SUMMARY INTRODUCTION. Accepted for publication 10 September 2004

Transcription

1 Aliment Pharmacol Ther 2004; 20: doi: /j x Mesalazine (5-aminosalicylic acid) micropellets show similar efficacy and tolerability to mesalazine tablets in patients with ulcerative colitis results from a randomized-controlled trial A. RAEDLER*, C. BEHRENS &P.BIAS *Department of Internal Medicine II Gastroenterology, Asklepios Westklinikum Hamburg, Teaching Hospital of the University of Hamburg, Hamburg; Department of Clinical Research, Merckle GmbH, Ulm, Germany Accepted for publication 10 September 2004 SUMMARY Background: Formulations containing 5-aminosalicylic acid, such as mesalazine, are the gold standard of treatment for mild-to-moderate ulcerative colitis. Current oral regimens require the use of large tablets and frequent dosing to reach the recommended treatment dose. Mesalazine micropellets were designed to allow less frequent dosing in an easier to swallow formulation. Aim: To compare the efficacy of mesalazine micropellets with the tablet formulation in patients with mildto-moderate ulcerative colitis. Methods: This phase 2, double-blind, active-controlled, parallel-group, multiple dose clinical trial randomized 362 patients to either mesalazine micropellets or tablets, at a dosage of 3 g/day. The primary efficacy end-point was the incidence of clinical remission within 8 weeks, defined as the sum of clinical activity index components 1 4 (CAI C1)4 ) 2. Results: CAI C1)4 decreased significantly in both treatment groups within 8 weeks. The micropellet formulation showed confirmatory non-inferiority with statistical significance compared with the tablet formulation, with regard to the incidence of clinical remission (odds ratio in according-to-protocol population 1.008; 95% CI: ). There was no significant difference in the incidence of adverse events. Conclusions: The mesalazine micropellet formulation is as effective as tablets in patients with mild-to-moderate ulcerative colitis, enabling a larger dose to be taken comfortably and conveniently, thereby potentially improving patient compliance, treatment response and quality of life. INTRODUCTION Ulcerative colitis is a chronic, recurrent inflammatory disease of the rectal and colonic mucosa 1 that has an unknown aetiology and is characterized by bloody diarrhoea and abdominal spasms. 2 4 The degree of disease activity can vary from mild to highly severe 3 and patients often receive intense and long-term therapy that frequently requires lifelong treatment. 5 Correspondence to: Dr C. Behrens, Department of Clinical Research, Merckle GmbH, Graf-Arco-Str. 3, D Ulm-Donautal, Germany. christoph.behrens@merckle.de As the cause of ulcerative colitis is unknown, therapy is symptomatic and targets general inflammatory mechanisms. 6 As a result of the long-term nature of treating this disease, patient compliance with therapy is an important consideration. Low compliance impairs the effectiveness of treatment and only high compliance will exploit the potential of treatment Furthermore, treatment strategies should be convenient and should not compromise a patient s quality of life. Formulations containing 5-aminosalicylic acid (5-ASA) such as mesalazine and sulfasalazine (sulphasalazine) have become the gold standard for treatment of ulcerative colitis. 12, 13 The clinical efficacy Ó 2004 Blackwell Publishing Ltd 1353

2 1354 A. RAEDLER et al. of 5-ASA therapies has been documented extensively 14, 15 and studies have shown that mesalazine is associated with a lower incidence of adverse events (AEs) compared with sulfasalazine. 16 Colorectal cancer is a serious complication of ulcerative colitis, and the risk of developing this cancer is associated with both the duration and extent of the disease. 17, 18 Importantly, studies have shown that 5-ASA therapy is linked to a significant reduction in this cancer. 8, 19, 20 Indeed, mesalazine therapy induces apoptosis, which is accompanied by a decrease in colorectal cell proliferation. 