Clinical trial: ulcerative colitis maintenance treatment with 5-ASA: a 1-year, randomized multicentre study comparing MMX® with Asacol®

Authors


Prof. C. Prantera, Divisione di Gastroenterologia, Azienda Ospedaliera S. Camillo Forlanini, Circonvallazione Giancolense, Roma 00149, Italy.
E-mail: prantera@tin.it

Summary

Background  5-ASA-MMX® (1.2 g/tablet) is a 5-aminosalicylic acid formulation, designed for once-daily dosing in the treatment of ulcerative colitis.

Aim  To evaluate the efficacy and safety of 5-ASA-MMX (2.4 g/day, once daily), compared with Asacol® (2.4 g/day, twice daily) in the maintenance of left-sided UC, through a double-blind, double-dummy, parallel-group, randomized, comparator study.

Methods  In all, 331 patients with UC were randomized to receive either 5-ASA-MMX 2.4 g/day, once daily, or Asacol 2.4 g/day, twice daily, for 12 months. All patients were in remission for ≥1 month prior to the trial, with ≥1 documented relapse in the previous year. The co-primary endpoints of this study were the proportion of patients in clinical, and clinical and endoscopic remission following 12 months’ treatment.

Results  In the intent-to-treat population, excluding those with major protocol deviations, 68.0 and 65.9% patients in the 5-ASA-MMX and Asacol groups, respectively, were in clinical remission (= 0.69), and 60.9 and 61.7% of patients, respectively, were in clinical and endoscopic remission (= 0.89). Diary card data revealed statistically significant treatment differences favouring 5-ASA-MMX. Both treatments were similarly tolerated.

Conclusions  Once-daily 5-ASA-MMX is similarly effective with a comparable safety profile to Asacol administered twice daily, for the maintenance treatment of ulcerative colitis.

Introduction

5-aminosalicylic acid (5-ASA) is the recommended therapy for the induction and maintenance of remission of ulcerative colitis (UC).1, 2 The drug acts topically at the colonic mucosa to reduce mucosal inflammation,3 yet because the active drug is rapidly absorbed in the stomach and small intestine,4 a number of oral formulations have been developed to deliver 5-ASA to the colon.3, 5

Whilst achieving effective delivery to the colon is vital, compliance with prescribed medication has been shown to be an important factor in UC treatment.6–9 Indeed, compliant patients substantially reduce their risk of disease flares.10 In a pilot trial to assess compliance rates following once-daily or multiple-daily 5-ASA dosing schedules in patients with quiescent UC, significantly higher compliance rates were demonstrated in the once-daily group compared with multiple-daily dosing groups (100 vs. 70%, respectively; = 0.04).6 Indeed, compliance with prescribed medication was emphasized in a recent Cochrane meta-analysis, which concluded that future trials investigating UC treatment should examine enhancing patient adherence with their medication, rather than comparing the efficacy of various 5-ASA agents.

Mesalazine with MMX Multi Matrix Systema (MMX) technology (Mesavancol®, Giuliani, S.p.A., Milan, Italy; hereafter referred to as 5-ASA-MMX) is a novel, high-strength (1.2 g/tablet) formulation of 5-ASA, designed for once-daily dosing, that has been approved for the induction and maintenance of clinical and endoscopic remission in patients with mild-to-moderate UC in Europe and for the induction of remission of active mild-to-moderate UC in the US. This formulation of 5-ASA utilizes MMX technology comprising lipophilic and hydrophilic excipients enclosed within a gastro-resistant, pH-dependent coating.11, 12 The gastro-resistant coating is thought to delay the release of 5-ASA until the tablet is exposed to a pH of 7 or higher, (normally in the terminal ileum). The tablet core consists of hydrophilic excipients (that are thought to cause the tablet to swell to a viscous gel mass, slowing the release of 5-ASA) and lipophilic excipients (that are thought to slow the penetration of aqueous fluids into the tablet core), which are believed to prolong exposure of the colonic mucosa to 5-ASA.3, 5 As the tablet core and surrounding gel mass progress through the colon, it is thought that pieces of the gel mass gradually break away from the core, slowly releasing 5-ASA.3, 5 Previous trials have demonstrated the efficacy of 5-ASA-MMX over placebo for both the induction13, 14 and maintenance15 of remission.

