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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Background  SPD476 (MMX™ mesalazine), is a novel, once daily, high-strength mesalazine formulation (1.2 g/tablet) that utilizes Multi Matrix System™ (MMX) technology to delay and extend delivery of the active drug throughout the colon.

Aim  To assess the safety and efficacy of MMX mesalazine in patients with mild-to-moderately active ulcerative colitis, in a pilot, phase II, randomized, multicentre, double-blind, parallel-group, dose-ranging study (SPD476-202).

Methods  Thirty-eight patients with mild-to-moderately active ulcerative colitis were randomized to MMX mesalazine 1.2, 2.4 or 4.8 g/day given once daily for 8 weeks. Remission ulcerative colitis-disease activity index (UC-DAI) ≤1, a score of 0 for rectal bleeding and stool frequency, and ≥1-point reduction in sigmoidoscopy score from baseline was the primary end point.

Results  Week 8 remission rates were 0%, 31% and 18% of patients receiving MMX mesalazine 1.2, 2.4 and 4.8 g/day respectively. No statistically significant difference in remission was observed between treatment groups. MMX mesalazine 2.4 and 4.8 g/day groups demonstrated greater improvement in overall UC-DAI and component scores from baseline, compared with the 1.2 g/day group.

Conclusion  MMX mesalazine given as 2.4 or 4.8 g/day once daily is well tolerated and effective for the treatment of mild-to-moderately active ulcerative colitis.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Ulcerative colitis (UC) is a chronic, life-long, recurrent disease with symptoms comprising diarrhoea containing blood and often mucous, faecal urgency, abdominal pain, anaemia, weight loss and generally feeling unwell.1 The lack of a non-surgical cure means that current therapies focus on the induction and maintenance of remission of symptoms. The current standard therapy for the induction and maintenance of remission in UC is 5-aminosalicylate [5-ASA; e.g. mesalazine (mesalamine)] therapy.2,3 A number of oral 5-ASA formulations that deliver the active moiety to the colon have been developed, including delayed-release tablets (Asacol; Procter & Gamble Pharmaceuticals, Cincinnati, OH, USA), controlled-release capsules (Pentasa; Shire Pharmaceuticals Inc., Wayne, PA, USA) and azo-bonded prodrug formulations (sulfasalazine, olsalazine and balsalazide). In addition, some patients with distal disease will also require rectal formulations, in the form of gels, foams and enemas, to achieve remission.

Existing oral formulations of mesalazine demand administration of multiple doses per day with a rather high number of tablets. The requirement for such complex dosing schedules can interfere with the normal daily activities of the patient, which may ultimately lead to non-compliance with the recommended dose.4,5 Patient non-compliance to treatment regimens for chronic diseases is widely known and, as a direct result of transient symptom occurrence, is particularly prevalent in patients with UC. Indeed, in periods of disease quiescence, compliance to 5-ASA dosing regimens has been reported to be as low as 40%,6 with patients citing too many pills and inconvenient dosing regimen as the reasons for their non-compliance.4,7,8 Moreover, patients with UC who do not comply with their dosing regimen have been found to have a fivefold increase in the risk of disease relapse.4 Ultimately, complex dosing regimens leading to lack of patient compliance can negatively impact on therapeutic efficacy and thus on patient quality of life through increased disease activity.9,10

SPD476 (MMX™ mesalazine; Shire Pharmaceuticals Inc., in partnership with Giuliani SpA, Milan, Italy) is a novel, high-strength formulation of 5-ASA (mesalazine, 1.2 g per tablet), which uses Multi Matrix System™ (MMX) technology designed to release 5-ASA throughout the colon. This patented delivery system utilizes hydrophilic and lipophilic matrices enclosed within a gastro-resistant, pH-dependent coating to facilitate prolonged exposure of the colonic mucosa to 5-ASA.11 The gastro-resistant coating that covers the multi-matrix core delays release of 5-ASA until the tablet is exposed to pH 7.0 or higher, normally in the terminal ileum, at which time the coating disintegrates. Due to the presence of the hydrophilic matrix, the tablet core swells upon exposure to intestinal fluid (in a manner similar to that of a sponge exposed to water) and a viscous gel mass is formed. This viscous gel mass is expected to slow the diffusion of the active drug from the tablet core into the colonic lumen. As the tablet and its surrounding gel mass progress through the colon, pieces of the gel mass gradually break away from the core. This allows release of some 5-ASA in proximity to the colonic mucosa. In addition, literature suggests that the hydrophilic matrix may also adhere to the colonic mucosa,12, 13 thus delivering 5-ASA to its site of action. The lipophilic matrix, together with 5-ASA, is interspersed within the hydrophilic matrix creating a partially hydrophobic environment, which slows the penetration of aqueous fluids into the tablet core. This is expected to slow the drug dissolution and provide a further extended release of the active medication, potentially prolonging therapeutic activity.