21 Currently, patients prefer oral 5-ASA over suppositories or enemas for the treatment of ulcerative colitis as a result of more convenient administration. Present practice recommendations include the use of high doses of 5-ASA for maintenance or remission therapy and required dosages have consistently increased over recent years. Daily doses of mesalazine 3 4 g are common, 22 and dosages of up to 4.8 g/day have been suggested 23 and recommended by therapy guidelines Such high doses can only be achieved by using large 5-ASA tablet sizes and more frequent dosing. However, tablet size is restricted to 500 mg because larger tablets are difficult to swallow. A patient would therefore have to take up to six to 10 of these large tablets to reach the recommended doses referenced above. In this study, an appropriate and common dose of 3 g/day was used for induction of remission. With increasing frequency of daily dosing, patient compliance decreases significantly when conventional tablets are prescribed. 9, 11 Furthermore, rectal formulations of 5-ASA are more effective than steroids, which highlights the potential for oral 5-ASA if higher doses are required. Therefore, a less frequent and more comfortable to swallow oral formulation would improve patient compliance and increase successful treatment of ulcerative colitis. A new formulation of mesalazine has been developed in response to the suggestion that adherence to treatment and outcomes may be improved by less frequent dosing. Mesalazine Eudragit-coated granulate (Eudragit Pharma Polymers, Roehm GmbH, Darmstadt, Germany) was designed to ensure that a larger dose of the drug could be taken comfortably and conveniently. Each sachet contains mesalazine 1.5 g (i.e. the equivalent of three 500 mg tablets) in an enteric-coated micropellet form. Therefore, patients have to take only two to three sachets a day for treatment of the active disease rather than six to nine tablets. Furthermore, mesalazine micropellets have similar pharmacokinetic properties to tablets in healthy volunteers. 4, 27 Mesalazine micropellets are targeted specifically to release their active ingredient in the region of the gastrointestinal tract mainly affected in inflammatory bowel diseases. The present trial investigated the efficacy and safety of the new mesalazine micropellet formulation in patients with ulcerative colitis. The aim of this non-inferiority trial was to compare the efficacy of mesalazine micropellets with the currently available tablet formulation, with the primary end-point of clinical remission in patients with mild-to-moderate ulcerative colitis. MATERIALS AND METHODS Trial population Men and women out-patients (aged years) with recurrent mild-to-moderate ulcerative colitis were eligible to participate in the trial. Mild-to-moderate disease was defined as a clinical activity index (CAI) for components 1 4 of 4 and an endoscopic activity index (EI) of The overall CAI (CAI C1)7 ) is calculated as the sum of the seven individual component scores: (i) number of stools/week, (ii) blood in stools, (iii) investigator s global assessment of symptomatic state, (iv) abdominal pain/cramps, (v) temperature caused by colitis, (vi) extraintestinal manifestations, and (vii) laboratory findings (Table 1). The CAI according to Rachmilewitz 28 records the activity of ulcerative colitis, and has been validated and used in numerous recent trials. 12, 13, 29, 30 Ulcerative colitis was diagnosed by clinical appearance, colonoscopy and histology. The disease extent had to be 12 cm proximally, with blood present in the stools, and a stool frequency of >18 stools in the week before treatment initiation. The EI according to Rachmilewitz 28 was used to assess inflammation in the intestinal mucosa. Eligible patients were also required to have a negative microbiological stool culture. Each patient provided written, informed consent. All patients underwent full colonoscopy prior to entry and at 8 weeks. Patients who reached the primary endpoint earlier ( last individual value ) underwent their last colonoscopy at that point. The endoscopic examination was documented according to the EI as predefined in the study protocol.

