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INTRODUCTION
Many placebo-controlled studies12345 have been conducted to investigate the efficacy of mesalazine for the maintenance of remission in UC. However, only a small number of studies has directly compared the efficacy between different formulations. According to a Cochrane report, there are no differences in the efficacy or safety between the various formulations of oral 5-aminosalicylic acid (5-ASA; mesalazine) in the maintenance of remission in UC.5
Multimatrix mesalazine (Lialda® in the United States; Mezavant™ XL in the United Kingdom, Ireland, and Malta; Mezavant™ elsewhere in the European Union) is approved in Europe and the United States for once-daily (QD) use in the induction and maintenance of remission of mild-to-moderate UC. The approved dose for the maintenance of remission is 2.4 g/day QD, which is taken as 2 tablets per day. The efficacy of multimatrix mesalazine 2.4 g/day QD for maintenance of remission in UC was previously confirmed in 2 active-controlled studies. One study was conducted with Asacol 1.6 g/day twice-daily used as the comparator, and the primary endpoint was set as endoscopic remission (defined as a modified UC-Disease Activity Index (UC-DAI) endoscopic score of ≤1) after 6 months of treatment.6 Asacol 1.6 g/day was the approved dose for the maintenance of remission of UC in the United States. The second study was conducted in patients with left-sided UC, with Asacol 2.4 g/day twice daily used the comparator. The co-primary endpoints were clinical remission (defined as a UC-DAI score of ≤1) and clinical and endoscopic remission (endoscopic remission defined as a normal appearance upon endoscopic examination) after 12 months of treatment.7
This study investigated the efficacy and safety of 48 weeks of treatment with multimatrix mesalazine 2.4 g/day (Multimatrix-2.4 g/day) QD in patients with UC in remission, in comparison with time-dependent (controlled-release) mesalazine 2.25 g/day (Time-2.25 g/day) 3 times-daily (TID) as the comparator.
METHODS
1. Patients
Eligible outpatients for the study fulfilled the following criteria: diagnosis of UC; age ≥16 years at the time of informed consent; UC in remission, as defined by a UC-DAI score ≤2 at randomization enrollment; and a rectal bleeding score of 0. UC-DAI is a disease activity index of UC that consists of 4 variables: stool frequency, rectal bleeding, sigmoidoscopic findings of mucosal appearance, and physician's global assessment. Each variable is evaluated on a 4-point scoring scale from 0 to 3, and the evaluation index is the total of the 4 scores (Table 1).8 Patients were excluded from the study for the following reasons: history of hypersensitivity to mesalazine and salicylic acid preparations; use of adrenal corticosteroids (oral, enema, suppository, medication for hemorrhoidal diseases, or injection) or cytapheresis therapy in the 2 weeks before randomization enrollment; received immune-regulating drug (oral, injection) or antitumor necrosis factor-α antibody in the 12 weeks before randomization enrollment; previous colonic resection (excluding appendectomy); moderate-to-severe renal or liver disorders; serious complications, including diseases of the blood, respiratory, gastrointestinal, or cardiovascular organs; diseases of the neuropsychiatric system; metabolic/electrolyte imbalance or hypersensitivity; or malignant tumor. The following groups were also excluded from the study: female patients who were pregnant, breastfeeding, possibly pregnant, or planning to get pregnant during the study period; and patients who had used other investigational products within the 4 months prior to enrollment into this study.
2. Study Drugs
Multimatrix mesalazine tablets (Lialda®; Shire US Inc., Wayne, PA, USA) were red-brown, oval, film-coated tablets that contained 1.2 g of mesalazine per tablet. The comparator, controlled-release mesalazine tablets (Pentasa®; Kyorin Pharmaceutical Co. Ltd., Tokyo, Japan), were white to paleyellow uncoated tablets with grayish-white to pale grayish-yellow maculae that contained 250 mg of mesalazine per tablet. The study adopted a double-dummy trial design. The drug compliance for each study drug was measured based on the patient diary.
