Oral and topical mesalazine formulations are effective in active ulcerative colitis, but little is known on the efficacy of combined treatment.
Oral and topical mesalazine formulations are effective in active ulcerative colitis, but little is known on the efficacy of combined treatment.
To compare the efficacy of oral mesalazine vs. combined oral and topical mesalazine in mildly to moderately active ulcerative colitis.
Patients with mildly to moderately active ulcerative colitis (Clinical Activity Index, CAI 4–12) were identified at 15 participating centres. They were randomized to receive either mesalazine 4 g orally plus placebo enema, or mesalazine 2 g orally plus mesalazine 2 g rectally as a liquid enema for 6 weeks. The rate of clinical remission (CAI < 4) or clinical remission/improvement (reduction of CAI of 50% from baseline) at 6 weeks and time to clinical remission/improvement were primary end-points; the rate of endoscopic remission was a secondary end-point.
67 patients were assigned to oral treatment and 63 to combined treatment. One patient in the oral group and 2 in the combined group discontinued the treatment due to adverse events. Following an intention-to-treat analysis, the rate of clinical remission was 82% for oral treatment and 87% for combined treatment (P=0.56); the mean time to remission 22.2 and 20.2 days, respectively (P=0.29); the rate of clinical remission/improvement and the rate of endoscopic remission were 85% and 91% (P=0.503) and 58% and 71% (P=0.21), respectively.
In patients with mild active ulcerative colitis, mesalazine 4 g orally and 2 g orally plus 2 g enema are equally effective in inducing disease remission.
Mesalazine preparations are a mainstay in the treatment of ulcerative colitis, both in active phases and in remission. This drug is currently available in oral and rectal formulations, both of which are thought to exert their therapeutic effect through topical delivery.
Several clinical trials have shown that both oral and rectal formulations are effective in inducing remission of mild to moderate active flares of ulcerative colitis.1–13 Maintenance of remission can also be obtained using either formulation3, 14–18 although a long-term use of rectal formulations may be hampered by patient compliance.
Thus, in clinical practice, oral formulations are generally used for maintenance therapy, whereas topical formulations are used in acute phases. However, to the best of our knowledge, only two published trials have directly compared the efficacy of oral vs. topical treatment in active disease.19, 20 In both of them, topical treatment proved to be superior to oral therapy. Only patients with proctitis were included in one of these studies,19 whereas patients with left-sided colitis were included in the other.20 In the latter, combined oral and topical treatment was even more efficacious than topical therapy alone, but a higher total dose of mesalazine was administered to patients assigned to the combined regimen than to patients assigned to either single regimen.20 No studies are available comparing oral and combined treatment in mild to moderate extensive colitis. On the other hand, combined therapy has been shown to be more effective than either oral or topical treatment in the long term maintenance of remission.21
In the present trial, we compared the efficacy of two regimens of mesalazine therapy providing the same total drug dose (4 g/day orally vs. 2 g/day orally plus 2 g/day rectally) in the treatment of acute mild to moderate ulcerative colitis, regardless of disease extension.
The study protocol was approved by the ethical committee of all participating centres. Written informed consent was obtained from all enrolled patients.
Ulcerative colitis patients were eligible for the study if they were aged from 18 to 75 years and were suffering from a mild to moderate flare of the disease as defined by a Clinical Activity Index (CAI) from 4 to 12 (see Table 1).3 Patients with proctitis (colonic involvement < 15 cm), severe disease activity, evidence of gastrointestinal infection, current or recent (< 30 days) steroid or immunosuppressive treatment, mesalazine intolerance, serious concurrent diseases, pregnancy or breast-feeding were excluded.
Eligible patients were randomly assigned to receive one of the following treatments for 6 weeks: (A) mesalazine, 500 mg eudragit L enteric-coated tablets (Salofalk), 8 tablets per day in two divided doses plus a placebo enema at bedtime (oral group); (B) mesalazine, 500 mg tablets, 4 tablets per day and 4 tablets of an identical placebo in two divided doses plus a mesalazine 2 g/60 mL enema (Salofalk 2 g/60 mL) at bedtime (combined group).
Patients were randomly allocated to one of the two treatment groups. Randomization was carried out in blocks of four using a single, centralized, computer generated randomization list. Active drugs and placebos of identical appearance were provided to participating centres in packages labelled only with the patients’ identification number. Codes were also provided in closed envelopes, and the centres were allowed to break them only in the occurrence of a severe adverse event.
At baseline, all patients underwent full clinical evaluation, blood chemistries (total blood count, liver and renal function tests, blood glucose, CRP and urinalysis) and colonoscopy.