The present study is the first comparative, 12-month maintenance trial to examine efficacy as the primary endpoint. In this study, we evaluated the efficacy and safety of 5-ASA-MMX 2.4 g/day administered once daily, compared with Asacol® delayed-release mesalazine (Giuliani, S.p.A., Milan, Italy; 2.4 g/day) administered twice daily, over 12 months, for the maintenance of left-sided UC.

Materials and methods

This was a randomized, double-blind, double-dummy, parallel-group study with patients recruited from centres in Italy, Poland and the Ukraine.

Participants

Patients, male and female, aged 18–75 years had an established diagnosis of left-sided UC (rectum to sigmoid colon, or colon up to the splenic flexure). Disease extent was established by sigmoidoscopy or colonoscopy and confirmed by histology. All patients were in remission (defined as a score of ≤1 on the UC Disease Activity Index [UC-DAI], supported by a rectal sigmoidoscopy in the preceding 3 months or colonoscopy in the preceding 6 months) for ≥1 month prior to entry into the trial and had experienced at least one clinically and/or endoscopically documented relapse during the previous 12 months.

Eligible patients had not received oral or topical corticosteroid treatment for ≥1 month and had not received immunosuppressant treatment for ≥3 months prior to entry into the study and were excluded from the study if they took these treatments during the study period. Patients were excluded from the study if they presented with proctitis (extent of inflammation ≤15 cm from the anus); bleeding disorders; active peptic ulcer; previous colon surgery; renal impairment (creatininaemia >1.5 mg/dL); malignancy or dysplasia in the colon. Patients were also excluded if they were receiving maintenance therapy with 5-ASA doses of >2.4 g/day, if they were known to be sensitive to 5-ASA, or if they had asthma. Furthermore, patients who, in the previous 12 months, had experienced disease activity and were unresponsive to a 12-week course of steroids (steroid refractory), were excluded from the study.

Interventions.  Eligible patients were randomized equally to either 5-ASA-MMX 2.4 g/day administered as two 1.2 g tablets in the morning and one placebo tablet in the evening, or Asacol 2.4 g/day administered as two 800 mg tablets in the morning and one 800 mg tablet in the evening. The treatment lasted 12 months and all tablets were provided as red/brown, ellipsoidal, film-coated tablets in plastic bottles.

Patients visited the clinic on six separate occasions [screening, randomization, and then after 3, 6, 9 and 12 months (or early withdrawal)]. At the randomization visit, eligible patients were allocated an individual, computer-generated, randomization number via an internet-based procedure. Patients were assigned equally (1:1) to one of the two treatment groups (5-ASA-MMX 2.4 g/day QD or Asacol 2.4 g/day BID). Alternative UC treatment was not allowed after the screening period. Patients were given a diary card in which to record details of disease-specific symptoms based on the first two items of the UC-DAI (stool frequency and rectal bleeding).

At all visits after screening, patients’ clinical symptoms were assessed; vital signs were measured; study medication was dispensed (except final visit); adverse events (AEs), concomitant medication and drug compliance (checked by tablet counts at each visit after the first visit) were recorded and patient diary cards were collected. At screening and week 8 (or early withdrawal) a urinalysis and physical examination were performed.

At the 12-month (or early withdrawal) visit, a colonoscopy or sigmoidoscopy, to the location of the previously examined inflammation, was requested to calculate the full UC-DAI score and evaluate remission status.

This study was conducted in accordance with current applicable regulations, International Conference on Harmonization and local ethical and legal requirements, and all patients signed an informed consent document prior to participation. This trial registered at EudraCT (http://eudract.emea.europa.eu/index.html), EudraCT number: 2004-000916-25.

Objectives and evaluations

The primary objectives of this study were: (a) to compare the proportion of patients in clinical remission [defined as a combined score of ≤1 on the UC-DAI scale, where the combined score was the total of the investigator’s assessment of the patient’s condition, stool frequency and rectal bleeding (only one of these three components could have a value of one)] after 12 months of treatment and (b) to compare the proportion of patients in clinical and endoscopic remission (defined as clinical remission, with a normal mucosal appearance upon endoscopic examination) after 12 months of treatment.

Secondary objectives included the time to relapse (UC-DAI score >1), defined as the time interval between the randomization date and the relapse date reported by the investigator, and assessment of the safety and tolerability of 5-ASA-MMX 2.4 g/day in the maintenance of UC.