3. Study Design
This was a multicenter, randomized, double-blind, activecontrolled, parallel-group study with a 48-week treatment period that was conducted at 46 study centers in Japan from January 2011 to August 2012 (Japan Pharmaceutical Information Center clinical trial registration number: JapicCTI-101381). After informed consent was obtained, patient eligibility was evaluated based on the inclusion/exclusion criteria, and the study drug was administered to eligible patients. Patients were randomized to 1 of the 2 groups in a 1:1 ratio by the permuted block method, with each study center as 1 block. The 2 groups that received the study drugs were as follows: the Multimatrix-2.4 g/day group and the Time-2.25 g/day group, and a double-dummy design was adopted to maintain blinding of the investigators and study participants. The Multimatrix-2.4 g/day group received 2 tablets of multimatrix mesalazine 1.2 g after breakfast QD and 3 tablets of controlled-release mesalazine placebo after each meal TID. The Time-2.25 g/day group received 2 tablets of multimatrix mesalazine placebo after breakfast QD and 3 tablets of controlled-release mesalazine 250 mg after each meal TID.
4. Efficacy and Safety Evaluation
During the study, patients were required to visit the study center every 4 weeks or at the time of discontinuation. At each visit, efficacy and safety were evaluated by the investigator. The mean scores of daily stool frequency and rectal bleeding were calculated for 3 days before each visit, based on the patient diary in which patients recorded stool frequency and rectal bleeding status. Colonoscopy was performed at the start of the treatment period and at week 48 or at the time of discontinuation, and the sigmoidoscopy score was evaluated by the same investigator with reference to the atlas of mucosal appearance. Each patient received an overall evaluation based on the clinical symptoms and endoscopic findings at the start of the treatment period and at week 48 or at the time of discontinuation, and the physician's global assessment score was evaluated.
Adverse events (AEs) were evaluated at each visit. Vital signs, body weight, and clinical laboratory tests were evaluated every 12 weeks or at the time of discontinuation. Clinical laboratory tests were also evaluated at week 4. AEs were summarized by preferred terms of the Medical Dictionary for Regulatory Activities version 15.0 (http://www.meddra.org/).
5. Objective/Endpoints
The primary objective of the efficacy evaluation was to verify the noninferiority of Multimatrix-2.4 g/day QD to Time-2.25 g/day TID based on the primary efficacy endpoint, which was defined as the proportion of patients without rectal bleeding (rectal bleeding score of 0) during the treatment period. The primary objective of safety was to evaluate the treatment with Multimatrix-2.4 g/day QD and Time-2.25 g/day TID in relation to AEs during the treatment period.
The secondary efficacy endpoints were: the duration of nonoccurrence of rectal bleeding (time to rectal bleeding score of ≥1 during the treatment period); relapse (UC-DAI score ≥3 and rectal bleeding score ≥1 at the end of the treatment period); change in the UC-DAI score (UC-DAI score at the end of the treatment period − UC-DAI score at baseline); and the change in each variable of the UC-DAI (score at the end of the treatment period − score at baseline). The secondary safety endpoints were AEs (screening period, follow-up period) and adverse drug reactions (treatment period, follow-up period).
6. Statistical Analysis
The full analysis set (FAS) consisted of enrolled patients who received the study drug at least once and received a minimum of 1 efficacy evaluation. The per protocol set (PPS) was the primary analysis set for the efficacy analysis, which consisted of patients in the FAS that received an evaluation to ascertain the presence/absence of rectal bleeding after the start of the treatment period, satisfied the inclusion criteria and did not meet any exclusion criteria, did not receive prohibited concomitant drugs or therapies, and had a drug compliance of ≥75%. The safety analysis set consisted of patients that received the study drug at least once and received a safety assessment.
The primary analysis for the efficacy was calculated from the proportion of patients without rectal bleeding (rectal bleeding score of 0 during the treatment period) and the two-sided 95% CI of the difference between the treatment groups. The noninferiority margin (Δ) was set at −10%.
The secondary endpoint was calculated from the hazard ratio of the time to occurrence of rectal bleeding for the Multimatrix-2.4 g/day group compared with the Time-2.25 g/day group and the two-sided 95% CI were calculated. The proportion of patients with relapse and two-sided 95% CI of the difference between treatment groups was calculated. The summary statistics of change in UC-DAI total score and individual variables were calculated. Subgroup analyses were carried out to support the primary endpoint. For the safety endpoint, the incidence of AEs was compared between the treatment groups.
