receiving twice-daily dosing (95% confidence interval for twice daily - once daily, -2.3 to 4.9). At month 12, 85.4% of patients receiving once-daily dosing had maintained clinical remission, compared with 85.4% of patients receiving twice-daily dosing (95% confidence interval for twice daily - once daily, -4.6 to 4.7). Both regimens had low rates of withdrawals as a result of adverse events and serious adverse events.

Conclusions

Once-daily dosing of delayed-release mesalamine at doses of 1.6–2.4 g/day was shown to be as effective as twice-daily dosing for maintenance of clinical remission in patients with UC.

Keywords: Ulcerative Colitis, Mesalamine, Maintenance, Controlled Trial

Abbreviations used in this paper: CI, confidence interval, MARS, Medication Adherence Report Scale, QDIEM, QD Dosing Investigation for Efficacy in UC Maintenance, SAE, serious adverse event, SCCAI, Simple Clinical Colitis Activity Index

Drugs that deliver mesalamine to the gastrointestinal tract as treatment for ulcerative colitis (UC) include sulfasalazine, olsalazine, balsalazide, and mesalamine.¹, ² These drugs historically have been administered in divided doses. The practice of divided dosing began in the 1940s with sulfasalazine³ and was driven by the need to minimize toxicity from sulfapyridine after sulfasalazine was cleaved to mesalamine and sulfapyridine.⁴ Divided dosing administration then was carried over into the clinical trial designs of olsalazine (twice-daily dosing),⁵, ⁶ Asacol (Procter & Gamble Pharmaceuticals, Inc, Mason, OH) (divided or 3 times daily dosing),⁷, ⁸, ⁹ Pentasa (Shire US Inc, Wayne, PA) (4 times daily dosing),¹⁰ and balsalazide (3 times daily dosing).¹¹, ¹² Although the mechanism of action of mesalamine is not understood fully, it appears to be topical rather than systemic. If mesalamine is given without any modifications to its release it is absorbed rapidly from the proximal gastrointestinal tract,¹³ thus with little potential therapeutic benefit. Sulfasalazine, olsalazine, and balsalazide are pro-drugs that release mesalamine in the right colon after rapid cleavage of the azo-bond by colonic bacteria.¹ The first generation of oral mesalamine formulations included the following: Asacol (Eudragit S-coated tablets, which dissolve at pH ≥ 7), which releases mesalamine in the terminal ileum and right colon (delayed-release mesalamine)¹⁴; and Pentasa (ethylcellulose-coated microgranules of mesalamine), which releases mesalamine throughout the gastrointestinal tract (prolonged or controlled-release mesalamine).¹⁵ Eventually divided dosing of these agents was incorporated into clinical practice based on Food and Drug Administration–approved labeling of these agents.

In 2006 D'Haens et al¹⁶ reported the use of an oral mesalamine formulation with the trade name Lialda (United States) and Mezavant or Mezavant XL (outside the United States), which is characterized by both a gastro-resistant coating (which breaks down at pH ≥ 7, normally in the terminal ileum) and a tablet core that contains mesalamine with hydrophilic and lipophilic excipients that is reported to prolong release in the colon.¹⁶ Clinical trials showed that Lialda (Shire Pharmaceuticals Inc, Wayne, PA) (Mezavant) can be administered once daily.¹⁷, ¹⁸, ¹⁹ Another oral mesalamine formulation also was developed with the trade name Apriso (Salofalk Granu-Stix), which is characterized by mesalamine granules that have both a gastric acid–resistant enteric coating (which dissolves at pH ≥ 6) that delays release and has a retarding polymer matrix in the granule core that extends release throughout the colon.²⁰ Clinical trials showed that Apriso can be administered once daily.²¹, ²², ²³ Clinical trials also were performed with Pentasa (ethylcellulose-coated, prolonged, or controlled-release mesalamine), again showing that it can be administered once daily.²⁴, ²⁵

The finding that Lialda (Mezavant), Apriso (Salofalk Granu-Stix), and Pentasa could be administered once daily challenged the conventional understanding of the pharmacokinetics of mesalamine, but potentially was explained by the fact that all 3 formulations were designed to reportedly prolong, extend, or sustain release of mesalamine in the colon. The applicability of these data to a delayed-release mesalamine formulation such as Asacol was uncertain. However, several pharmacokinetic studies and 2 pilot clinical trials raised the possibility that Asacol may be similarly effective when administered once daily.²⁶, ²⁷, ²⁸, ²⁹

Here we present the results of the QD Dosing Investigation for Efficacy in UC Maintenance (QDIEM) trial, a 12-month noninferiority study to determine the efficacy and assess the safety of Asacol 1.6–2.4 g administered once daily compared with Asacol 1.6–2.4 g/day administered as a divided twice-daily dose for maintenance of clinical remission in patients with UC who generally have experienced a mild-to-moderate disease course.

Back to Article Outline

Materials and Methods 

Patients 

This multicenter, randomized, investigator-blinded, active-control trial enrolled patients at 193 sites in the United States, Puerto Rico, and Canada between August 2007 and July 2009. The institutional review board at each site approved the protocol, and all patients gave written informed consent.