Following the database lock, an advisory board composed of both principal investigators of this study and other independent gastroenterologists reviewed the blinded data. An overall low relapse rate prompted the concern that relapses may have been underreported in the case report forms. Prior to unblinding the data, the advisory board recommended that patients reporting a diary card score of >1 for at least 2 consecutive weeks with a rectal bleeding score of ≥1 be classified as clinical relapse at date of the first day of the week of onset.

Safety and tolerability were assessed via AE reporting, laboratory testing (haematology, biochemistry and urinalysis), physical examination and vital signs. AEs were defined as any untoward medical occurrences that were not necessarily caused by treatment (in any patient who was administered study medication) and were classified as mild, moderate or severe. A serious AE (SAE) was defined as any medical event or experience that at any dose resulted in death, was life-threatening, was permanently disabling or resulted in patient hospitalization or prolonged hospitalization.

Study populations.  The intent-to-treat (ITT) and safety populations were defined as including any patient who received at least one dose of study medication. To minimize the impact on the response rates of patients withdrawn because of purely administrative reasons that were clearly independent of treatment, a modified ITT (mITT) population was defined as the ITT population with the exclusion of patients who either, (a) withdrew from the study for a reason reported by the investigator as clearly independent of treatment, or, (b) remained in the study for 2 days or less. Withdrawals for any other reason were counted as failures (i.e. reasons potentially correlated with lack of efficacy). All patients excluded from the mITT were determined prior to breaking the blind. The per-protocol (PP) population was defined as all patients in the ITT population with no major protocol violations. A major protocol violation was defined as a deviation likely to affect treatment efficacy significantly.

Statistical analysis

Efficacy.  The proportion of patients in clinical and clinical and endoscopic remission at the 12-month visit in the two treatment groups was compared using the chi-squared test and a 95% confidence interval (CI) for the difference of proportions provided. The odds ratio (OR; and CI) between 5-ASA-MMX and Asacol was also calculated and presented.

Log-linear models, whose terms included country, treatment and the interaction of country by treatment, were used to investigate country effect and a possible heterogeneity of treatment effect across country.

For time to relapse (defined as the time interval between the dates of randomization and relapse), the two treatment groups were compared by survival analysis using the Kaplan-Meier method; in this analysis, patients who did not relapse were censored at the last date of study participation and patients withdrawn were censored at the date of withdrawal.

All the above analyses were performed for both the mITT and the PP populations, with the population of primary interest being the mITT population. All statistical tests were 2-sided with a significance level of 5%.

Safety.  The number of patients reporting AEs, and the types of AEs, were summarized by treatment group, body system, preferred term, severity and causality and SAEs were summarized separately. AEs were classified according to MedDRA Version 9.1.

Sample size.  Sample size and power calculations were based on a comparison of the proportion of treatment successes between the Asacol and the 5-ASA-MMX groups, assuming that the proportion of patients in clinical remission in the Asacol arm at 1 year was 50%. A clinically significant increase of such a proportion by 15% was needed to declare superiority (65% of patients in remission at 1 year) at a significance level of 5%.

A study with 135 patients per group would have a power of 0.80 to detect the above stated difference between groups, if it existed. To achieve this target, with an estimated drop-out rate of 10%, 300 patients were to be recruited, with 150 patients in each treatment group.

Results

Participant flow

The study was conducted between 9 October 2004 and 5 January 2007. Overall, 334 patients were randomized to treatment (Figure 1), from 34 centres in Italy, seven centres in Poland and six centres in the Ukraine.

Figure 1.

 Patient flow. * Remission was defined as a UC-DAI score of ≤1 for ≥1 month, supported by a rectum-sigmoidoscopy not older than 3 months or a colonoscopy not older than 6 months; Three patients did not receive any study medication and were not included in the ITT/safety population. 5-ASA: 5-aminosalicylic acid; MMX: MMX Multi Matrix System; s.d.: standard deviation; UC-DAI: Ulcerative Colitis Disease Activity Index.

In total, 331 patients received at least one dose of study medication and were included in the ITT/safety population (162 in the 5-ASA-MMX group, 169 in the Asacol group). Eight patients did not meet the mITT criteria and were excluded from the mITT population (= 323); reasons for exclusion were relocation to another city or country and withdrawal of informed consent within the first 2 days of the randomization visit. Protocol violations occurred in 49 patients and occurred with similar frequency between the treatment groups; 17.9 and 12.4% in the 5-ASA-MMX group and Asacol group respectively. The PP population therefore included 282 patients.