The primary purpose of this study (SPD476-202) was to investigate the efficacy of three different doses of MMX mesalazine (1.2, 2.4 and 4.8 g/day) administered once daily for induction of remission of mild-to-moderately active UC. In addition, the change in sigmoidal and rectal histology from baseline to week 8 of treatment and the correlation between the oral dose of MMX mesalazine and mucosal and plasma concentrations of 5-ASA and acetyl (Ac)-5-ASA were also examined.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Design and setting

This was a randomized, phase II, multicentre, double-blind, parallel-group, dose-ranging study conducted in accordance with the ethical principles of Good Clinical Practice and the Declaration of Helsinki and with the approval from the appropriate Institutional Review Board/Independent Ethics Committee. The study was conducted in eight clinical practice centres across Belgium, the Netherlands and the United Kingdom.

Patients

All patients gave written, informed consent prior to participation in the study, in accordance with the International Conference on Harmonisation General Code of Practice Guidelines. Male and female patients aged ≥18 years who had histologically confirmed, newly diagnosed or relapsing [relapsed ≤6 weeks prior to baseline) mild-to-moderate UC (score of 4–10 on the UC-disease activity index (UC-DAI), with a sigmoidoscopy score of ≥1 and a Physician's Global Assessment (PGA) score of ≤2] were enrolled into the study. Female patients were postmenopausal, sterile or had a negative urine pregnancy test prior to entering the study and used adequate contraception during the study.

Disease-related exclusion criteria included: Crohn's disease; proctitis (where the extent of inflammation was ≤15 cm); bleeding disorders; active peptic ulcer disease; asthma (if mesalazine-sensitive); positive stool culture for enteric pathogens or with ova or parasites as detected by microscopy; previous colonic surgery; moderate or severe renal impairment; current or recurrent disease that could affect the colon, or the action, absorption or disposition of the study medication, or clinical or laboratory assessments.

Previous illness-related exclusion criteria included: current or relevant previous history of serious, severe or unstable (acute or progressive) physical or psychiatric illness, any medical disorder that may have required treatment or made the patient unlikely to fully complete the study, or any condition that presented undue risk from the study medication or procedures.

Patients were not eligible if they had: relapsed on maintenance therapy with doses of mesalazine >2.0 g/day; relapsed within 2 weeks of a mesalazine dose reduction from >2.0 to ≤2.0 g/day; unsuccessfully treated a current relapse with steroids or with mesalazine doses >2.4 g/day; used systemic or rectal steroids within 4 weeks prior to baseline, or immunosuppressants within 6 weeks prior to baseline; used antibiotics or repeatedly used non-steroidal anti-inflammatory drugs (e.g. aspirin or ibuprofen) within 7 days prior to baseline (although prophylactic use of a stable dose of aspirin up to 325 mg/day for cardiac disease was permitted). Patients were not permitted to self-medicate with topical 5-ASA preparations.

Protocol

Patients visited the clinic on four occasions: at the screening/baseline visit (week 0) and then at weeks 2, 4 and 8 (end of study/withdrawal visit). Screening and baseline visits could be performed on different days if this was more convenient.

A full physical examination, including weight and height, was performed at screening and at the end of study/withdrawal visit. Stool samples were collected at the screening visit and assessed for the presence of Clostridium difficile toxin or enteric pathogens. Stools were also examined for ova and parasites. Patients were withdrawn if the stool sample was positive for any of the above parameters.

Blood samples for biochemistry and haematology were taken at every study visit. Clinically relevant changes from screening in haematology or biochemistry parameters were recorded as adverse events (AEs).

Urinalysis was performed locally at the screening visit and at the end of study/withdrawal visit. If any urinalysis parameter was deemed abnormal, the urine sample was sent to the central laboratory for analysis and microscopic examination. All women of child-bearing potential completed a urine pregnancy test at the screening visit, and the end of study visit or upon withdrawal from the study.