The criteria for eligibility were male or female patients 18 years of age or older with a diagnosis of UC maintained in clinical remission for at least 3 months on Asacol at a stable dose ranging from 1.6 to 2.4 g/day. Clinical remission was defined as a Simple Clinical Colitis Activity Index (SCCAI) score of 2 points or fewer. Patients must have experienced at least one flare of UC in the previous 18 months. Patients were excluded from study participation if they had a history of or current renal or hepatic disease or a history of co-existing acute or chronic organic or uncontrolled functional or mental disease. Additional exclusion criteria were a history of allergy or hypersensitivity to salicylates, aminosalicylates, or any component of the Asacol tablet; a history of human immunodeficiency virus infection or acquired immune deficiency syndrome; or a history of alcohol or drug abuse. Patients also were excluded if they had received an oral mesalamine-containing product at a dose greater than 2.4 g/day within the past 3 months, had used rectal mesalamine therapy within 14 days, had taken any corticosteroid (oral, intravenous, intramuscular, or rectal) within the past 90 days, had taken immunosuppressive drugs (including azathioprine, 6-mercaptopurine, methotrexate, cyclosporine) within the past 90 days, had received any antidiarrheal and/or antispasmodic drugs within the previous 1 month, had received aspirin (except for cardioprotective indications up to a maximum dose of 325 mg/day) or other nonsteroidal anti-inflammatory drugs within the past week, had used antibiotics (other than topical antibiotics) within 1 month, had received infliximab, adalimumab, certolizumab pegol, or other biologic treatment within the past 90 days, had participated in any drug or device clinical study within the past 30 days, or had traveled outside the United States and Canada within 2 weeks of the screening visit. Pregnant and/or lactating women were excluded from study participation.

After randomization, patients were prohibited from taking aspirin (for any indication other than cardioprotection, for which the maximum allowed dose was 325 mg/day) or other nonsteroidal anti-inflammatory drugs except for occasional use, other medications containing or metabolized to mesalamine (eg, sulfasalazine, olsalazine, balsalazide), corticosteroids, immunomodulatory agents, metronidazole, antibiotics (other than topical antibiotics) for more than 10 days throughout the study, topical rectal therapies, antidiarrheal and/or antispasmodic medications (except for occasional use), or any investigational or marketed drug that might interfere with the evaluation of the study medication.

Study Design 

Eligible patients were randomized (in a 1:1 ratio) to receive either a once-daily or twice-daily dosing regimen of Asacol (400-mg tablet) at the same total daily dose that the patients were receiving at baseline (1.6 g/day up to 2.4 g/day). The randomization was performed centrally via an interactive voice response system, and treatment allocation was stratified by prior mesalamine dose within a site. An investigator-blinded trial design was used. The patients, who were not blinded, were instructed not to share their dosing regimen treatment assignment with the investigator.

Patient Schedule and Efficacy/Safety Evaluations 

Patients were assessed at screening and months 0 (baseline), 3, 6, 9 (via telephone), and 12. The SCCAI score was used for the assessment of disease severity and efficacy.³⁰ The components of the SCCAI include the following: bowel frequency (during the day), bowel frequency (at night), urgency of defecation, blood in stool, general well being, and extracolonic features (arthritis, pyoderma gangrenosum, erythema nodosum, uveitis) (Supplementary Table 1).³⁰ These clinical assessments were completed by the investigator at screening and at months 0, 3, 6, and 12/exit visit and were based on the patient's recall over the 24 hours before the assessment. Relapse was defined as any SCCAI score of 5 points or higher. Patients who had not relapsed were considered to be in remission.

In addition, at months 6 and 12 patients completed via an interactive voice response system the Patient-Defined Remission Index consisting of one question (“Is your ulcerative colitis in remission?”) to which the patient answered yes or no.³¹ Patient adherence with a once- or twice-daily regimen was assessed by patient completion of the Medication Adherence Report Scale (MARS) (Supplementary Table 2)³² via interactive voice response system at months 0, 3, 6, and 12/exit. The maximum MARS score is 45 points, and higher scores indicate higher levels of reported adherence. Patient satisfaction and preference with a once- or twice-daily regimen were assessed by a Patient Satisfaction and Preference Questionnaire (Supplementary Table 3) via an interactive voice response system at months 0, 6, and 12/exit.

At each visit, serious adverse events (SAEs) and concomitant medications were recorded. Serum creatinine level was assessed at the screening and months 6 and 12/exit visits.

Statistical Analysis 

The primary end point was maintenance of clinical remission at month 6 in the primary efficacy analysis population (the intention-to-treat population for whom disease status [remission or response] at month 6 could be determined and was available for analysis). The intention-to-treat population included all patients who were randomized and took one or more doses of study medication. For patients whose primary efficacy end point could not be calculated because of no or insufficient data the primary efficacy end point was missing and excluded from the primary efficacy analysis. Three sensitivity analyses were performed to assess the robustness of the primary efficacy result: (1) a set-to-failure analysis in which outcome was set to relapse if disease status [remission or relapse] could not be determined; (2) a per-protocol analysis including patients in the intention-to-treat population who had no major protocol deviations; and (3) a last observation carried forward analysis in which the last posttreatment efficacy evaluation was carried forward to month 6. Secondary end points included the following: the time to relapse measured from the first dosing date to diagnosis of relapse; maintenance of clinical remission at months 3 and 12; patient-defined remission at months 6 and 12; MARS assessment at months 3, 6, and 12; and patient satisfaction and preference with treatment regimen at months 6 and 12.

The primary efficacy analysis was designed to assess whether the once-daily dosing regimen was noninferior to the twice-daily dosing regimen for maintenance of clinical remission at month 6. The noninferiority margin was set at 10% with a 1-sided hypothesis test, with an α level of .025 indicating significance. A 2-sided 95% confidence interval for the difference between the twice-daily and the once-daily groups was computed. Noninferiority of the once-daily dosing regimen would be established if the upper boundary of the 95% confidence interval was less than 10%.

It was assumed that the true rate of clinical remission at month 6 would be 70% and that there would be no difference in clinical remission rates between the once-daily and twice-daily dosing regimens. The noninferiority margin was set at 10%. Based on these assumptions, to establish noninferiority for clinical remission at a 2-sided upper confidence interval of 95% with 90% power, 442 patients per treatment group were required to be analyzable for the primary end point. Assuming that approximately 10% of enrolled patients would not be analyzable, we planned to enroll 500 patients per group, for a total of 1000 patients.