Overall, 114 patients withdrew from the study prematurely. The rate of withdrawal was similar between the 5-ASA-MMX and Asacol groups (34.6 and 34.3% respectively). The most frequent reasons for premature discontinuation in both groups were relapse (89 cases, 24.1% of the 5-ASA-MMX group and 29.6% of the Asacol group) and patient request (12 cases, 4.9% of the 5-ASA-MMX group and 2.4% of the Asacol group).

Patient demographics.  Overall, patient demographics and disease history were similar between the two treatment groups (Table 1); however, slightly more patients in the Asacol group (12.4%) compared with the 5-ASA-MMX group (8.6%) were smokers. A slightly higher proportion of patients presented with rectosigmoid disease (58.9%) compared with left-sided disease (41.1%); however, no substantial differences were observed between these groups. All patients were in clinical remission, with a UC-DAI score at baseline of ≤1; however, a slightly lower percentage of patients in the 5-ASA-MMX group (54%) compared with the Asacol group (60%) entered the study with a total UC-DAI score of 0.

Table 1.   Patient demographics
 5-ASA-MMX (= 162)Asacol (= 169)Overall (= 331)
  1. 5-ASA, 5-aminosalicyclic acid; MMX, MMX Multi Matrix System; s.d., standard deviation; UC-DAI, Ulcerative Colitis Disease Activity Index.

Gender; n (%)
 Male99 (61.1)102 (60.4)201 (60.7)
 Female63 (38.9)67 (39.6)130 (39.3)
Age (years)
 Mean (s.d.)45.4 (14.1)44.5 (13.5)44.9 (13.8)
 Min, max18, 7418, 7518, 75
Disease extension; n (%)
 Left-side colitis70 (43.2)66 (39.1)136 (41.1)
 Rectum sigmoid92 (56.8)103 (60.9)195 (58.9)
Duration of disease (years)
 Mean (s.d.)7.02 (6.07)6.96 (6.28)6.99 (6.17)
 Min, max0.08, 260.25, 290.08, 29
Number of relapses in the last year; n (%)
 1140 (86.4)143 (84.6)283 (85.5)
 219 (11.7)20 (12.4)39 (11.8)
 ≥33 (1.8)6 (3.6)9 (2.7)
Time in remission (months)
 Mean (s.d.)5.07 (2.89)4.74 (2.99)4.90 (2.93)
 Min, max1, 121, 111, 12
5-ASA maintenance therapy dose; n (%)
 <1.6 g27 (19.4)39 (26.3)66 (23.0)
 1.6–<2.4 g43 (30.9)38 (25.7)81 (28.2)
 ≥2.4 g69 (49.6)71 (48.0)140 (48.8)
UC-DAI total score; n (%)
 088 (54.3)101 (59.8)189 (57.1)
 173 (45.1)67 (39.6)140 (42.3)
 Missing1 (0.6)1 (0.6)2 (0.6)
Smoking; n (%)
 No148 (91.4)148 (87.6)296 (89.4)
 Yes14 (8.6)21 (12.4)35 (10.6)

Concomitant medications taken during the treatment period were generally similar between the two groups, although a slightly higher proportion of salicylates and Angiotensin-Converting Enzyme inhibitors were used by patients in the 5-ASA-MMX group (9.3 and 8.6%, respectively) compared with the Asacol group (5.9 and 3.0% respectively). With the exception of aminosalicylic acid, no other previous medication had been taken by any more than three patients in either treatment group.

Compliance

Most patients (303/331; 91.5%), took ≥80% of the study medication, with similar numbers in each treatment group (5-ASA-MMX 88.9%; Asacol 94.1%; = 0.09).

Efficacy

At month 12, 68.0% of patients in the 5-ASA-MMX group and 65.9% of patients in the Asacol group were in clinical remission (= 0.69, OR, 1.10; Table 2). The difference of 2.1% in the proportion of patients in remission did not reach statistical significance. Patient diary data were used to investigate whether patients in remission at 12 months had experienced a worsening in stool frequency and increased rectal bleeding (a score of ≥2, with a score of ≥1 for rectal bleeding, for a duration of at least 2 weeks). At month 12, 62.2% of patients in the 5-ASA-MMX group and 51.5% of patients in the Asacol group were in clinical remission by this definition and the difference between the groups (10.7%) bordered statistical significance (= 0.05; OR, 1.55; Table 2).