Vital signs (blood pressure and pulse) were measured at all study visits. Clinically significant changes from baseline in vital signs were recorded as AEs.

A sigmoidoscopy was performed by the same investigator at baseline (or for newly diagnosed patients at screening) and week 8 (or at the withdrawal visit for patients discontinuing early). Mucosal appearance was examined on the area of worst inflammation within 15 cm of the anal verge (or in the sigmoid colon if the rectum was not inflamed) and was appraised on a scale of 0–3 [0 = normal (intact vascular pattern, no friability or granulation), 1 = mild (erythema, decreased vascular pattern, friability, minimal granularity), 2 = moderate (marked erythema, granularity, absent vascular pattern, bleeding with minimal trauma, no ulcers), 3 = severe (ulcers, spontaneous bleeding)].

Biopsies from the sigmoid and rectum were taken at baseline and week 8. Histology scores were calculated as the sum of scores for four individual areas (epithelial cells, crypts, mononuclear cells in the lamina propria and neutrophils in the lamina propria). In addition, at week 8, additional biopsies were taken from the least inflamed area for the measurement of mucosal concentrations of 5-ASA and Ac-5-ASA, and a blood sample was taken for the measurement of 5-ASA and Ac-5-ASA plasma concentrations. These concentrations were measured by high-performance liquid chromatography in a central laboratory (Tepnel Scientific Services, Glasgow, UK).

Throughout the study, patients recorded written details of disease-specific symptoms (stool frequency and rectal bleeding) and AEs in a diary card. Scores for symptoms of rectal bleeding (0 = normal, 1 = streaks of blood, 2 = obvious blood, 3 = mostly blood) and stool frequency (0 = normal, 1 = 1–2 stools more than normal, 2 = 3–4 stools more than normal, 3 = greater than 4 stools more than normal) were calculated at all visits by averaging the total score over the last available 3 days prior to the study visit. Data older than 5 days were not used. The PGA was completed by the same investigator at baseline and week 8. This assessment was scored on a scale from 0 to 3 (0 = no active disease, 1 = mild disease, 2 = moderate disease, 3 = severe disease). The UC-DAI total score was calculated at baseline and week 8 (or at the withdrawal visit for patients discontinuing early) as the sum of scores of rectal bleeding, stool frequency, mucosal appearance (sigmoidoscopy) and PGA parameters.

Rescue medication was not permitted and patients considered to be treatment failures were withdrawn and assigned an appropriate alternative UC treatment by the investigator. Compliance was assessed throughout the study by determining the amount of unused medication. Records were kept of all medication dispensed, used and returned by each patient. At the end of the study, all unused trial medication and used packaging was returned to the clinical research officer at PCI Clinical Services, UK. All study medication was accounted for and any discrepancies documented.

Changes to the planned protocol

Changes to the planned protocol were made to facilitate recruitment of newly diagnosed and relapsing patients including: permission to perform screening and baseline visits on different days; amending diagnosis and criteria for admission to include patients with a sigmoidoscopy score of ≥1; amending the definition of remission to include a reduction from baseline in sigmoidoscopy score of at least 1-point; extension of the period of relapse from 4 to 6 weeks for patients who had been in relapse; and permission to use a stable dose of aspirin (up to 325 mg/day) for cardiac disease or paracetamol for mild acute pain.

In addition, to prevent recruitment of patients possibly resistant to therapy or likely to relapse following a reduction in mesalazine dose, the exclusion criteria were changed to exclude patients who relapsed within 2 weeks of a mesalazine dose reduction, from >2.0 to ≤2.0 g/day, or had unsuccessfully treated their current relapse with steroids or mesalazine at doses of >2.4 g/day. To allow separate screening and baseline visits, patients were excluded if they had used rectal steroids within 4 weeks prior to baseline or immunosuppressants 6 weeks prior to baseline.

Assignment

Patients were randomly assigned to one of the three dose groups; MMX mesalazine 1.2, 2.4 or 4.8 g/day given once daily (QD) in a 1:1:1 ratio in a double-blind fashion. Randomization was stratified by centre and randomization numbers were not reassigned in the event of patient withdrawal.

Masking

MMX mesalazine and placebo tablets were identical in appearance, with each MMX mesalazine tablet containing 1.2 g/day of mesalazine (5-ASA) and administered orally. Each patient received four visually identical tablets on each treatment day: 1.2 g/day QD group (one MMX mesalazine tablet and three placebo tablets); 2.4 g/day QD group (two MMX mesalazine tablets and two placebo tablets); 4.8 g/day QD group (four MMX mesalazine tablets).