3 MESALAZINE MICROPELLETS AND TABLETS HAVE SIMILAR EFFICACY WITH UC 1355 Table 1. Components of clinical activity index (CAI) and endoscopic index according to Rachmilewitz 28 Clinical activity index Number of stools 0 ¼ <18, 1 ¼ 18 35, 2 ¼ 36 60, 3 ¼ >60 Blood in stools 0 ¼ none, 2 ¼ little, 4 ¼ a lot Investigator s global assessment 0 ¼ good, 1 ¼ average, 2 ¼ poor, 3 ¼ very poor of symptomatic state Abdominal pain/cramps 0 ¼ none, 1 ¼ mild, 2 ¼ moderate, 3 ¼ severe Temperature due to colitis ( C) 0 ¼ 37 38, 3 ¼ >38 Extraintestinal manifestations 3 ¼ iritis, 3 ¼ erythema nodosum, 3 ¼ arthritis Laboratory findings 1 ¼ sedimentation rate >50 mm in first hour, 2 ¼ sedimentation rate >100 mm in first hour, 4 ¼ haemoglobin <100 g/l Endoscopic index Granulation scattering 0 ¼ no, 2 ¼ yes reflected light Vascular pattern 0 ¼ normal, 1 ¼ faded/disturbed, 2 ¼ completely absent Vulnerability of mucosa 0 ¼ none, 2 ¼ slightly increased (contact bleeding), 4 ¼ greatly increased (spontaneous bleeding) Mucosal damage (mucus, fibrin, 0 ¼ none, 2 ¼ slight, 4 ¼ pronounced exudates, erosions, ulcer) CAI < 4: clinical remission; CAI in-between 4 and 8: mild colitis; CAI > 8: active colitis. Patients were excluded from the trial if they had a first appearance of ulcerative colitis at baseline; severe ulcerative colitis/toxic megacolon; radiogenic or druginduced colitis; bacterial enterocolitis; bowel complications such as stenoses, fistulae, perforations or rectal bleedings requiring transfusions; active malignant disease or severe dysplasia confirmed by histological findings; clinically relevant haematological, endocrine, cardiovascular, hepatic, renal or infectious disease; an acute or duodenal ulcer; pathological laboratory values indicating clinically relevant liver or renal disease or severe anaemia; a history of hypersensitivity to salicylic acid and its derivatives or benzoates; or alcohol or drug abuse. Patients were also excluded if they had received immunosuppressives in the last 90 days, antibiotics to treat colitis in the last 30 days or glucocorticoids in the last 3 days before enrolment. Concomitant treatments resulting in exclusion were 5-ASA-containing drugs, corticosteroids, fish-oil preparations, immunosuppressives, antibiotics to treat ulcerative colitis, antispasmodics, analgesics, antidiarrhoea agents, anticoagulants, sulphonylureas, probenecid, sulfinpyrazone, spironolactone, furosemide or rifampicin. Women were required to be postmenopausal or sterilized, or to have confirmed usage of adequate contraception. Women were excluded if they were pregnant or lactating. Trial design and treatment This clinical phase II, randomized, double-blind, activecontrolled, parallel-group, multiple dose trial compared the efficacy and safety of a new micropellet formulation of mesalazine (Merckle GmbH, Ulm, Germany) with mesalazine tablets (Claversal500; Merckle GmbH). Treatment was administered over 8 weeks and a double-dummy technique was used to ensure blinding. The trial was undertaken at 38 European centres. Investigation was carried out in accordance with the guidelines and ethical principles of the Declaration of Helsinki (1996) and its subsequent revisions, and the trial protocol was approved by the appropriate national and regional ethics committees. Compliance was assessed by tablet and sachet counts. Patients were asked to return all used, partly used and unused medication packages, sachets and blisters at each postbaseline visit. A calculated usage of % (relative to the time period of actual treatment) was considered as adequate compliance. Pre-trial examination, enrolment and randomization. A pre-trial examination was carried out at baseline, during which the inclusion and exclusion criteria were assessed for each patient, a medical history was taken, and the details of any relevant previous and concomitant diseases and medication were recorded. In addi-