Total MARS scores at each visit were analyzed by analysis of variance to examine the regimen effect after adjusting for prior dose. Patient satisfaction at each visit was analyzed using the Cochran–Mantel–Haenszel chi-square test with prior dose as a stratum variable to assess the dosing regimen difference. To assess patient preference at each visit a binomial proportion, exact confidence interval, and exact P value were computed separately for the regimens.

Subgroup analyses were conducted for the primary end point of clinical remission to evaluate the consistency of treatment effects across various patient populations. Predefined subgroup analyses included demographic parameters (age, sex, race, weight, smoking status), prior maintenance regimen, prior dose, disease history (anatomic extent of disease, length of disease history, prior UC medication use, relapse frequency), and baseline disease activity measures (bowel frequency [day], bowel frequency [night], urgency of defecation, blood in stool, general well being, extracolonic features [arthritis, pyoderma gangrenosum, erythema nodosum, uveitis]). For all subgroup analyses the Cochran–Mantel–Haenszel chi-square test was used to determine the overall treatment effect, and the 95% confidence intervals for the treatment difference between the treatment groups also were computed.

Back to Article Outline

Results 

Characteristics and Disposition of Patients 

A total of 1027 patients were randomized to a treatment regimen and 1023 were dosed (512 once daily and 511 twice daily). A summary of patient disposition is provided in Figure 1. The baseline characteristics were similar in the 2 treatment groups (Table 1). At baseline, 28% of patients were receiving 1.6 g/day, 2% of patients were receiving 2.0 g/day, and 70% of patients were receiving 2.4 g/day. In addition, at baseline, 4% of patients were receiving a once-daily dosing regimen, 62% were receiving a twice-daily dosing regimen, 33% were receiving a 3 times daily dosing regimen, and 1.0% were receiving an “other” dosing regimen. Baseline disease activity was similar in the 2 treatment groups with the exception of the extracolonic features component (note that all extracolonic features were arthritis); there were more cases in the once-daily regimen (15%) compared with the twice-daily regimen (10%) (P = .006). Almost 50% of patients had baseline relapse frequency of less than once per year, 22% of patients previously had received corticosteroid therapy, and less than 3% of patients previously had received immunosuppressive or biologic therapy. These baseline clinical characteristics are consistent with a patient population that generally could be described as having mild-to-moderate UC that was in clinical remission at the time of enrollment into the study.

• 
  • View Large Image
  • Download to PowerPoint

• Figure 1. 

  Patient disposition. A total of 1023 patients were randomized to either a once-daily or twice-daily treatment regimen and dosed with delayed-release mesalamine 1.6–2.4 g/day.

Table 1. Baseline Characteristics of Patients with UC in Remission

Efficacy 

The primary objective of noninferiority was met. At month 6, 90.5% (428 of 473) of patients dosed once daily had maintained clinical remission compared with 91.8% (435 of 474) of those dosed twice daily (95% confidence interval [CI] for twice daily - once daily, -2.3 to 4.9) (Figure 2A). The results of the sensitivity analyses confirmed these results with point estimates for the treatment difference between twice daily and once daily, ranging from 1.1 to 1.5, which was very consistent with the 1.3-point estimate observed in the primary analysis (data not shown). Similar to the results at month 6, there were no significant differences between the 2 dosing regimens in the rates of clinical remission at months 3 (treatment difference 0.8 with 95% CI, -1.8 to 3.5) and 12 (treatment difference 0.0 with 95% CI, -4.6 to 4.7) (Figure 2A). Time-to-relapse also was similar between the once-daily and twice-daily dosing regimens at month 6 (hazard ratio, 1.17; 95% CI, 0.76, 1.80) and month 12 (hazard ratio, 1.01; 95% CI, 0.71, 1.42) (Figure 2B and C). There were no significant differences in Patient-Defined Remission between the 2 dosing regimens at month 6 with 83.1% (343 of 413) and 86.6% (356 of 411) of patients dosed once daily and twice daily, respectively (95% CI for twice daily - once daily, -1.3 to 8.5) or at month 12 with 83.4% (286 of 343) and 85.4% (280 of 328) of patients dosed once daily and twice daily, respectively (95% CI for twice daily - once daily, -3.5 to 7.5).

• 
  • View Large Image
  • Download to PowerPoint

• Figure 2. 

  (A) Maintenance of clinical remission at months 3, 6, and 12. The once-daily dosing regimen was noninferior to the twice-daily dosing regimen for the end point of maintaining clinical remission at months 3, 6, and 12. (B) Time to relapse (month 6). At month 6 the time to relapse was 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). At month 12 the time to relapse was similar between the once-daily and twice-daily dosing regimens (hazard ratio, 1.01; 95% CI, 0.71, 1.42).

Based on the MARS questionnaire, medication adherence was high in both treatment groups (Figure 3). There were minor, but statistically significant, differences in MARS questionnaire scores between the once-daily and twice-daily dosing regimens at month 3 (P = .04); differences were not statistically significant at months 6 or 12 (P = .18 and P = .12) (Figure 3). Patients who relapsed had similar MARS questionnaire scores as compared with those who did not relapse (Supplementary Table 4). At month 6, there was no statistically significant difference in patient satisfaction between the once-daily and twice-daily dosing regimens (P = .08); however, at month 12 patients were more satisfied with the once-daily regimen (P = .01) (Table 2). Overall, patients preferred taking medication fewer times a day with twice daily preferred over 3 times daily (P < .0001 and P < .0001), once daily preferred over twice daily (P < .0001 and P < .0001), and once daily preferred over 3 times daily (P < .0001 and P < .0001) at months 6 and 12, respectively.

• 
  • View Large Image
  • Download to PowerPoint

• Figure 3. 