Primary objective and outcomes

The primary objective of this study was to compare the percentage of patients in remission at the end of the 8-week treatment period for the three dose groups. Remission was defined as a UC-DAI score ≤1 with a score of 0 for rectal bleeding and stool frequency, and at least a 1-point reduction from baseline in sigmoidoscopy score.

Secondary objectives and outcomes

Secondary objectives were to compare the change in UC-DAI score, sigmoidoscopic appearance and histology from baseline to week 8, and the change in symptoms (rectal bleeding and stool frequency) from baseline to weeks 2, 4 and 8 for the three dose groups. UC-DAI score and remission were summarized by diagnosis (newly diagnosed vs. relapsing UC) and centre. In addition, the relationship between oral dose of MMX mesalazine and mucosal and plasma concentrations of 5-ASA and Ac-5-ASA were investigated. Safety and tolerability were assessed by recording and evaluating AEs, laboratory tests (haematology, biochemistry and urinalysis), physical examination and evaluating vital signs.

Study populations

The safety population was defined as all randomized patients who received at least one dose of study medication. The intent-to-treat (ITT) population was defined as all randomized patients who received at least one dose of study medication and who had a baseline and at least one post-baseline efficacy assessment for one of the four components of the UC-DAI score. Patients who had received at least one dose of study medication and were later found not to fulfil the eligibility criteria after screening (based on blood test and stool culture result) were included in the ITT population. The evaluable population was defined as all patients in the ITT population, except for those patients who were randomized but were found not to fulfil the eligibility criteria after screening.

Statistical analysis

Assuming a linear trend in the remission rate vs. log dose, and a 45% remission rate at the middle dose (2.4 g/day), it was calculated that 12 patients would be required to be randomized per treatment arm to achieve approximately 80% power (using a two-tailed 5% significance level) to detect a linear trend with a difference between successive doses of 28%.

The primary analysis was performed on the evaluable population using a last observation carried forward (LOCF) approach for patients discontinuing early. This allowed data from a patient's discontinuation visit to be carried forward to week 8. The percentage of patients in remission in each dose group was assessed using the Fisher's exact test (lack of patients in remission in one treatment arm prohibited the use of the planned logistic regression analysis). As a secondary sensitivity worst case analysis, patients who discontinued before week 8 were considered not to be in remission (i.e. the LOCF approach was not used).

Owing to the exploratory nature of this study, no formal statistical analyses were carried out on any secondary end points. Data for these end points were summarized appropriately for the evaluable population using descriptive statistics and frequency counts and/or graphical displays. Safety data were summarized for the safety population and plasma and mucosal concentration of 5-ASA and Ac-5-ASA were summarized for the ITT population.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Patient demographics

Patient demographics (Table 1) were generally similar for all dose groups; any baseline differences that occurred were as expected for the small study population. Forty patients were enrolled into the study at eight different centres between February 2003 and October 2004. Of these, 38 patients were randomized: 13 into the MMX mesalazine 1.2 g/day QD group; 14 into the MMX mesalazine 2.4 g/day QD group and 11 into the MMX mesalazine 4.8 g/day QD group. A total of 36 patients were evaluable for efficacy and 38 patients for safety analysis (Figure 1). All patients except one (Asian) were Caucasian. There were no important differences between the groups in terms of concurrent illnesses. Ten patients prematurely discontinued study medication (Figure 1).

Table 1.   Patient demographics for the intent-to-treat population
 MMX mesalazine [1.2 g/day given QD (n = 13)]MMX mesalazine [2.4 g/day given QD (n = 14)]MMX mesalazine [4.8 g/day given QD (n = 11)]
  1. * Involvement of sigmoid and/or descending colon.

  2. QD, once daily.

Male:female ratio9:47:78:3
Age [years; median (range)]41 (22–72)39 (23–74)48 (31–79)
Weight [kg; median (range)]80.0 (62.9–95.2)75.4 (49.0–93.8)70.7 (48.0–85.0)
Duration of disease [months; median (range)]28.3 (0.0–248.7)47.0 (0.0–207.1)22.3 (0.1–178.9)
Number of episodes of ulcerative colitis within the last year [median (range)]2 (0–12)1 (0–5)1 (0–5)
Classification of disease, n (%)
 Left sided*10 (83.3)11 (78.6)7 (63.6)
 Involvement of transverse colon001 (9.1)
 Pancolitis2 (16.7)3 (21.4)3 (27.3)
 Missing100
image

Figure 1.  Patient flow. * Patients 01–098 had a positive stool culture. QD, once daily; ITT, intent-to-treat; LOCF, last observation carried forward.