Follow-up visits were performed at weeks 2, 4 and 6. At each visit, biochemical evaluations were repeated and the Clinical Activity Index was calculated. Colonoscopy was repeated at the end of the treatment (week 6). Mucosal biopsies were taken at both baseline and follow-up colonoscopy and sent to a single laboratory for processing and histological evaluation.
The primary end-points of the study were the rate of achievement of clinical remission or clinical remission/improvement at 6 weeks and time to clinical remission/improvement.
A secondary end-point was the rate of achievement of endoscopic remission. Clinical remission was defined as a Clinical Activity Index of < 4 and clinical improvement as a decrease in CAI of > 50% from baseline.
Endoscopic activity was assessed by an Endoscopic Activity Index (EAI) according to Rachmilewitz3 calculated for each colonic segment involved by the disease. Endoscopic remission was defined as an EAI < 4 in all segments.
Treatments were discontinued at the end of 6 weeks or if any of the following events occurred: disease deterioration requiring other forms of treatment, adverse event severe enough to make discontinuation of treatment advisable, pregnancy, poor compliance, impossibility to attend follow-up visits. Treatment could also be discontinued at any time following a patient’s request.
On the basis of previous trials, the rate of remission was estimated as 30% for oral therapy1, 5 and 65% for the combined treatment.19 Thus, allowing for a 35% rate of exclusion in each group, an enrolment of about 65 patients per group was deemed necessary to obtain a 90% chance of demonstrating this difference with an α error of 0.05.
Efficacy analysis was carried out by using both ‘intention-to-treat’ (ITT) and ‘per protocol’ (PP) strategies. Patients were excluded from the per protocol analysis if they had dropped out for any reason, if they had discontinued the treatment for at least 3 days or if they had assumed less than 80% of the prescribed dosage during any of the intervals between follow-up visits. All randomised patients were included in the intention-to-treat analysis and those interrupting the study were considered as a treatment failure, whereas those who had temporarily discontinued the drug or taken less than 80% of the prescribed dosage were evaluated according to their outcome. Since the two analyses gave similar results, only the ITT analysis is reported.
The rates of remission/improvement in the two groups were compared by a two-tailed χ2 test; the time of achievement of remission/improvement was evaluated according to the Kaplan–Meier method and the results in the two groups were compared by Log-rank test.
One hundred and thirty patients were enrolled: 67 of them were randomized to oral treatment (mesalazine, 4 g orally) and 63 to combined treatment (mesalazine, 2 g orally + 2 g by enema). The two groups were well balanced for all demographic and clinical features evaluated (see Table 2).
Twenty-three patients (10 in the oral group and 13 in the combined group) discontinued the treatment: 16 because of poor compliance (oral group 6, combined group 10), five because of a lack of efficacy (oral group 3, combined group 2) and two because of adverse events (1 in each group). All were considered in the intention-to-treat analysis (Figure 1).
No significant difference was found between the two groups at any of the predefined end-points. In particular, using intention-to-treat analysis, the proportion of patients achieving clinical remission was 82% (55/67) for the oral treatment and 87% (55/63) for the combined treatment (P=0.56). In the two groups, the number of patients obtaining either clinical remission or clinical improvement (as defined above) were 85% (57/67) and 91% (57/63), respectively (P=0.50). The mean time to achieve clinical remission was 22.2 days in the oral group A and 20.2 days in the combined group (P=0.29), the mean time to achieve either clinical remission or clinical improvement was also similar in the two groups (mean time 21.5 and 19.8, respectively, P=0.307) as were the actuarial curves of remission (P=0.29, Figure 2). The rate of patients achieving endoscopic remission was 58% (36/62) in the oral group and 71% (41/58) in the combined group (P=0.21).
We then evaluated—although this was not defined in advance as a study end-point—the number of patients achieving both clinical and endoscopic remission: again, no significant difference was observed between the two groups using either intention-to-treat or per protocol analysis. According to the former, the rate was 49% (33/67) for the oral treatment and 59% (37/63) for the combined treatment (P=0.36).
No differences were found between the two groups even when patients were stratified according to disease extension. Indeed, patients with proctosigmoiditis had a response rate of 86% with oral therapy and 93% with the combined therapy, and patients with more extensive colitis had a response rate of 83% and 86%, respectively.
Five patients in the oral group (8%) and four patients in the combined group (6%) reported adverse events. Adverse events leading to treatment discontinuation occurred in only one patient randomized to oral therapy (headache and fever) and one patient randomized to combined therapy (flu-like syndrome).