The statistical analysis program SAS version 9.2 (SAS Institute, Cary, NC, USA) was used for calculations. With the assumption that the proportion of patients without rectal bleeding was 77% in Multimatrix-2.4 g/day group and 69% in Time-2.25 g/day group, we set the number of patients required to demonstrate the noninferiority to 95 patients per group at a one-sided type 1 error (α) of 2.5%, 80% power, and Δ=−10%.
7. Ethical Considerations
The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki, the Ministerial Ordinance on Good Clinical Practice for Drugs, and other relevant laws, regulations, and standards. Written informed consent was obtained from each patient. Prior to commencement of the study, the study protocol, a sample case report form, the patient information sheet, and informed consent form were approved by the Institutional Review Board at each study center; the appropriateness of the conduct of the clinical trial was also approved.
Results
1. Patient Disposition and Baseline Characteristics
Consent was obtained from 220 patients. Seventeen patients withdrew before randomization and 203 received the study drugs (Multimatrix-2.4 g/day group, 100; Time-2.25 g/day group, 103). Of the 203 patients who received the study drugs, 165 patients completed the treatment of the study drugs and 38 patients (Multimatrix-2.4 g/day group, 17; Time-2.25 g/day group, 21) discontinued the study drugs during the treatment period (Fig. 1). In all treatment groups, the main reason for discontinuation was AEs, which included the aggravation of UC (Multimatrix-2.4 g/day group, 12; Time-2.25 g/day group, 11). The disposition of FAS and PPS is shown in Fig. 1. No patients were excluded from the FAS. Four patients were excluded from the PPS (Multimatrix-2.4 g/day group, 1; Time-2.25 g/day group, 3). The reasons for exclusion from the PPS were use of a prohibited concomitant drug, failing the inclusion criteria, and drug compliance of <75%. The mean rate of drug compliance in all analysis sets was not less than 95% in both treatment groups. There were no intergroup differences in patient background factors in the FAS (Table 2).
2. Efficacy
1) Primary Endpoint
In the PPS, the proportion of patients without rectal bleeding, the primary endpoint, was 84.8% (84/99) in the Multimatrix-2.4 g/day group and 78.0% (78/100) in the Time-2.25 g/day group (Fig. 2). The difference between the 2 groups was 6.8% (two-sided 95% CI, −3.9% to 17.6%). The lower limit of the two-sided 95% CI of the intergroup difference exceeded the noninferiority margin (−10%), thus demonstrating the noninferiority of Multimatrix-2.4 g/day QD to Time-2.25 g/day TID. In the FAS, the proportion of patients without rectal bleeding was 85.0% (85/100) in the Multimatrix-2.4 g/day group and 78.6% (81/103) in the Time-2.25 g/day group. The difference between the Multimatrix-2.4 g/day group and the Time-2.25 g/day group was 6.4% (two-sided 95% CI, −4.2% to 16.9%), which was comparable to the results from the PPS.
2) Secondary Endpoints
Fig. 3 shows the Kaplan-Meier plot for the duration of the nonoccurrence of rectal bleeding. Cox regression analysis was performed for the duration of the nonoccurrence of rectal bleeding and the result showed that the hazard ratio of occurrence of rectal bleeding in the Multimatrix-2.4 g/day group compared with the Time-2.25 g/day group was 0.677 (two-sided 95% CI, 0.351–1.305). The risk of rectal bleeding occurring in the Multimatrix-2.4 g/day group decreased by 32.3% in comparison with that of the Time-2.25 g/day group. The relapse rate at the end of treatment was 13.1% (13/99) in the Multimatrix-2.4 g/day group and 18.0% (18/100) in the Time-2.25 g/day group (Fig. 4). Table 3 shows the change in the UC-DAI score (mean±SD) at the end of treatment and the change in each subscore of the UC-DAI (mean±SD). The results for secondary endpoints supported the results for the primary endpoint.
3) Subgroup Analyses
With regard to the main UC categories (classification by disease course, extent of disease, and UC-DAI score at baseline), the Multimatrix-2.4 g/day group showed consistent efficacy in all patient subgroups (Table 4).