4 1356 A. RAEDLER et al. tion, demographic data and the history of ulcerative colitis were documented. A physical examination was performed and baseline vital signs (blood pressure, pulse, bodyweight) and laboratory variables (haematology, clinical chemistry, urinalysis) were recorded. A complete CAI (components 1 7) assessment and a microbiological investigation of faeces were also carried out. A diary was supplied and explained to each patient. The number of stools/week, daily occurrence of blood in stools and abdominal pain/cramps were to be documented in the diary by the patient each day. These components referred to the time period 1 week before each visit. At baseline, patients who met the criteria for entry into the trial were enrolled and randomly assigned to receive mesalazine micropellets or mesalazine tablets. Treatment period. Randomized patients received mesalazine 3.0 g/day in micropellet or tablet form. Micropellets were administered orally as one 1.5 g sachet, taken twice daily (morning and evening). Micropellets were emptied onto a spoon and taken with a sufficient amount of liquid (about one glass or 180 ml). Mesalazine tablets were administered orally as two 500 mg film-coated tablets, taken three times daily (morning, noon and evening) and tablets were ingested with a glass of liquid (about 180 ml). To ensure blinding, all study medication was administered three times daily 1 h before a meal. The morning and evening dose consisted of one sachet and two tablets, and the noon dose consisted of two tablets only. Patients took blinded trial medication for 8 weeks, with visits at weeks 2, 4, 6 and 8. Treatment commenced on the evening of the baseline visit, and the last intake was scheduled for the morning of the final visit. As mesalazine tablets and sachets are different in appearance, a double-dummy technique was used to maintain blinding. Each active drug and the matching placebo were identical in appearance, form, smell and taste. Medication labels were identical for both treatments. Therefore, the dispensing investigator, the patient, the Contract Research Organization, the sponsor staff involved in the management of the trial, the central laboratory and the pathologist carrying out the histological evaluation remained blinded to each patient s treatment group. Clinical efficacy assessments The primary efficacy end-point was clinical remission within 8 weeks of treatment (individual last value). This was defined to have occurred if the sum of CAI components 1 4 according to Rachmilewitz 28 (CAI C1)4 ) was 2. As the first four parameters of this CAI characterize the dynamic changes of the acute disease more precisely than the entire index, these four parameters were chosen as primary efficacy end-point. CAI C1)4 was determined at each postbaseline visit (2, 4, 6 and 8 weeks). Secondary efficacy end-points included: complete clinical remission (defined as the sum of CAI components 1 7; CAI C1)7 < 4), EI according to Rachmilewitz, 28 endoscopic remission (EI 2), histological evaluation (rectum/sigma), additional symptoms such as impulse to defecate and tenesmus, patient and doctor assessment of global subjective efficacy (recorded on a 5-point verbal rating scale of very good to very poor ), and patient assessment of improved efficacy since the last visit (recorded on a 5-point verbal rating scale of much better to much worse ). The histological examination of the intestinal mucosa was performed to check the diagnosis of ulcerative colitis and the activity of disease, allowing classification as remission, low-grade inflammation, moderate-grade active inflammation, high-grade active inflammation and no ulcerative colitis. The secondary endpoints were evaluated to provide an indication of the duration for which a patient remained in remission (EI and histological examination) and to reveal the effects on quality of life (additional symptoms). CAI C1 7, endoscopic evaluation and histological examination were carried out at baseline and Week 8. Overall efficacy (as assessed by patients and physicians) and improvement in efficacy (as assessed by patients) were recorded at each postbaseline visit. Clinical safety assessments Safety and tolerability were assessed by monitoring AEs, relevant changes in laboratory parameters/vital signs, global assessment of tolerability by patient and doctor (recorded on a 5-point verbal rating scale of very good to very poor ) and a complete physical examination. All safety and tolerability parameters were assessed at baseline and week 8 except for global assessment of tolerability, which was assessed at each postbaseline visit. AEs, classified according to the World Health Organization s Adverse Reaction Terminology, were also recorded throughout the trial and for 30 days following trial conclusion.