  MARS (months 3, 6, and 12) medication adherence between the once-daily and twice-daily dosing regimens was significantly different at month 3 (P = .04) but not at month 6 (P = .18) or month 12 (P = .12).

Table 2. Patient Satisfaction by Visit

Treatment outcomes at month 6 (primary end point) and month 12 were consistent among subgroups with only one subgroup (baseline trace blood in stool on SCCAI, P = .02 at month 6 and P = .04 at month 12 in favor of the twice-daily regimen) showing a statistically significant difference between regimens (Figure 4A–C, and Supplementary Table 5).

• 
  • View Large Image
  • Download to PowerPoint

• Figure 4. 

  Treatment outcome by subgroups at month 12. The maintenance of clinical remission rate was consistent among most subgroups for the once-daily and twice-daily dosing regimens.

Safety 

The incidence of withdrawals as a result of AEs was slightly higher in the twice-daily group whereas the incidence of SAEs was slightly higher in the once-daily group (Table 3, Table 4). All SAEs were judged by the investigator to be doubtfully related to the study drug with the exception of one patient in the twice-daily group who experienced acute renal failure. Nine patients were withdrawn from the study because of AEs (2 patients [0.4%] in the once-daily group and 7 patients [1.4%] in the twice-daily group). The most common AEs reported as reason for withdrawal were of gastrointestinal nature (3 patients [0.6%] in the twice-daily group). There were 18 patients (3.5%) with SAEs in the once-daily group and 9 patients (1.8%) in the twice-daily group. The only SAEs reported by more than 1 patient were acute renal failure (2 patients in the twice-daily group), cholelithiasis (2 patients in the once-daily group), and appendicitis (2 patients in the once-daily group). One death occurred in the study (myocardial infarction judged to be doubtfully drug related). Overall, there were no significant changes in serum creatinine level in either treatment group.

Table 3. Adverse Events Leading to Withdrawal

MedDRA, Medical Dictionary for Regulatory Activities; N, number of patients within specified treatment; n, number of patients within category and treatment group; %, percentage of patients within category and treatment group: (n/N)*100.

Table 4. Serious Adverse Events

MedDRA, Medical Dictionary for Regulatory Activities; N, number of patients within specified treatment; n, number of patients within category and treatment group; %, percentage of patients within category and treatment group: (n/N)*100.

Back to Article Outline

Discussion 

In this study, delayed-release mesalamine (Asacol) administered once daily at doses of 1.6–2.4 g/day was shown to be as effective as twice-daily dosing for the maintenance of clinical remission in patients with a history of mild-to-moderate UC. Specifically, the trial showed that once-daily dosing is noninferior to twice-daily dosing for the end point of clinical remission. Subgroup analyses showed consistent efficacy for once-daily dosing in a wide range of subgroups. The results also were consistent whether maintenance of remission was measured by either the SCCAI or by the Patient-Defined Remission Index. There were no significant differences in withdrawals owing to AEs or SAEs between the 2 dosing regimens.

Previous studies with Lialda (Mezavant), Apriso (Salofalk Granu-Stix), and Pentasa have shown that mesalamine can be administered once daily.¹⁷, ¹⁸, ¹⁹, ²¹, ²², ²³, ²⁵ Because these 3 mesalamine formulations reportedly prolong, extend, or sustain release throughout the colon, it was speculated that successful once-daily dosing was linked to the characteristics of the delivery systems. In contrast to these 3 formulations, Asacol is a delayed-release formulation that releases mesalamine in the terminal ileum and right colon; however, clinical trials clearly have shown that it is effective in patients regardless of anatomic extent of UC (proctitis, left-sided disease, and pancolitis). The results of our study (a large, prospective, controlled UC study) show that Asacol administered once daily was effective for the maintenance of clinical remission of UC, thus indicating that precise delivery of mesalamine throughout the colon is not required for successful once-daily dosing. A previous pharmacokinetic study in healthy volunteers showed that Lialda administered once daily and Asacol administered once daily had similar pharmacokinetic profiles and that both drugs administered once daily had a different pharmacokinetic profile from Asacol administered 3 times a day.²⁷ The totality of these data suggests that the success of once-daily dosing for all of these compounds may be owing to the pharmacodynamic properties of mesalamine and may not depend on the specific characteristics of the formulation determining drug delivery.

Previous maintenance of remission trials with olsalazine, Asacol, and Pentasa recruited patients with endoscopic remission, and the primary end point was maintenance of endoscopic remission.⁵, ⁶, ⁹, ³³ More recent maintenance trials with Lialda and Apriso used disease activity indexes that included an endoscopic component.¹⁹, ²², ²³ In contrast, the instruments used to assess efficacy in the QDIEM trial did not include endoscopy.³⁰, ³¹ Higgins et al³⁴ have shown that the SCCAI and the Patient-Defined Remission Index have good correlation with the UC Disease Activity Index, suggesting that these clinical instruments are clinically meaningful and can be used as a basis for clinical practice. Another recent study reported that the SCCAI is a valid, reliable, and responsive noninvasive index to assess disease activity in adult patients with UC.³⁵

Nonadherence to medication is associated with an increased risk of relapse in patients with UC.³⁶ Our study showed significant differences in adherence as measured by the MARS questionnaire in favor of the once-daily dosing group at 3 months but not at 6 or 12 months, thus reinforcing the complicated and multifactorial nature of adherence. Patients who relapsed had similar MARS questionnaire scores as those who did not relapse. It should be noted, however, that the adherence rates were very high (MARS questionnaire scores of approximately 42 points out of a possible 45 points at all time points) in both dosing groups. Similar findings were reported with other mesalamine products.¹⁹ However, when patients in our study were asked their preference, they preferred dosing regimens that required taking medication fewer times per day. There are data to show that it is at 3 months when patients diverge, and either remain adherent or stop their maintenance medications.³⁷ It thus would be important in a real-world setting to follow up with patients at this time period to ensure continued adherence.