Table 2.   Patients in remission following 12 months’ treatment (mITT population)
 5-ASA-MMXAsacol
Clinical (= 156)Clinical and endoscopic (= 156) Clinical (= 167)Clinical and endoscopic (= 167)
  1. * Difference of 2.1%; = 0.69.

  2. † Difference of 0.8%; = 0.89.

  3. ‡ Patients without endoscopy data were classified as treatment failures under the clinical and endoscopic remission criteria.

  4. § Difference of 10.7%; = 0.053.

  5. ¶ Difference of 7.3%; = 0.19.

  6. 5-ASA, 5-aminosalicyclic acid; MMX, MMX Multi Matrix System; mITT, modified intent-to-treat population.

Patients in remission following 12 months’ treatment (mITT)
 Remission; n (%)106 (68.0)*95 (60.9)†110 (65.9)*103 (61.7)†
 Treatment failures; n (%)50 (32.0)61 (39.1)57 (34.1)64 (38.3)
 Relapse39 (25.0)50 (29.9)
 Adverse event3 (1.9)3 (1.8)
 Other‡8 (5.1)18 (11.5)4 (2.4)9 (5.4)
Patients in remission following 12 months’ treatment, including diary card data (mITT)
 Remission; n (%)97 (62.2)§87 (55.8)¶86 (51.5)§81 (48.5)¶
 Treatment failures; n (%)59 (37.8)69 (44.2)81 (48.5)86 (51.5)
 Relapse48 (30.8)74 (44.3)
 Adverse event3 (1.9)3 (1.8)
 Other‡8 (5.1)18 (11.5)4 (2.4)9 (5.4)

In the PP population at month 12, 73.1% of patients in the 5-ASA-MMX group and 69.6% of patients in the Asacol group were in remission (= 0.51; OR, 1.19; Table 3). In the PP population, including patient diary data, at month 12, 67.2% of patients in the 5-ASA-MMX group and 54.1% of patients in the Asacol group were in remission (= 0.025; OR, 1.74; Table 3).

Table 3.   Patients in remission following 12 months’ treatment (PP population)
 5-ASA-MMXAsacol
Clinical (= 134)Clinical and endoscopic (= 134) Clinical (= 148)Clinical and endoscopic (= 148)
  1. * Difference of 3.5%; = 0.51.

  2. † Difference of 0.3%; = 0.96.

  3. ‡ Patients without endoscopy data were classified as treatment failures under the clinical and endoscopic remission criteria.

  4. § Difference of 13.1%; = 0.025.

  5. ¶ Difference of 9.2%; = 0.12; PP, per protocol; 5-ASA, 5-aminosalicyclic acid; MMX, MMX Multi Matrix System.

Patients in remission following 12 months’ treatment (PP)
 Remission; n (%)98 (73.1)*90 (67.2)†103 (69.6)*99 (66.9)†
 Treatment failures; n (%)36 (26.9)44 (32.8)45 (30.4)49 (33.1)
 Relapse31 (23.1)40 (27.0)
 Adverse event1 (0.8)2 (1.4)
 Other‡4 (3.0)12 (9.0)3 (2.0)7 (3.4)
Patients in remission following 12 months’ treatment, including diary card data (PP)
 Success; n (%)90 (67.2)§83 (61.9)¶80 (54.1)§78 (52.7)¶
 Failures; n (%)44 (32.8)51 (38.1)68 (45.9)70 (47.3)
 Relapse39 (29.1)63 (42.6)
 Adverse event1 (0.7)2 (1.4)
 Other‡4 (3.0)11 (8.3)3 (2.0)5 (3.4)

Analysis of remission rates by country showed a higher proportion of patients in Poland and Ukraine were in remission at month 12 than patients in Italy (Table 4). In all analyses, the country effect was significant (< 0.001).

Table 4.   Remission rates by country
 Remission rate (%)Difference (5-ASA-MMX vs. Asacol)P value
5-ASAAsacol
  1. 5-ASA, 5-aminosalicyclic acid; MMX, MMX Multi Matrix System; mITT, modified intent-to-treat; PP, per protocol.