5 MESALAZINE MICROPELLETS AND TABLETS HAVE SIMILAR EFFICACY WITH UC 1357 Statistical analysis The intent-to-treat (ITT) and according-to-protocol (ATP) populations were used for analysis of the primary efficacy end-point. The ITT population was defined as those patients who were treated at least once with one of the study medications. Patients with a major protocol violation were included in this population. Patients without protocol violations were included in the ATP population. The safety population was defined as those patients who had been enrolled and randomized to treatment and who had been treated at least once with one of the trial medications. The one-sided hypothesis of non-inferiority was confirmed using the assumption that the estimated clinical remission rate in the tablet group would be 50 60%, and a difference in the clinical remission rate of <20% was clinically reasonable, justified and of no medicinal relevance. 31 The odds ratio was used to demonstrate non-inferiority, and the lower limit was set at A Mantel Haenszel test was used to assess the treatment difference in change in histological assessment scores. All other efficacy end-points and demographic variables were evaluated by descriptive methods only. Changes from baseline in safety variables and frequency of AEs were tested with the independent t-test for between-group differences. Neither an interim analysis nor subgroup analyses were performed. The statistical software used was SAS 6.12 or higher. Sample size Based on the assumption that the clinical remission rate after 8 weeks of treatment with mesalazine tablets would be approximately 55% 12,32 and that the remission rate in micropellet recipients would be equivalent, the required sample size was 131 patients per treatment group. This was based on a one-sided equivalence limit difference of 20%, a one-sided-a of 2.5% and a statistical power of 90%. However, the confirmatory statistical analysis was carried out with data from the ATP population because the dropout rate and all cases could not be evaluated in the ITT population. Assuming an exclusion rate from the ATP population of 25%, at least 175 [131/(1 ) 0.25)] patients per treatment group were required. RESULTS Baseline demographics and patient characteristics A total of 363 patients with recurrent, active, mild-tomoderate ulcerative colitis were enrolled in the trial. One patient with an EI < 4 was excluded. Thus, 362 patients were randomized to receive treatment and comprised the safety population. Each treatment group contained 181 patients (Figure 1). Five patients belonging to the safety population were excluded from the ITT population because of missing postbaseline measurements (two patients in the micropellet group and three in the tablet group). Therefore, Mesalazine pellets Mesalazine tablets overall Randomized Safety population ITT population Figure 1. Allocation of patients to treatment groups and patient populations. ATP, according-to-protocol; ITT, intent-to-treat. ATP population

6 1358 A. RAEDLER et al. 357 patients were included in the ITT population (179 in the micropellet group and 178 in the tablet group; Figure 1). Thirty-five patients from the ITT population were excluded from the ATP population owing to protocol violations; 19 from the micropellet group and 16 from the tablet group (Figure 1). The first patient was enrolled on 29 January 2001 and the trial was completed on 18 July The mean patient age was 44 years. Baseline demographics and clinical characteristics did not differ significantly between treatment groups (Table 2) groups were well matched with respect to age, height, weight, body mass index (BMI) and Broca index. The first appearance of the ulcerative colitis within the safety population was a mean (±s.d.) 8.77 ± 8.50 years ago. The last acute episode was in mean 1.19 ± 1.25 years ago. The active disease lasted in mean 1.01 ± 0.98 months. The mean duration of treatment, which was not significantly different between treatment groups, was 56.1 days. Table 2. Summary of the demographic data gender, ethnic origin, and age group by treatment group and overall in the ITT population (n ¼ 357) Pellets (n ¼ 179) Tablets (n ¼ 178) Overall (n ¼ 357) Gender Male 77 (43.0) 86 (48.3) 163 (45.7) Female 102 (57.0) 92 (51.7) 194 (54.3) Ethnic origin Caucasian 178 (99.4) 177 (99.4) 355 (99.4) Asian 1 (0.6) 1 (0.6) 2 (0.6) Age group < (94.4) 164 (92.1) 333 (93.3) (5.6) 14 (7.9) 24 (6.7) Values in parentheses expressed as percentage. ITT, intent-to-treat. A total of 124 patients received concomitant medication: 56 (30.9%) in the micropellet group and 68 (37.6%) in the tablet group. The most common concomitant drugs were progestogens and oestrogens in fixed combinations (n ¼ 29), followed by salicylic acid and derivatives (n ¼ 26). Two patients were receiving mesalazine (dose not specified). Clinical remission within 8 weeks The CAI C1)4 decreased significantly in both treatment groups and in both analysis populations (ITT and ATP) within 8 weeks (Figure 2). Within 8 weeks in the ATP population, CAI C1)4 decreased from 6.4 at baseline to an individual last value of 2.2 in micropellet recipients and from 6.2 at baseline to an individual last value of 2.2 in tablet recipients. Within 8 weeks, in the ITT population, clinical remission was achieved in 67.0% of patients in the micropellet group and 62.9% of patients in the tablet group (Table 3). In the ATP population, remission was achieved in 64.4% and 64.2% of patients, respectively. In comparison with the tablet formulation, the micropellet formulation showed confirmatory non-inferiority with statistical significance, with respect to the incidence of clinical remission within 8 weeks (odds ratio in ATP population 1.008; 95% CI: ). As the lower boundary of the confidence interval was >0.4444, non-inferiority was demonstrated clearly. The data from the ITT population also confirmed this finding (Table 3). Clinical and endoscopic remission. Compared with the tablet formulation, the micropellet formulation showed statistically significant non-inferiority, with respect to the incidence of the secondary efficacy end-point of complete clinical remission (CAI C1)7 ) within 8 weeks in Figure 2. Summary of CAI C1)4 (mean ± s.d.) by treatment group in: the (a) ATP (n ¼ 322) and (b) ITT (n ¼ 357) populations. ATP, according-to-protocol; CAI C1)4, sum of clinical activity index for components 1 4; ITT, intent-to-treat.

7 MESALAZINE MICROPELLETS AND TABLETS HAVE SIMILAR EFFICACY WITH UC 1359 Table 3. Incidence of patients in clinical remission and odds ratio with 95% confidence interval within 8 weeks (individual last value, confirmatory analysis of the primary efficacy criterion) ATP population within 8 weeks ITT population within 8 weeks Patients in clinical remission (%) Pellets Tablets Difference (pellets tablets, %) % confidence interval Lower bound )10.2 )5.7 Upper bound Odds ratio % confidence interval Lower bound Upper bound ITT, intent-to-treat; ATP, according-to-protocol. the ITT population (Table 4). The endoscopic score decreased considerably in both treatment groups and both analysis populations between baseline and week 8 (ITT: 39.4% and 40.8% in micropellet and tablet recipients, respectively; ATP: 37.9% and 39.4%, respectively). Histological examination. In the micropellet group, histological sigmoid scores improved significantly between baseline and week 8 (P < 0.033, ITT) compared with the tablet group. Rectum scores also improved in both treatment groups (Table 5). Urgency of defecation and tenesmus. Over time, the incidence of the urgency of defecation was reduced; this reduction was marginally higher in the micropellet Table 4. Number of patients showing clinical (CR), endoscopic (ER) and clinical and endoscopic (CR + ER) remission after 8 weeks of treatment, and cumulative number [individual last value (ILV)] of patients with clinical remission ITT (n ¼ 357) ATP (n ¼ 322) Pellets (n ¼ 179) Tablets (n ¼ 178) Pellets (n ¼ 160) Tablets (n ¼ 162) CR 8 weeks 116 (69.0% of 168) 111 (65.3% of 170) 101 (66.4% of 152) 103 (65.2% of 158) ILV 120 (67.0% of 179) 112 (62.9% of 178) 103 (64.4% of 160) 104 (64.2% of 162) ER (8 weeks) 67 (39.4% of 170) 71 (40.8% of 174) 58 (37.9% of 153) 63 (39.4% of 160) CR + ER (8 weeks) 61 (34.1% of 179) 59 (36.9% of 160) 52 (32.5% of 160) 53 (32.7% of 162) ITT, intent-to-treat; ATP, according-to-protocol. Table 5. Changes in histological score from baseline to the last performed post-treatment visit by treatment group and patient populations Treatment groups Improvement Deterioration* )3 )2 )1 No change (0) 1 2 P-value ITT Rectum Pellets Tablets Sigmoid Pellets Tablets ATP Rectum Pellets Tablets Sigmoid Pellets Tablets * No deterioration of +3 occurred. The P-value of the comparison between the treatment groups was calculated using the Cochran-Mantel Haenszel test.