The patient population recruited in this trial generally could be described as having mild-to-moderate UC that was in clinical remission at the time of enrollment into the study. Almost 50% of patients had a baseline relapse frequency of less than once per year, 22% of patients previously had received corticosteroid therapy, and less than 3% of patients previously had received immunosuppressive or biologic therapy. The results of this study cannot necessarily be generalized to patients receiving maintenance therapy with mesalamine doses greater than 2.4 g/day or to those with more severe UC.

Both dosing regimens of Asacol had low rates of withdrawals as a result of AEs and SAEs. SAEs occurred in 3.5% of patients in the once-daily group and 1.8% of patients in the twice-daily group (difference was not significant). All SAEs were judged by the investigators to be doubtfully related to the study drug with the exception of 1 patient in the twice-daily dosing group who experienced acute renal failure. The only SAEs reported by more than 1 patient were as follows: acute renal failure (2 patients in the twice-daily group), cholelithiasis (2 patients in the once-daily group), and appendicitis (2 patients in the once-daily group). There were no clinically significant changes in serum creatinine level in either treatment group or between the treatment groups. Overall, these findings show a similar safety profile in the once-daily and twice-daily treatment groups.

Once-daily dosing of delayed-release mesalamine (Asacol) at doses of 1.6–2.4 g/day was shown to be as effective as twice-daily dosing for maintenance of clinical remission in patients with UC.