Italy
 mITT56.254.6+1.60.81
 PP60.957.5+3.40.64
 mITT + diary51.436.4+15.00.026
 PP + diary54.037.2+16.80.010
Poland
 mITT90.077.8+12.20.27
 PP72.969.6+3.30.60
 mITT + diary75.070.4+4.60.73
 PP + diary73.776.0−2.30.86
Ukraine
 mITT93.696.7−3.10.57
 PP100.096.6+3.40.32
 mITT + diary90.390.0+0.30.97
 PP + diary96.489.7+6.70.32

Clinical and endoscopic remission was also assessed (defined as a complete UC-DAI evaluation with a total UC-DAI score ≤1 with no endoscopic evidence of active disease). Patients who withdrew prematurely from the study, provided no post-baseline data, or did not have an endoscopic assessment, were considered as not being in clinical remission for this analysis. Of the 217 patients in the mITT population who completed the 12-month study period, 198 (91.2%) had an endoscopic evaluation. Of these patients, at month 12, 60.9% (95/156) of patients in the 5-ASA-MMX group and 61.7% (103/167 patients) in the Asacol group were in clinical and endoscopic remission (= 0.89; OR, 0.97; Table 2). No difference in clinical and endoscopic remission rates between the groups was observed for the PP population (Table 3).

Time to relapse was defined as the time interval between the randomization date and the relapse data reported by the investigator. The difference between time to relapse between the two groups was not significant when patient diary data were not considered (= 0.48; Figure 2), but was statistically significant upon the inclusion of diary card data (= 0.031).

Figure 2.

 Time to relapse (mITT population) 5-ASA: 5-aminosalicylic acid; mITT: modified intent-to-treat.

Safety

A total of 191 treatment-emergent AEs were reported (Table 5), with the majority being mild or moderate in severity. There were no notable differences between the treatment groups with respect to the frequency of treatment-emergent AEs and there was no evidence of a dose–response relationship for 5-ASA-MMX or Asacol for any safety parameter. Eleven patients experienced an SAE (six in the 5-ASA-MMX group and five in the Asacol group). In the 5-ASA-MMX group, three SAEs were coded as ‘UC’, one patient experienced ‘melaena’, one patient experienced ‘acute pancreatitis’ and one patient experienced ‘nephrolithiasis’. In the Asacol group, patients were separately coded as experiencing ‘UC’, ‘perianal abscess’, ‘haemorrhoids’, ‘renal colic’ or ‘proteinuria’.

Table 5.   Adverse events
 Number of patients; n (%)
5-ASA-MMX (= 162)Asacol (= 169)Overall (= 331)
  1. 5-ASA, 5-aminosalicyclic acid; MMX, MMX Multi Matrix System; AE, adverse event; NOS, not otherwise specified; SAE, serious AE.

Any AE92 (56.8)99 (58.6)191 (57.7)
Any treatment-related AE13 (8.0)16 (9.5)29 (8.8)
Any SAE6 (3.7)5 (3.0)11 (3.3)
AE that led to withdrawal3 (1.9)3 (1.8)6 (1.8)
Treatment-emergent AEs reported by ≥2% of patients (ITT/safety population)
 System organ class Preferred term
 Total92 (56.8)99 (58.6)191 (57.7)
  Gastrointestinal disorders77 (47.5)76 (45.0)153 (46.2)
  Ulcerative colitis42 (25.9)50 (29.6)92 (27.8)
  Frequent bowel movements13 (8.0)11 (6.5)24 (7.3)
  Haematochezia8 (4.9)8 (4.7)16 (4.8)
  Diarrhoea NOS4 (2.5)3 (1.8)7 (2.1)
  General disorders and   administration site conditions4 (2.5)7 (4.1)11 (3.3)
  Influenza-like illness2 (1.2)4 (2.5)6 (1.8)
  Nervous system disorders8 (4.9)7 (4.1)15 (4.5)
  Headache8 (4.9)6 (3.6)14 (4.2)

A total of 29 treatment-related AEs were reported [13 (8.0%) in the 5-ASA-MMX group, 16 (9.5%) in the Asacol group]. The most common treatment-related AEs were gastrointestinal disorders (4.3 and 4.1% of patients in the 5-ASA-MMX and Asacol groups respectively).