3. Safety
The incidence of AEs during the treatment period was 82.0% (82/100) in the Multimatrix-2.4 g/day group and 85.4% (88/103) in the Time-2.25 g/day group (Table 5). The incidence of adverse drug reactions (side effects) during the treatment period was 17.0% (17/100) in the Multimatrix-2.4 g/day group and 25.2% (26/103) in the Time-2.25 g/day group. The frequency, type, and time to onset of AEs and adverse drug reactions during the treatment period in each treatment group were comparable. In the Multimatrix-2.4 g/day group, there was no increase in the incidence of AEs nor adverse drug reactions correlated with the length of the treatment period. There were no deaths. The following serious AEs occurred during the treatment period: cervix carcinoma (1 patient) and aggravation of UC (1 patient) in the Multimatrix-2.4 g/day group, and ovarian cyst (1 patient) in the Time-2.25 g/day group. No causal relationship was found with the study drugs.
DISCUSSION
The efficacy of QD dosing compared with that of multiple dosing of the same formulation of mesalazine has been investigated in several previous studies. A double-blind, double-dummy study of controlled-release mesalazine demonstrated the noninferiority of QD to TID after 52 weeks of administration at the dose of 1.5 g/day to 2.25 g/day.9 Another randomized, single-blind, phase III study of pH-dependent delayed-release mesalazine 1.6 g/day to 2.4 g/day showed that QD dosing was noninferior to twice-daily dosing in the maintenance of clinical remission for 6 months.10 A randomized, single-blind, phase III study of controlled-release mesalazine reported that the proportion of patients that maintained remission after 12 months of treatment with QD dosing was significantly higher than in the twice-daily dosing group.11 The present study demonstrated that the efficacy of multimatrix mesalazine 2.4 g/day QD in the maintenance of the absence of rectal bleeding was noninferior to that of multiple-dose formulation of mesalazine, Time-2.25 g/day TID, with a comparable safety profile. This is aligned with the European Crohn's and Colitis Organisation consensus that once-daily administration of 5-ASA is at least as effective as twice- or 3 times-daily administration, with no increased side effects, in the maintenance of remission of UC.12
This study adopted rectal bleeding as the primary endpoint, and the proportion of patients who maintained a rectal bleeding score of 0 for 48 weeks was 84.8% in the Multimatrix-2.4 g/day group and 78.0% in the Time-2.25 g/day group. Similar results were obtained in a previous noninferiority study of pH-dependent delayed-release mesalazine 2.4 g/day TID, which also assessed rectal bleeding as the primary endpoint compared with controlled-release mesalazine 2.25 g/day TID.13 The proportion of patients without rectal bleeding for 48 weeks was 76.9% in the pH-dependent delayed-release mesalazine 2.4 g/day TID group and 69.2% in the controlled-release mesalazine 2.25 g/day TID group. In another phase IIIb/IV open-label study of multimatrix mesalazine (the MOMENTUM trial), rectal bleeding was also investigated as one of the secondary endpoints during maintenance treatment with multimatrix mesalazine 2.4 g/day.14 The proportion of patients who maintained a rectal bleeding score of 0 for 12 months was 65.4% in patients with complete remission (modified UC-DAI score ≤1 with a score of 0 for both rectal bleeding and stool frequency, and ≥1-point reduction in endoscopy score from baseline) after induction treatment with multimatrix mesalazine 4.8 g/day for 8 weeks.
The results for the secondary endpoints (duration of nonoccurrence of rectal bleeding, relapse, change in the UC-DAI score, and change in the UC-DAI subscores) supported the results of the primary endpoint. In the subgroup analysis, Multimatrix-2.4 g/day QD demonstrated consistent efficacy results regardless of disease type, extent of lesion, and baseline UC-DAI score. The safety was comparable between the 2 treatment groups.
Since this study adopted a double-dummy design, the compliance with both multimatrix mesalazine tablets and controlled-release mesalazine tablets was measured in all patients. In this well-controlled study, the mean rates of compliance with each drug in all analysis sets were not less than 95% in both treatment groups. Although this situation does not reflect clinical practice, a difference in compliance between QD dosing and TID dosing was not detected in this study.
In conclusion, this study showed that QD multimatrix mesalazine administered as 2 tablets achieved a remission maintenance effect that was not inferior to a controlled-release mesalazine 2.25 g/day formulation administered TID.
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