Back to Article Outline

Acknowledgments 

The authors wish to thank the QD Dosing Investigation for Efficacy in UC Maintenance (QDIEM) Investigators who participated in this study, as listed below in alphabetical order: Charles Adelmann (Norwalk, CT), Nisar Ahmed (Houston, TX), Naeem Akhtar (Madera, CA), Robert Albares (Dothan, AL), Stephen Amann (Tupelo, MS), Shirish Amin (Indiana, PA), Leonard Baidoo (Pittsburgh, PA), Arthur Baluyut (Indianapolis, IN), Leslie Bank (Binghamton, NY), Alpha Banks (College Park, MD), Alfonso Barbati (Clairton, PA), Michael Basista (Toledo, OH), Isaac Bassan (North Miami Beach, FL), Clint Behrend (Idaho Falls, ID), Nicholas Bellicini (Pittsburgh, PA), Arthur Berman (Largo, FL), Crystal Bernstein (Seattle, WA), Magued Beshay (Mission Hills, CA), Jitender Bhandari (Bloomington, IN), Sudhir Bhaskar (Orlando, FL), Philip Bowden (Memphis, TN), Jack Bragg (Columbia, MO), Myron Brand (New Haven, CT), Edward Brettholz (New York, NY), Whitney Brooks (Norfolk, VA), Michael Brown (Athen, AL), Paul Brown (Louisville, KY), Mushtaq Bukhari (Morganton, NC), Charles Calabrese (Uniontown, PA), Joseph Cappa (Hartford, CT), Victor Carlo (San Juan, PR), George Catinis (Metairie, LA), Anthony Celifarco (Lake Success, NY), Maurice Cerulli (Brooklyn, NY), Shekhar Challa (Topeka, KS), Tawfik Chami (Zephyrhills, FL), Adam Cheifetz (Boston, MA), Naoki Chiba (Guelph, ON, Canada), Mihnea Chiorean (Indianapolis, IN), Allan Coates (Wyoming, MI), Albert Cohen (Montreal, QC), James Corkum (Reisterstown, MD), Dale Coy (Lake Barrington, IL), Israel Crespo (Trinity, FL), John Dalena (Cedar Knolls, NJ), Chrystian Dallaire (Quebec, QC, Canada), Yvette David (Mission Hills, CA), Carleton Davis (Monroe, WI), Glenn Davis (Little Rock, AR), Fadi Deeb (Wichita, KS), Rajiv Dhingra (New Port Richey, FL), James Dimitroff (St. Louis, MO), James DiSario (Monterey, CA), Gerald Dryden (Louisville, KY), Ben Echols (Houston, TX), Craig Ennis (Orange, CA), William Essilfie (Long Beach, CA), William Eubanks (Tampa, FL), Peter Eweje (Jacksonville, NC), Abraham Fallah (Homewood, IL), Steven Fein (Pasadena, TX), Bernard Feldman (Clive, IA), Nelson Ferreira (Hagerstown, MD), Brian First (San Diego, CA), David Flavin (Somersworth, NH), Ronald Fogel (Chesterfield, MI), Keith Friedenberg (Mentor, OH), William Futch (Newbern, NC), Burnett Gallman (Columbia, SC), Franco Gallo (Port Jefferson Station, NY), Subhas Ganguli (Hamilton, ON, Canada), David Gatof (Lafayette, CO), Howard Gogel (Albuquerque, NM), Richard Golding (Hackensack, NJ), Jeffrey Goldstein (Rochester, NY), Michael Goldstein (Great Neck, NY), Glenn Gordon (Mexico, MO), Bruce Greenberg (Arlington Heights, IL), Eugene Greenberg (Urbana, IL), Suryakanth Gurudu (Scottsdale, AZ), Howard Guss (Ocean, NJ), Alexandra Gutierrez (Birmingham, AL), Kumar Gutta (Fort Worth, TX), Flavio Habal (Toronto, ON, Canada), Howard Hamat (Houston, TX), Stephen Hanauer (Chicago, IL), Richard Hansen (Golden, CO), Robert Hardi (Chevy Chase, MD), Raouf Hilal (Maitland, FL), William Holderman (Tacoma, WA), Ken Holt (Torrance, CA), John Hong (Murrieta, CA), CT Hung (Upland, CA), Michael Ibach (Jackson, TN), Ike Ibegbu (Kinston, NC), Gilles Jobin (Montreal, QC, Canada), Jerry Jones (Charlotte, NC), Ronald Joseph (Salt Lake City, UT), Thomas Judge (Camden, NJ), Mirza Kajani (Newnan, GA), Rokay Kamyar (La Mesa, CA), Carl Kanun (Tucson, AZ), Robert Kaplan (Greensboro, NC), Steven Kaster (Wenatchee, WA), Mustafa Kathawala (Bismarck, ND), Seymour Katz (Great Neck, NY), Barry Kaufman (Egg Harbor Township, NJ), Michael Kestell (Spokane, WA), Noor Khaiser (Peoria, IL), Sardar Khan (Houston, TX), Richard Kim (Sewickley, PA), Chung Kim (Pittsford, NY), Joshua Korzenik (Boston, MA), Tarun Kothari (Rochester, NY), Ravindranath Kottoor (Jacksonville, FL), Louis Kouo (Cape Girardeau, MO), George Koval (Portland, OR), Piyush Kumar (Encinitas, CA), Mark Lamet (Hollywood, FL), Bret Lashner (Cleveland, OH), Thomas Lee (Elgin, IL), Leonard Leichus (Tallahassee, FL), Bernard Leman (Clive, IA), Scott Levenson (San Carlos, CA), Michael LeVine (Marietta, GA), Simon Lichtiger (New York, NY), Mark Lijewski (Greer, SC), Robert Lindenberg (Torrington, CT), Neil Lobo (Babylon, NY), Thomas Loludice (Akron, OH), John Lowe (Ogden, UT), Joseph Lowney (Warwick, RI), Ramesh Luther (Cheektowaga, NY), William Lyles (Alexandria, LA), Uma Mahadevan (San Francisco, CA), Pramod Malik (Chesapeake, VA), Robert Manning (Pueblo, CO), Siva Maran (Morristown, TN), Stefano Marcuard (Greenville, NC), James Marion (New York, NY), Michael Mastrangelo (Wilmington, NC), Elizabeth May (Detroit, MI), Paul McRae (St Petersburg, FL), Peter Miller (Birmingham, AL), Douglas Miller (Meriden, CT), Perry Milman (Lake Success, NY), Kenneth Mirkin (Fairfax, VA), Morry Moskovitz (Beaver Falls, PA), Sam Moskowitz (Brooklyn, NY), Sam Moussa (Tucson, AZ), Sivakumar Munnangi (Merced, CA), Tobin Naidorf (Alexandria, VA), Partha Nandi (Troy, MI), Frank Nemec (Las Vegas, NV), Jacque Noel (Lafayette, LA), Thomas Nowak (Anderson, IN), Frederick Nunes (Philadelphia, PA), David Oelsner (West Valley City, UT), Terry Ortego (Lowell, AR), Pierre Pare (Quebec, QC, Canada), Nimisha Parekh (Orange, CA), Mehul Patel (Indianapolis, IN), Devang Patel (South Plainfield, NJ), Pankaj Patel (South Bend, IN), Ramanbhai Patel (Lancaster, CA), Teressa Patrick (Dayton, OH), Stephen Pearce (Chico, CA), Allan Peck (Cincinnati, OH), Jack Peicher (Fort Lauderdale, FL), Glenn Pfitzner (Mt. Airy, NC), Raymond Phillips (Naples, FL), Henryk Pluta (Abbotsford, BC, Canada), Arthur Poch (Shreveport, LA), Vijayalakshmi Pratha (San Diego, CA), Jeffrey Pressman (San Diego, CA), Nazir Rahim (Folsom, CA), Bal Raj Bhandari (Monroe, LA), Charles Randall (San Antonio, TX), Rawel Randhawa (Phoenix, AZ), Udipi Rao (Odessa, TX), Prakash U Rau (Braintree, MA), Donald Rauh (Bowling Green, KY), Suresh Reddy (Waterloo, IA), Alvaro Reymunde (Ponce, PR), Donato Ricci (Port Orange, FL), Dean Rider (San Francisco, CA), Dennis Riff (Anaheim, CA), Elizabeth Rock (Phoenixville, PA), Richard Roman (Englewood, CO), Allen Rosenbaum (Berwyn, IL), Andrew Rosenberg (Garden City, NY), Fred Rosenberg (Highland Park, IL), Soraya Ross (Beverly Hills, CA), Michael Safdi (Cincinnati, OH), Fred Saibil (Toronto, ON, Canada), William Sandborn (Rochester, MN), Barry Sanders (Lewisville, TX), Raymond Sandler (Aventura, FL), Sheldon Scheinert (St. Petersburg, FL), Ronald Schwarz (Raleigh, NC), Richard Sears (Winchester, VA), Fayez Seif (Greenville, TX), Ira Shafran (Winter Park, FL), Gaurang Shah (Jacksonville, FL), Mushtaq Shah (Greenbelt, MD), Umedchandra Shah (Hollywood, MD), Bradley Shapiro (Hoffman Estates, IL), Tarun Sharma (Kalamazoo, MI), Aasim Sheikh (Marietta, GA), Roland Shepard (Tampa, FL), Alex Sherman (New York, NY), Bavikatte Shivakumar (Davenport, IA), Vasanth Siddalingaiah (Milwaukee, WI), Ann Silverman (West Bloomfield, MI), Timothy Simmons (Los Angeles, CA), Rolando Sineneng (Dayton, OH), Shayne Skarda (Longview, TX), Duane Smoot (Washington, DC), Charles Sninsky (Gainesville, FL), Bob Souder (Jackson, TN), John Stagias (Southbridge, MA), William Steinberg (Rockville, MD), Michael Steinbook (Columbus, GA), William Stern (Rockville, MD), Mark Stern (Decatur, GA), Scott Stern (Bangor, ME), David Stockwell (Virginia Beach, VA), Neil Stollman (Oakland, CA), James Strohecker (Columbia, SC), Daniel Suiter (Pratt, KS), Thomas Swantkowski (Pinehurst, NC), Richmond Sy (Ottawa, ON, Canada), Biswarup Syam (Cortland, NY), Mousab Tabbaa (Westlake, OH), Ike Tanabe (Boise, ID), Harvey Tatum (Tulsa, OK), Jawahar Taunk (Palm Harbor, FL), Abdul Thannoun (Amarillo, TX), James Thornton (Souderton, PA), Douglas Trate (Boone, NC), Michael Ufberg (Allentown, PA), Michael Van Ness (Canton, OH), Rajeer Vasudeva (Columbia, SC), Ravikumar Vemuru (Odessa, TX), Subramanian Venkataraman (Oak Lawn, IL), Bruce Waldholtz (Chesapeake, VA), Joseph Wang (Jefferson City, MO), Frederick Weber (Savannah, GA), Joseph Webster (Tallahassee, FL), Zelman Weingarten (Los Angeles, CA), Michael Weisberg (Plano, TX), Dale Whitebloom (Lancaster, PA), Douglas Wolf (Atlanta, GA), Robert Yin (Lutherville, MD), Homan Zadeh (Palm Springs, CA), and Oren Zaidel (Torrance, CA).