Six patients withdrew from the study because of AEs. In the 5-ASA-MMX group, prostate cancer (= 1) and amenorrhoea (= 1) were considered not related to the study medication, and melaena (= 1) was considered possibly related to the study medication. In the Asacol group, ankylosing spondylitis (= 1) was considered not related to study treatment, and a case of increased pancreatic enzymes without clinical symptoms (= 1) and epistaxis (= 1) was judged possibly related to study treatment.

Discussion

The data from this study indicate that 5-ASA-MMX 2.4 g/day (administered once daily) and Asacol 2.4 g/day (administered twice daily) are similarly tolerated and effective in the maintenance of remission of left-sided UC. The original hypothesis of this comparative study (superiority of 5-ASA-MMX for the primary endpoint) was not confirmed; however, while this trial did not meet its primary endpoints, both formulations maintained a majority of patients in clinical remission. Overall, 68.0% of patients in the 5-ASA-MMX group and 65.9% of patients in the Asacol group were in clinical remission at 12 months. Clinical and endoscopic remission was maintained in 60.9 and 61.7% in the 5-ASA-MMX and Asacol groups respectively at 12 months. The results obtained for the primary endpoints (clinical remission and clinical/endoscopic remission) in this study were similar.

Remission rates were higher than expected16–18 and highlight important discrepancies seen during this trial. While both groups received active treatment, given the proven efficacy of 5-ASA for the treatment of UC, there is little doubt that placebo administration would have eventually decreased the remission rates. These differences may, therefore, be explained by examining the effect of the study country upon the data. Indeed, the proportion of patients in remission was not homogeneously distributed, with Poland and Ukraine showing a higher proportion of patients in remission (in all analyses, country effect < 0.001). This variation may reflect differences in practice between the national health services in each study country. Poland and Ukraine reported relatively high remission rates in all study populations, with 77.8–96.7% of patients maintaining remission at 12 months (mITT population). In contrast, patients from the Italian centres demonstrated consistently lower remission rates as low as 56.2% (5-ASA-MMX group) and 54.6% (Asacol group) at 12 months in the mITT population, which is consistent with the current available literature. A possible explanation for this discrepancy is that 79.2% of the Italian population were taking an adequate maintenance dose of 5-ASA (≥1.6 g/day) at baseline (Table 6). In contrast, only 49.0 and 36.1% of patients in Poland and the Ukraine were using similar maintenance therapy. It is therefore possible that investigators in Poland and the Ukraine included patients with milder UC, who were in remission without adequate therapy. Examining only the Italian population, including the diary card data, a significant difference was observed between the 5-ASA-MMX group and the Asacol group, in both the mITT population (= 0.026) and the PP population, (= 0.010; Table 4). Given the high number of clinical trials performed with multiple, international centres, the role of heterogeneous inclusion of patients should be taken into account when evaluating trial data.

Table 6.   5-ASA dose on trial entry
Country; n (%)5-ASA dose at entryTotal
Patients receiving less than recommended maintenance
5-ASA
Patients receiving at least recommended maintenance
5-ASA
No 5-ASA<1.6 g/day≥1.6 g/day
  1. 5-ASA, 5-aminosalicyclic acid.

Italy20 (9.0)26 (11.8)175 (79.2)221
Poland1 (2.0)24 (49.0)24 (49.0)49
Ukraine23 (37.7)16 (26.2)22 (36.1)61
Total44 (13.3)66 (19.9)221 (66.8)331

The low relapse rates observed during this trial also prompted a further check of the diary card data. Examination of the patient diary card data revealed that some patients experienced rectal bleeding and increased stool frequency during the periods in between study centre visits. These symptoms were not necessarily reported by patients, leading to potential differences in the observed and reported remission rates. This study included the recommendation from an advisory board (which reviewed data when still blinded) to reclassify as relapsed any patient with a diary score of >1 for at least 2 consecutive weeks with rectal bleeding (a score of ≥1) regardless of whether they were otherwise classified as a treatment success. When considering diary data in the mITT population, fewer patients maintained remission over 12 months: 62.2% of patients who received 5-ASA-MMX and 51.5% of patients who received Asacol (= 0.053). In the PP population 67.2% of patients who received 5-ASA-MMX and 54.1% of patients who received Asacol maintained remission over 12 months (= 0.025).