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A total of 31 patients (81.6%) had relapsing UC. The median duration of disease was longer in the 2.4 g/day QD dose group compared with the 1.2 and 4.8 g/day QD dose groups (median = 47 vs. 28 vs. 22 months, respectively). However, the duration of the current episode was slightly shorter in the 1.2 g/day QD group compared with the 2.4 and 4.8 g/day QD groups (median = 14 vs. 21 vs. 21 days, respectively). Similarly, the extent of disease was less in the 1.2 g/day QD dose group compared with the 2.4 and 4.8 g/day QD groups (28 vs. 40 vs. 50 cm, respectively).

Almost half of the patients had taken 5-ASA medication (other than MMX mesalazine) in the 6 weeks prior to starting study treatment (38.5% in the 1.2 g/day QD group, 42.9% in the 2.4 g/day QD group and 45.5% in the 4.8 g/day QD group) and the majority received concomitant medications during the study, most frequently analgesics, systemic antibacterial agents, β-blocking agents and drugs for acid-related disorders. Concomitant medications were taken by a similar percentage of patients in all dose groups. All patients were ≥80% compliant with study medication.

Efficacy

Remission

Six patients in the evaluable population achieved remission (primary end point; UC-DAI score ≤1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction from baseline in sigmoidoscopy score) at week 8 [LOCF; four patients (30.8%) in the 2.4 g/day QD dose group; two patients (18.2%) in the 4.8 g/day QD dose group; no patient achieved remission in the 1.2 g/day QD dose group]. There was no statistically significant difference between the groups in terms of remission (P = 0.130). Only one patient (4.8 g/day QD dose group) who achieved remission had been newly diagnosed with UC.

UC-DAI and PGA scores

At week 8 (LOCF), the greatest median improvement in UC-DAI score from baseline was achieved in the 4.8 g/day QD dose group (5.7-points), which resulted in a median UC-DAI score of 1.0-point (Figure 2). This improvement was almost double that achieved in the 2.4 g/day QD dose group [3.3-points; median UC-DAI score of 2.3-points at week 8 (LOCF)] and almost six times that achieved in the 1.2 g/day QD dose group [1.0-point; median UC-DAI score of 5.0-points at week 8 (LOCF); Figure 2]. Overall, the 2.4 and 4.8 g/day QD dose groups showed greater response to treatment compared with the 1.2 g/day QD dose group.

image

Figure 2.  Median improvement in ulcerative colitis-disease activity index (UC-DAI) and Physician's Global Assessment (PGA) score at week 8 (last observation carried forward). † Median improvement in PGA score for the 1.2 g/day (QD) group = 0. QD, once daily.

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A clinically relevant median improvement in PGA score from baseline of 1.0-point was achieved in the 2.4 and 4.8 g/day QD dose groups (Figure 2), while the median scores (1.0-point for 2.4 g/day QD dose group and 0.0-point for the 4.8 g/day QD dose group) indicate an improvement from moderate to mild disease. No improvement was obtained in the 1.2 g/day QD dose group.

Stool frequency and rectal bleeding

The median improvement in stool frequency from baseline to week 8 (LOCF) was similar for all MMX mesalazine groups, ranging from 0.67-point in the 1.2 and 4.8 g/day QD dose groups to 1.00-point in the 2.4 g/day QD dose group (Table 2). At week 8 (LOCF) the median stool frequency score was 0.00-point (normal stool frequency) in the MMX mesalazine 2.4 g/day QD group, 1.00-point (1–2 stools more than normal per day) in the MMX mesalazine 4.8 g/day QD dose groups and 1.33-points in the MMX mesalazine 1.2 g/day QD group.

Table 2.   Baseline and change from baseline in assessed scores for the evaluable population
 MMX mesalazine [1.2 g/day given QD (n = 12)]MMX mesalazine [2.4 g/day given QD (n = 13)]MMX mesalazine [4.8 g/day given QD (n = 11)]
  1. Values are expressed as Median (range).