8 1360 A. RAEDLER et al. group than in the tablet group (ITT: 60.3% of patients at baseline vs. 17.9% at week 8 in micropellet group, and 62.4% vs. 21.3%, respectively, in the tablet group). The incidence of tenesmus decreased from 39.3% at baseline to 6.5% at week 8 in ITT micropellet recipients and from 45.5 to 8.2%, respectively, in ITT tablet recipients. Global subjective assessment of efficacy by patient and doctor. At week 8 in the ITT population the proportion of patients rating therapy as very good or good was 74.4% in the micropellet group and 72.9% in the tablet group. Corresponding values in the ATP population were 72.4% and 73.4%, respectively. Similarly, doctor ratings of very good or good efficacy after 8 weeks of treatment were reported for 76.2% and 72.9% of patients in the ITT micropellet and tablet groups, respectively. In the ATP population, respective ratings were 74.3 and 72.8%. Verbal rating scale of improved efficacy. In the ITT population, the incidence of patients verbal efficacy ratings of better or much better increased from 77.6% in the micropellet group and 73.4% in the tablet group at week 2, to 89.3% and 91.2%, respectively, at week 8. Compliance. In the ITT population, 171 patients (96%) in the micropellet group and 175 patients (98%) in the tablet group were considered to be compliant with the study medication as assessed by tablet and sachet counts. Compliance could not be assessed in 13 patients owing to missing data (eight patients in the micropellet group and five patients in the tablet group). Safety evaluation In the safety population (n ¼ 362), AEs were reported in 99 patients; 56 of 181 (30.9%) of these patients received micropellets and 43 of 181 (23.8%) received tablets. Headache and nausea were the most frequently reported AEs. The majority of AEa were mild and most are already documented as related to mesalazine treatment. No significant difference between treatment groups was observed in the incidence of AEs possibly or probably related to therapy (P ¼ 0.43) (Table 6). Serious AEs were reported by nine patients (three in the micropellet group and six in the tablet group). All these events were considered as related to ulcerative colitis rather than trial medication. In all cases, the patients recovered. Six patients discontinued the trial Table 6. Number of patients in the safety population who experienced adverse events (AEs) and that were assessed to be possibly or probably related to the study drug Adverse event because of AEs (five in the micropellet group and one in the tablet group). One of the discontinuations in the micropellet group was actually caused by intake of prohibited concomitant medication due to inefficacy of trial medication. Another discontinuation in this group was actually due to detection of adenocarcinoma of sigma at histological examination. This meant that the patient met the secondary exclusion criteria. In a global subjective assessment of tolerability, 89.3% of patients in the micropellet group and 93.3% of patients in the tablet group rated tolerability as good or very good after 8 weeks. This was confirmed by doctor assessment of tolerability: very good or good in 91.6% and 92.1% of the micropellet and tablet groups, respectively. No new or more frequent side-effects were seen with the micropellets and no deaths occurred during the trial. No clinically significant changes from baseline in haematological and biochemical parameters in either treatment group were observed. Moreover, no betweengroup differences in these parameters were reported. DISCUSSION Possible Probable Pellets Tablets Pellets Tablets General disorders Headache Abdominal pain Flatulence Nausea Other GI system disorders Liver and billiary system disorders Respiratory system disorders Other Total 15* 10* 3* 2* GI, gastrointestinal tract. * Statistical comparison of 18 (pellets) vs. 12 (tablets) possible or probable AEs by the exact chi-squared test: P ¼ Patients may have experienced more than one AE. The new mesalazine micropellet formulation was shown to be as effective as mesalazine tablets at all efficacy endpoints in patients with mild-to-moderate ulcerative colitis. With respect to the primary end-point of the