Editorial and writing support were provided by Judith M. Pepin, Terri Gaffney, and Christi A. Messer, employees of Procter & Gamble Pharmaceuticals.

The QDIEM Steering Committee of academic investigators (William Sandborn, Joshua Korzenik, Bret Lashner, Jonathan Leighton, Uma Mahadevan, James Marion, Michael Safdi, Charles Sninsky, and Sunanda Kane) were involved in the design and execution of the study, interpretation of the results, and drafting and final approval of the manuscript; Raman Patel and Keith Friedenberg were involved in the execution of the study, interpretation of the results, and drafting and final approval of the manuscript; Procter & Gamble scientists (Preston Dunnmon and David Ramsey) were involved with the conception and design of the study, assembly, analysis, and interpretation of data, and drafting and final approval of the manuscript; data were collected by Procter & Gamble Pharmaceuticals and a clinical research organization, and analyzed by Procter & Gamble Pharmaceuticals; William Sandborn wrote the first draft of the manuscript and the QDIEM Steering Committee made the decision to publish; the authors had full access to and vouch for the veracity and completeness of the data and data analyses.

Back to Article Outline

Supplementary material 

Supplementary Table 1. SCCAI

Data from Walmsley et al,³⁰ and Jowett et al (“Defining relapse of ulcerative colitis using a symptom-based activity index.” Scand J Gastroenterol 2003;38:164–171)

NOTE. There is a possible maximum score of 19. A score of 5 or more defines relapse/flare with 92% sensitivity, 91% specificity, 85% positive predictive value, and 89% negative predictive value.

Supplementary Table 2. MARS Questionnaire

MARS questionnaire modified with approval from Horne and Weinman.³²

aReverse scored.

Supplementary Table 3. Patient Satisfaction and Preference Questionnaire

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

N, number of patients in given categories; n, number of patients in given categories with nonmissing MARS scores; SE, standard error of mean.

aP value from relapse yes vs no comparison using analysis of variance with prior dose category as factor.

bDifference in least square mean.

c95% CI for the difference in relapse with prior dose category as stratification.

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

n (%), number and percentage (n/total × 100) of patients in treatment with specified outcome.

aQD compared with BID using the chi-square test.

bRisk difference between QD and BID.