  2. For baseline, ‘range’ = minimum and maximum scores. For change in values at given weeks, ‘range’ = maximum reduction to maximum increase in score.

  3. QD, once daily; LOCF, last observation carried forward.

Stool frequency score
 Baseline2.00 (+0.67 to 3.00)2.00 (0.00–3.00)1.67 (0.67–3.00)
 Week 2−0.67 (−1.67 to +0.33)−0.67 (−2.33 to +1.00)−0.67 (−3.00 to +0.33)
 Week 4−0.83 (−2.33 to +1.00)−0.67 (−2.67 to +0.00)−0.83 (−3.00 to +0.33)
 Week 8 LOCF−0.67 (−2.00 to +1.00)−1.00 (−3.00 to +1.00)−0.67 (−3.00 to +0.67)
Rectal bleeding score
 Baseline1.83 (0.00–2.33)2.00 (0.00–3.00)1.67 (0.00–2.00)
 Week 2−0.33 (−2.00 to +2.00)0.00 (−2.00 to +0.00)−1.33 (−2.00 to +0.00)
 Week 4−0.17 (−2.00 to +0.67)−1.00 (−2.33 to +0.00)−1.00 (−2.00 to +0.00)
 Week 8 LOCF0.00 (−1.67 to +1.00)−1.00 (−3.00 to +1.33)−1.00 (−2.00 to +1.00)

Scores for rectal bleeding were improved to 0.00-point (median change: 1.00-point) in both the 2.4 and 4.8 g/day QD dose groups at week 8 (LOCF; Table 2), but there was no improvement in score in the 1.2 g/day QD group (median change: 0.0-point).

Sigmoidoscopy and histology scores

Baseline sigmoidoscopy and histology scores were similar in each treatment arm. The greatest median improvement from baseline to week 8 (LOCF) in sigmoidoscopy and histology scores was in the 4.8 g/day QD dose group, compared with the other two doses (Figure 3a). For sigmoidoscopy score, the highest dose group (4.8 g/day QD) achieved a median improvement of 2.0-points (median score of 0.0-point), double the improvement achieved in the other two dose groups (Figure 3a).

image

Figure 3.  (a) Median improvement in sigmoidoscopy score at week 8 [last observation carried forward (LOCF)] from baseline (evaluable population). (b) Geometric mean mucosal 5-ASA/acetyl (Ac)-5-ASA (ng/mg) at week 8 (LOCF). † Median improvement in rectal biopsy for the 1.2 g/day (QD) group = 0. QD, once daily.

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The greatest median improvement in histology scores from baseline to week 8 (LOCF) was achieved in the 4.8 g/day QD dose group [3.0-points (rectal), 4.5-points (sigmoid); Figure 3a] bringing the median histology scores to 1.0-point (rectal) and 0.0-point (sigmoid) in this dose group. A comparatively lower median improvement from baseline in biopsy scores was achieved in the 2.4 g/day QD dose group [0.5-point (rectal), 3.0-points (sigmoid); Figure 3a], which resulted in median scores of 5.0-points (rectal) and 2.0-points (sigmoid) at week 8 (LOCF). No median improvement in rectal histology score and a median worsening in sigmoid histology score of 1.0-point were observed in the 1.2 g/day QD dose group from baseline to week 8 (LOCF). Overall, patients in the 4.8 g/day QD dose group experienced better mucosal healing, as evidenced by improvement in histology scores, compared with those in the other two dose groups.

Pharmacokinetics

Plasma concentrations of 5-ASA and Ac-5-ASA increased with rising doses of study drug at week 8. Geometric mean plasma 5-ASA concentrations of 283.6, 511.4 and 1926.0 ng/mL, and Ac-5-ASA concentrations of 783.0, 1513.5 and 2864.6 ng/mL were observed in the 1.2, 2.4 and 4.8 g/day QD dose groups respectively. Geometric mean mucosal 5-ASA concentration was greater in the 4.8 g/day QD dose group (48.8 ng/mg) than the 1.2 g/day QD (11.2 ng/mg) and 2.4 g/day QD (6.9 ng/mg) dose groups (Figure 3b). Similarly, the geometric mean mucosal Ac-5-ASA concentration was greater in the 4.8 g/day QD dose group (29.7 ng/mg) than the 1.2 g/day QD (8.6 ng/mg) and 2.4 g/day QD (7.0 ng/mg) dose groups. Scatter plots of mucosal vs. plasma levels of 5-ASA or Ac-5-ASA did not suggest any strong relationships (data not shown). Similarly, scatter plots of mucosal and plasma 5-ASA and Ac-5-ASA levels vs. UC-DAI score did not show any strong relationships (data not shown). However, in addition to having the highest mucosal concentrations of 5-ASA and Ac-5-ASA, the 4.8 g/day QD group also had the best median histology (sigmoid and rectal) and sigmoidoscopy scores at week 8 (LOCF) when compared with the lower dose groups.