9 MESALAZINE MICROPELLETS AND TABLETS HAVE SIMILAR EFFICACY WITH UC 1361 incidence of clinical remission (CAI C1)4 ) within 8 weeks, the micropellet formulation showed confirmatory non-inferiority with statistical significance compared with the tablet formulation. The non-inferiority of micropellets compared with tablets was confirmed by the incidence of the secondary efficacy end-point of complete clinical remission (CAI C1)7 ) within 8 weeks in the clinically relevant ITT population. Complete clinical remission was achieved in 69.0% of micropellet and 65.3% of tablet recipients in the ITT population. Corresponding values in the ATP population were 66.4% and 65.2%, respectively. Global subjective assessments of efficacy by patient and doctor were consistent with these findings. Moreover, in both groups, efficacy improved rapidly and was sustained through to week 8 according to patient assessment. No statistically significant difference between treatment groups was observed with respect to all other secondary efficacy end-points except for that of histological sigmoid scores; a significant improvement was seen between baseline and 8 weeks in micropellet compared with tablet recipients (P < 0.033; ITT). With respect to safety, no major differences between the treatment groups were observed despite higher doses at each intake in the micropellet group. An increase in AEs reduces compliance over a prolonged treatment period. 33 For both formulations, AEs were generally mild and had been previously recorded with mesalazine use. No serious AEs were considered to be related to the trial drug. Compliance to study medication was high with similar rates of compliance observed in the micropellet and tablet groups (96% and 98% of patients, respectively). However, patient compliance in controlled clinical trials, where careful records are kept and treatment is believed to be potent, is often poorly related to that found in clinical practice. 10 Patients often do not take their medication as prescribed and patient compliance in daily practice may be only 50% of the required dose. 34 Mesalazine micropellets have been shown to offer similar release properties as tablets. 4,27 However, micropellets have a distinct advantage over tablets because they are easier to swallow and less frequent dosing is required. Instead of taking up to six large difficult-to-swallow 500 mg tablets, patients need take only two sachets per day to maintain stable dosing and compliance. Conventional 5-ASA formulations are available as tablet and capsule formulations. A combination of oral and rectal administration is another widespread, efficient option, 35 which is frequently used in practice. However, the micropellet formulation investigated here is likely to have advantages over these additional formulations as tablets and capsules require more frequent dosing. 36 Intake mistakes and patient noncompliance are expected and probably; therefore, an adequate treatment response may be jeopardized by the long-standing 5-ASA formulations. With mesalazine micropellets, twice daily dosing will be possible in the treatment of acute ulcerative colitis, with a likely impact on patient compliance, treatment response and quality of life. Studies have shown that reducing the dosage regimen from three times daily (as with mesalazine tablets) or greater to once or twice daily improves patient compliance. 33, 37, 38 Indeed, in another trial comparing granules with tablets, patients reported preference to twice daily dosing with granules over four times daily dosing with granules and four times daily dosing with tablets. In this trial, granules were reported to be as effective as tablets, and the twice daily dosing regimen was as effective as more frequent dosing. 39 Economic aspects should also be considered. Improved patient compliance leads to better treatment responses and consequently less active disease when mesalazine micropellets are used. Once daily dosing for remission maintenance therapy also be a possibility, 40, 41 which could help to reduce total treatment costs per patient year. The increased risk of colorectal cancer in ulcerative colitis patients and the associated decrease of colorectal cancer risk during aminosalicylic and non-steroidal anti-inflammatory treatment are additional aspects when considering 5-ASA remission maintenance treatment A previous study examining cancer rates in patients who had suffered from ulcerative colitis for 10 years reported a cancer rate of 31% in noncompliant patients compared with a 3% rate in treatment-compliant patients. 8 As the mesalazine moiety also has therapeutic benefits in Crohn s disease 45, 46 the mesalazine micropellet formulation may have further applications in this form of inflammatory bowel disease. In conclusion, this trial demonstrates the confirmatory non-inferiority with statistical significance of mesalazine micropellets compared with mesalazine tablets in patients with mild-to-moderate ulcerative colitis. The development of a mesalazine micropellet enables a larger dose of the drug to be administered comfortably and

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