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

Back to Article Outline

References 

1. Sandborn WJ, Hanauer SB. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment Pharmacol Ther. 2003;17:29–42
   • View In Article
   • MEDLINE
   • CrossRef
2. Sandborn WJ. Oral 5-ASA therapy in ulcerative colitis: what are the implications of the new formulations?. J Clin Gastroenterol. 2008;42:338–344
   • View In Article
   • CrossRef
3. Svartz N. Salazopyrin, a new sulfanilamide preparation. Acta Med Scand. 1942;110:577–598
   • View In Article
   • CrossRef
4. Das KM, Eastwood MA, McManus JP, et al. Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med. 1973;289:491–495
   • View In Article
   • MEDLINE
   • CrossRef
5. Sandberg-Gertzen H, Jarnerot G, Kraaz W. Azodisal sodium in the treatment of ulcerative colitis (A study of tolerance and relapse-prevention properties). Gastroenterology. 1986;90:1024–1030
   • View In Article
   • Abstract
   • Full-Text PDF (918 KB)
6. Ireland A, Mason CH, Jewell DP. Controlled trial comparing olsalazine and sulphasalazine for the maintenance treatment of ulcerative colitis. Gut. 1988;29:835–837
   • View In Article
   • MEDLINE
   • CrossRef
7. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis (A randomized study). N Engl J Med. 1987;317:1625–1629
   • View In Article
   • MEDLINE
   • CrossRef
8. Sninsky CA, Cort DH, Shanahan F, et al. Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis (A multicenter study). Ann Intern Med. 1991;115:350–355
   • View In Article
   • MEDLINE
9. The Mesalamine Study Group. An oral preparation of mesalamine as long-term maintenance therapy for ulcerative colitis (A randomized, placebo-controlled trial). Ann Intern Med. 1996;124:204–211
   • View In Article
   • MEDLINE
10. Hanauer S, Schwartz J, Robinson M, et al. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial (Pentasa Study Group). Am J Gastroenterol. 1993;88:1188–1197
    • View In Article
    • MEDLINE
11. Green JR, Lobo AJ, Holdsworth CD, et al. Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis (The Abacus Investigator Group). Gastroenterology. 1998;114:15–22
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (1879 KB)
    • CrossRef
12. 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
    • View In Article
    • MEDLINE
    • CrossRef
13. Myers B, Evans DN, Rhodes J, et al. Metabolism and urinary excretion of 5-amino salicylic acid in healthy volunteers when given intravenously or released for absorption at different sites in the gastrointestinal tract. Gut. 1987;28:196–200
    • View In Article
    • MEDLINE
    • CrossRef
14. Dew MJ, Hughes PJ, Lee MG, et al. An oral preparation to release drugs in the human colon. Br J Clin Pharmacol. 1982;14:405–408
    • View In Article
    • MEDLINE
15. Rasmussen SN, Bondesen S, Hvidberg EF, et al. 5-aminosalicylic acid in a slow-release preparation: bioavailability, plasma level, and excretion in humans. Gastroenterology. 1982;83:1062–1070
    • View In Article
    • Abstract
16. D'Haens G, Hommes D, Engels L, et al. Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a phase II, dose-ranging study. Aliment Pharmacol Ther. 2006;24:1087–1097
    • View In Article
    • MEDLINE
    • CrossRef
17. Kamm MA, Sandborn WJ, Gassull M, et al. Once-daily high concentration MMX mesalamine in active ulcerative colitis. Gastroenterology. 2007;132:66–75
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (314 KB)
    • CrossRef
18. Lichtenstein GR, Kamm MA, Boddu P, et al. Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol. 2007;5:95–102
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (487 KB)
    • CrossRef
19. Kamm MA, Lichtenstein GR, Sandborn WJ, et al. Randomized trial of once- or twice-daily MMX™ mesalazine for maintenance of remission in ulcerative colitis. Gut. 2008;57:893–902
    • View In Article
    • CrossRef
20. Brunner M, Greinwald R, Kletter K, et al. Gastrointestinal transit and release of 5-aminosalicylic acid from 153Sm-labelled mesalazine pellets vs. tablets in male healthy volunteers. Aliment Pharmacol Ther. 2003;17:1163–1169
    • View In Article
    • MEDLINE
    • CrossRef
21. Kruis W, Kiudelis G, Racz I, et al. Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial. Gut. 2009;58:233–240
    • View In Article
    • CrossRef
22. Kruis W, Jonaitis L, Pokrotnieks J, et al. Once daily 3 g mesalamine is the optimal dose for maintaining clinical remission in ulcerative colitis: a double-blind, double-dummy, randomized, controlled, dose-ranging study. Gastroenterology. 2008;134(Suppl 1):A489
    • View In Article
23. Prescribing information for Apriso (extended release mesalamine). Morrisville, NC: Salix Pharmaceuticals, Inc; 2009;
    • View In Article
24. Gandia P, Idier I, Houin G. Is once-daily mesalazine equivalent to the currently used twice-daily regimen? (A study performed in 30 healthy volunteers). J Clin Pharmacol. 2007;47:334–342
    • View In Article
    • MEDLINE
    • CrossRef
25. Dignass AU, Bokemeyer B, Adamek H, et al. Mesalamine once daily is more effective than twice daily in patients with quiescent ulcerative colitis. Clin Gastroenterol Hepatol. 2009;7:762–769
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (594 KB)
    • CrossRef
26. Hussain FN, Ajjan RA, Kapur K, et al. Once versus divided daily dosing with delayed-release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters. Aliment Pharmacol Ther. 2001;15:53–62
    • View In Article
    • MEDLINE
    • CrossRef
27. Sandborn WJ, Balan G, Kuzmak B, et al. Comparable pharmacokinetics (PK) of two delayed release formulations of oral mesalamine. Am J Gastroenterol. 2007;102:S465
    • View In Article
28. Kane S, Huo D, Magnanti K. A pilot feasibility study of once daily dosing versus conventional dosing mesalamine for maintenance of ulcerative colitis. Clin Gastroenterol Hepatol. 2003;1:170–173
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (70 KB)
    • CrossRef
29. Kane S, Holderman W, Jacques P, et al. Once daily versus conventional dosing of pH-dependent mesalamine long-term to maintain quiescent ulcerative colitis: preliminary results from a randomized trial. Patient Prefer Adherence. 2008;2:253–258
    • View In Article
30. Walmsley RS, Ayres RC, Pounder RE, et al. A simple clinical colitis activity index. Gut. 1998;43:29–32
    • View In Article
    • MEDLINE
    • CrossRef
31. Higgins PDR, Schwartz M, Mapili J, et al. Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis. Gut. 2005;54:782–788
    • View In Article
    • MEDLINE
    • CrossRef
32. Horne R, Weinman J. Self-regulation and self-management in asthma: exploring the role of illness perceptions and treatment beliefs in explaining non-adherence to preventer medication. Psychol Health. 2002;17:17–32
    • View In Article
    • CrossRef
33. Miner P, Hanauer S, Robinson M, et al. Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis (Pentasa UC Maintenance Study Group). Dig Dis Sci. 1995;40:296–304
    • View In Article
    • MEDLINE
    • CrossRef
34. Higgins PD, Schwartz M, Mapili J, et al. Is endoscopy necessary for the measurement of disease activity in ulcerative colitis?. Am J Gastroenterol. 2005;100:355–361
    • View In Article
    • MEDLINE
    • CrossRef
35. Turner D, Seow CH, Greenberg GR, et al. A systematic prospective comparison of non-invasive disease activity indices in ulcerative colitis. Clin Gastroenterol Hepatol. 2009;7:1081–1088
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (306 KB)
    • CrossRef
36. Kane S, Huo D, Aikens J, et al. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med. 2003;114:39–43
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (112 KB)
    • CrossRef
37. Kane SV, Accortt NA, Magowan S, et al. Predictors of persistence with 5-aminosalicylic acid therapy for ulcerative colitis. Aliment Pharmacol Ther. 2009;29:855–862
    • View In Article
    • CrossRef