Safety

Generally, MMX mesalazine was well tolerated. Treatment-emergent AEs were experienced by 28 patients (73.7%) in the safety population (Table 3). These occurred slightly more frequently in the 4.8 g/day QD dose group than the other two dose groups. All treatment-emergent AEs were of mild or moderate severity, with the exception of one severe AE of autoimmune hepatitis (1.2 g/day QD dose group) that was considered to be unrelated to study medication in a patient with a history of hepatitis. This patient's condition was diagnosed after the blood samples collected at screening were processed. Consequently, this patient received study medication but was withdrawn from the study as a screen failure on day 12.

Table 3.   Adverse events (AEs) and related discontinuations in the intent-to-treat/safety population
 MMX mesalazine [1.2 g/day given QD (n = 13)]MMX mesalazine [2.4 g/day given QD (n = 14)]MMX mesalazine [4.8 g/day given QD (n = 11)]
  1. All AEs are treatment-emergent, defined as an AE with onset on or after the date of first dose of study treatment and up to and including 30 days after the last dose was taken.

  2. QD, once daily.

Number (%) of patients with:
 any AE9 (69.2)9 (64.3)10 (90.9)
  At least one mild AE6 (46.2)9 (64.3)10 (90.9)
  At least one moderate AE6 (46.2)2 (14.3)2 (18.2)
  AE related to treatment3 (23.1)5 (35.7)2 (18.2)
 any serious AE (SAE)1 (7.7)00
  SAEs related to treatment000
Number (%) of patients who discontinued study due to AEs000
Number (%) of patients who died due to an AE000

Headache was the most frequent AE [eight patients (21.1%)] experienced by a similar number of patients in all dose groups. All remaining AEs occurred in no more than two patients in any dose group. Treatment-related AEs, other than headache, occurred in no more than one patient in any dose group and consisted of diarrhoea and nausea (reported only in the 1.2 g/day QD dose group), upper-abdominal pain, aphthous stomatitis, constipation and pruritis (reported only in the 2.4 g/day QD dose group) and somnolence (reported only in the 4.8 g/day QD dose group). The one patient with treatment-related somnolence demonstrated low red blood cell and haematocrit levels whilst receiving study medication; however, the condition was resolved without additional medication. No renal or urinary disorders or hepatobiliary disorders were reported and no deaths occurred. No patients withdrew from the study because of AEs.

There were no clinically significant differences between the dose groups with respect to laboratory parameter findings, with the majority of patients in all dose groups having laboratory values within the normal range at all study visits. The frequency of clinically significant out-of-range haematology values was low: three patients (23.1%) in the 1.2 g/day QD group, one patient (7.1%) in the 2.4 g/day QD group and one patient (9.1%) in the 4.8 g/day QD dose. Of the five patients with out-of-range values, one was a screen failure with autoimmune hepatitis, which was recorded as a serious AE unrelated to study medication; one had high white blood cell (WBC) and neutrophil counts at both weeks 2 and 4, which were recorded as mild AEs unrelated to study medication; and one had a low WBC value at week 8, which was recorded as a mild AE that was unrelated to study medication. The frequency of clinically significant out-of-range biochemistry values was also low: two patients (15.4%) in the 1.2 g/day QD group and one patient in the 2.4 g/day QD group (7.1%). Of these three patients, one was the screen failure with autoimmune hepatitis as described above, one had a high alanine transaminase value at week 2, which was recorded as a mild AE unrelated to study treatment, and the remaining patient had low potassium at baseline. Only one patient had a clinically significant urinalysis result, testing positive for occult blood at baseline, which was recorded as a mild AE unrelated to study medication.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

MMX mesalazine is a novel, high-strength formulation of 5-ASA (1.2 g per tablet), which uses MMX technology designed to release 5-ASA throughout the colon. The aim of this study was to evaluate the efficacy of three different doses of MMX mesalazine given once daily for the induction of remission of mild-to-moderately active UC and to determine the optimal dose for this patient population.