The disparities observed between reported symptoms and patient diary card data may be explained by the presence of symptoms, typical of a relapse, that manifest days or even weeks before the scheduled study visits. Patients may therefore neglect to report these to an investigator immediately. Many motives may explain such behaviour, such as difficulty in reaching the hospital, a dislike of sigmoidoscopies or examinations, reluctance to interrupt a study that provides therapy free of charge or an underestimation of symptoms. Such disparities are especially problematic in long-term trials such as this, where patients may not have a scheduled visit for up to 3 months after experiencing symptoms. In these trials, the contribution of diary cards is of particular value.

The difference in remission rates observed between the reported symptoms and the patients’ personal records highlights an important disconnect between patients’ views and expectations about their disease and the information that they report to their physicians. Indeed, similar disparities have been revealed in a number of investigations into patient perceptions and patient–physician relationships.19–21

The symptoms reported in the patient diary cards were therefore of major importance for the analysis of time to relapse. Patients receiving maintenance treatment with 5-ASA-MMX remained in remission slightly longer than patients treated with Asacol. The difference between time to relapse between the two groups was not significant when the patient diary data were not considered (P = 0.48). These differences became statistically significant after the inclusion of diary data (P = 0.031).

5-aminosalicylic acid therapy was well tolerated. Indeed, the AE profile reported here is similar to that reported in other long-term studies of 5-ASA-MMX or Asacol.15, 22 A majority of AEs in this study were mild or moderate in severity. Treatment-related AEs were reported infrequently and, among these, 11 patients reported SAEs. Six patients, three in each group, withdrew because of AEs; however, the relationship to study medication was only considered ‘possible’ in one MMX patient and three Asacol patients. Pancreatitis, a known idiosyncratic side effect of mesalazine, was seen in one patient in the 5-ASA-MMX group and resolved without discontinuation of treatment.

Despite the long duration of this study, 91.5% of all patients in the safety/ITT population were compliant with study medication (taking ≥80% of study medication), including 88.9% of patients in the 5-ASA-MMX group and 94.1% in the Asacol group. This is much higher than compliance rates generally observed in a non-trial setting, as patients in clinical trials are often more likely to be compliant with study medication because of close monitoring during the study. This disparity between compliance rates in controlled trials and the community setting is well known.23 Furthermore, as this study was designed to distribute medication in a double-dummy fashion, the compliance data cannot be considered representative of a once-daily dosing regimen. Therefore, further community-based studies will be required to determine compliance with 5-ASA-MMX and other 5-ASA therapies and the association of dosing regimen with treatment acceptance and success.

Compliance with prescribed medication has been shown to be an important factor in UC treatment.6–9 Furthermore, patients with UC in remission who are non-compliant with 5-ASA maintenance therapy have a 5-fold greater risk of disease flares than compliant patients10 and the symptoms of UC disease flares substantially decrease patients’ quality of life.24–28 As patients often cite frequency of dosing and complicated, multiple-daily dosing regimens as reasons for nonadherence,29 it is anticipated that the availability of a once-daily formulation will aid compliance, as observed for conditions such as hypertension and coronary heart disease.30, 31

In summary, once-daily 5-ASA-MMX appears to have a similar safety and efficacy profile to that of Asacol in the maintenance of remission of UC, although the patient diary data suggest some intriguing potential differences, in favour of 5-ASA-MMX, for the remission rates reported between these two formulations. Furthermore, the once-daily dosing strategy possible with 5-ASA-MMX may, in a community setting, improve patient compliance and thus therapeutic efficacy.

Footnotes

  • a

    MMX Multi Matrix System is a registered trademark of Cosmo S.p.A., Milan, Italy and MMX is a trademark of Cosmo Technologies Limited, Wicklow, Ireland, licensed to Giuliani International, Dublin, Ireland for the delivery of 5-ASA.

Acknowledgements

Declaration of personal interests: The statistical analysis of the entire data sets has been independently confirmed by Alfredo Ardia, an independent statistical consultant. Declaration of funding interest: Cosimo Prantera, Renzo Caprilli and Alfredo Ardia have served as consultants for Giuliani S.p.A. Salvatore Bellinvia is an employee of Giuliani S.p.A. This study was funded in full by Giuliani S.p.A. Writing support was provided by Duncan Campbell (GeoMed) and editorial support was provided by Sarah Wright (GeoMed), funded by Giuliani S.p.A.

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