In the present study, two mesalazine regimens for the treatment of active ulcerative colitis were compared. Both oral and topical mesalazine therapies are known to be effective in the treatment of ulcerative colitis flares; however, very few studies have compared the efficacy of the two modalities of treatment and only one study evaluated combined oral and topical treatment vs. single therapies.20
In our series of patients, both oral and combined treatments proved to be highly effective in inducing remission of mildly to moderately active ulcerative colitis. Indeed, no difference between the two treatment modalities was observed, with an 82% of patients achieving clinical remission on oral therapy and 87% on the combined therapy. No significant difference was observed in time to remission (22.2 days vs. 20.2 days) and in the rate of patients achieving either endoscopic (58% vs. 71%) or combined clinical and endoscopic remission (49% vs. 59%). A slight and nonsignificant trend in favour of the combined treatment was found in all these end-points. A much greater number of enrolled patients would have been required to show a statistical significance in such differences. Indeed, the power of the study was calculated as being appropriate for detecting a 30% difference in the rate of clinical remission, as could have been anticipated on the basis of previous experiences.1, 5, 19 Anyway, it is questionable that the slight differences observed in the present study could be of any clinical value.
Our results are somewhat surprising, since they are at great variance with those reported by Safdi et al.,20 who observed a significantly higher response rate (88%) using combined therapy compared with oral (46%) and topical (68%) formulations alone. It has been suggested that the results of Safdi’s study may derive from the use of different total mesalazine dosages in the three groups evaluated (6.4 g daily in a combined treatment, 4 g daily in topical treatment and 2.4 g daily in oral treatment).22 In our study, two identical total mesalazine dosages (4 g daily) were compared.
By comparing the results of these studies, one could note that the rate of remission obtained with a combined treatment was nearly identical (87% vs. 88%) in spite of a different total mesalazine dosage, whereas a much higher response rate with oral therapy alone (82% vs. 45%) was found in our study. This difference could be related to the use of a higher mesalazine dosage in the present study for patients treated solely orally (4 g vs. 2.4 g), whereas similar oral dosages (associated with different rectal dosages) were used for patients who received the combination treatment (2 g vs. 2.4 g). Indeed, it is known that the effects of oral mesalazine are dose-dependent,1, 23 whereas the effects of topical mesalazine do not show such an obvious trend.10, 12
However, in the present study a disproportionately higher remission rate was found with oral mesalazine, when compared with the results of two previous trials using similar dosages.1, 5 In those trials, the remission rate was 24% and 29%, respectively. A factor that could explain such a difference could be the mild disease activity of patients included in the present trial. Indeed, although patient enrolment was planned to include both mildly and moderately active disease, most patients that were enrolled were in fact suffering from a mild flare-up. This is shown by the mean CAI at enrolment, which was 6, and by the fact that in about 90% of our patients the CAI was ≤ 8 (data not shown). Inclusion criteria in the two previously cited studies1, 5 were very similar to ours, but the mean disease severity of enrolled patients was not reported.
On the other hand, disease extension (another factor that could influence the efficacy of oral therapy) was very similar in all three studies; indeed, only 25–30%; of enrolled patients had extensive disease.1, 5
Finally, it is possible that the discrepancies between the results of the present study and those of previous ones are due to the different method used for defining disease remission. In fact, we chose to use the Clinical Activity Index described by Rachmilevitz, and to define disease remission as a score < 4. By using this criterion, Rachmilevitz reported a very high remission rate (74%) using an oral mesalazine dosage as low as 1.5 g per day.3 Other papers which reported much lower remission rates1, 4, 5 applied a more strict definition of disease remission, i.e. normal bowel frequency and absence of blood in the stools. In our series, such a strict definition (data not shown) would have resulted in a remission rate of 51% for oral therapy and 68% for combined treatment, difference which is approaching statistical significance (P=0.06).
In conclusion, our data show that the two treatment regimens tested (mesalazine 4 g orally and mesalazine 2 g orally plus 2 g rectally) are well tolerated and have a similar efficacy in inducing the remission of mild flares of ulcerative colitis. The relative efficacy of oral and combined mesalazine regimens in patients with more active disease should be tested in further studies.
This trial was supported by the pharmaceutical company Ravizza Farmaceutici S.p.A., Muggiò, Italy.
Other participants in The Study Group for Oral vs. Combination Mesalazine in Ulcerative Colitis: G. Aprile (Catania) A. Balestrieri (Cagliari), E. Bertinelli (Ravenna), G. Biasco (Bologna), F. Bortoluzzi (Mestre), R. Carratù (Napoli), T. Casetti (Ravenna), E. Gaia (Orbassano), S. Gullini (Ferrara), G. Minoli (Como), A. C. Plancher (Reggio Emilia), A. Prada (Rho), G. Riegler (Napoli), A. Russo (Catania), A. Saggioro (Mestre), S. Saibeni (Milano), R. Stabilini (Monza).