The data from this pilot study show that in our small, but randomized, patient population, MMX mesalazine 2.4 or 4.8 g/day given once daily is well tolerated and efficacious for the improvement in symptom scores of mild-to-moderate UC. The remission rates in our study were modest, possibly due to the high number of withdrawals. As this was a phase II, dose-ranging, pilot study, it is difficult to compare our remission rates with those of previously reported studies. This is compounded by the fact that various definitions of remission have been employed in clinical trials of 5-ASAs for UC,14,15 which are not directly comparable with those used in our study. Specifically, number and frequency of dosing of 5-ASA tablets, differences in endoscopic scoring systems and differences in study populations (e.g. mild-to-moderately active UC vs. moderately active UC) are key factors that differ between clinical trials of 5-ASAs. This said, our remission rates can be tentatively compared with those of a similarly small Asacol study reported by Schroeder et al.16 In the Schroeder et al.16 study of Asacol 1.6 (n = 11) and 4.8 g/day (n = 38) vs. placebo (n = 38), the authors reported that 9%, 24% and 4% of patients with mild-to-moderate UC achieved a ‘complete response’ (remission) in each study arm respectively.16

The efficacy of existing formulations given once daily vs. two or three times daily for the induction of remission has not yet been studied. A small pilot study of a currently available oral mesalazine formulation demonstrated that patients with quiescent UC receiving once daily dosing experienced a similar number of relapses to those receiving two or three times daily dosing after 6 months.17 However, the study was only powered to compare compliance rates between groups.

Improvement in UC-DAI, sigmoidoscopy and histology scores from baseline to week 8 (LOCF) of treatment were numerically greatest for the MMX mesalazine 4.8 g/day QD dose group. Although no obvious relationships between plasma or mucosal concentrations of 5-ASA and Ac-5-ASA and the UC-DAI score were seen, the high levels of mucosal 5-ASA recorded for the 4.8 g/day group may have contributed to the greater improvement in sigmoidoscopy and histology scores achieved at week 8 (LOCF) compared with the lower doses. The reasons for the similar mucosal 5-ASA concentrations for the 1.2 and 2.4 g/day groups are unclear, especially given the relatively high mucosal 5-ASA concentrations seen in the 4.8 g/day group; however, the potential for intrapatient and interpatient variability in our small study may have been a contributing factor. The superior efficacy of high doses of 5-ASA has recently been demonstrated in a number of clinical trials. In a combined analysis of two phase III, randomized, double-blind, controlled trials comparing a high-strength 5-ASA tablet (2 × 800 mg t.d.s.; 4.8 g/day) with a lower dose tablet [2 × 400 mg tablets t.d.s. (2.4 g/day)] in patients with moderately active UC (n = 423), the 4.8 g/day 5-ASA dose was superior to the 2.4 g/day dose for overall treatment success and sigmoidoscopic improvement after 6 weeks of treatment.18 Similarly, the results of a recent longitudinal study of 18 patients with UC in clinical remission (but had experienced at least four moderate-to-severe relapses in the previous 2 years) who switched from 2.4–3.2 g/day oral 5-ASA to 3.2–4.8 g/day oral plus 4.0 g/day topical 5-ASA showed a significant reduction in relapses over a 2-year period in comparison with the 2 years prior to switching.19

Our data also indicate that MMX mesalazine, given as a single, morning dose is well tolerated. There was no association between mucosal and plasma concentrations of 5-ASA or Ac-5-ASA with treatment-emergent AEs. The low incidence of AEs and serious AEs in this trial is consistent with the known safety profile of 5-ASA.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Our results demonstrate that MMX mesalazine 2.4 or 4.8 g/day given once daily is well tolerated and effective for the treatment of mild-to-moderately active UC. By combining high-strength tablets with advanced MMX technology to provide convenient once daily dosing and extended delivery of 5-ASA throughout the colon, MMX mesalazine may improve patient compliance and enhance overall treatment success. The data from this study support the rationale for the investigation of MMX mesalazine 2.4 and 4.8 g/day for the induction of remission of mild-to-moderately active UC in further, large, placebo-controlled clinical trials.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

The authors acknowledge the contribution of Gareth Worthington (GeoMed) for medical writing assistance and Shire Pharmaceuticals Inc. for financial support.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References
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