Rectal formulations of mesalazine are the treatment of choice in mildly to moderately active ulcerative colitis. A new foam formulation of mesalazine was developed to improve both drug delivery and patient acceptance.
Rectal formulations of mesalazine are the treatment of choice in mildly to moderately active ulcerative colitis. A new foam formulation of mesalazine was developed to improve both drug delivery and patient acceptance.
In this multicentre, randomized, double-blind, parallel-group study, 111 patients with mildly to moderately active proctitis, proctosigmoiditis, or left-sided ulcerative colitis received mesalazine foam enema or placebo enema (2 g mesalazine per day) for 6 weeks. Disease activity was monitored on the basis of the Clinical Activity Index, Endoscopic Index, Histological Index, and global efficacy assessment by the investigators. Safety assessments included the recording of adverse events, laboratory variables and vital signs.
Clinical remission was more frequent in the mesalazine group than the placebo group (65% vs. 40%; P=0.0082), particularly in patients with mild disease and patients with proctosigmoiditis. The frequency of patients with an endoscopic remission was higher in the mesalazine group (57%) than in the placebo group (37%). Similarly, 59% of patients receiving mesalazine but only 41% of those receiving placebo showed an improved Histological Index. The foam enemas were generally well-tolerated, and no treatment-related changes on laboratory variables and vital signs were noted.
Mesalazine foam enema was well-tolerated and was more effective than placebo in the treatment of patients with distal ulcerative colitis.
Ulcerative colitis is a chronic illness which usually begins in the rectum and may subsequently spread proximally into any segment of the colon. The illness is characterized by a variable degree of inflammation of rectal and colonic mucosa, causing rectal bleeding, diarrhoea, and abdominal cramps. These symptoms cause varying degrees of physical and social disruption of normal daily activity. In patients with mildly to moderately active disease, treatment aims to rapidly relieve the symptoms, thus allowing the patient to sustain normal life.
Salicylate-type drugs, such as mesalazine, sulphasalazine, or olsalazine, and systemic corticosteroids, such as prednisolone, betamethasone, or methylprednisolone, are used in the treatment of ulcerative colitis, depending on the severity of the acute episode.1–3 At present, rectal administration of salicylate-type drugs constitutes the treatment of choice in proctitis, proctosigmoiditis, and left-sided ulcerative colitis.4, 5 A meta-analysis comprising 11 clinical trials with mesalazine, demonstrated that rectal mesalazine formulations are effective in the treatment of ulcerative colitis.6 The rectal route of administration is of particular merit since local concentrations of active drug at the affected site are sufficiently high for therapeutic activity. Moreover, systemic absorption is considerably lower after rectal administration than after oral administration because the rate of mesalazine absorption decreases from proximal to distal parts of the intestine. In this way, both the efficacy and tolerability of mesalazine are optimized.
Both suppositories and enemas containing mesalazine have been widely used. Suppositories are of limited usefulness because they do not provide sufficient spread of the active ingredient. The spread of enema formulations is generally good, but patient acceptance may sometimes be compromised by difficulties with either self-administration or retention, and the necessity for prolonged bed rest.
In an effort to optimize drug delivery to the affected site and improve patient acceptance, foam enema formulations of mesalazine have been developed. A study comparing patient acceptance of a liquid and a foam enema containing mesalazine in 233 patients with active distal ulcerative colitis showed that a significantly higher proportion of patients receiving the foam enema reported good acceptance (81% vs. 49%; P < 0.01). Among the patients treated with foam, 81% preferred this formulation to the previously used liquid enema because of better retention and improved comfort.7 In a recent study in 195 patients with distal ulcerative colitis, efficacy and patient acceptance of a liquid and a foam enema containing mesalazine (2 g/60 mL) were equally favourable.8
Previous clinical studies with mesalazine foam enemas at daily mesalazine doses of 2 g to 4 g and enema volumes of 60 mL to 200 mL confirmed their efficacy in the treatment of ulcerative colitis.7, 9, 10 This paper reports the findings for efficacy and tolerability of a new mesalazine foam enema (Salofalk foam) vs. placebo, given for 6 weeks, in patients with mildly to moderately active ulcerative colitis.
This was a multicentre, randomized, double-blind, placebo-controlled, parallel-group Phase IIb study in 111 patients suffering from mildly to moderately active proctitis, proctosigmoiditis, or left-sided ulcerative colitis. Patients were randomly assigned to either placebo or mesalazine foam enema, based on a computer-generated randomization scheme. Treatment lasted for 6 weeks (42 days). Control visits were scheduled after 2 and 4 weeks of treatment.
The protocol was approved by the Ethics Committee of each participating centre.
After obtaining written, informed consent from each patient, 111 patients (57 in the placebo group, 54 in the mesalazine group) of either sex (aged between 19 and 69 years) were recruited in 10 study centres (range: 4–24 patients) between November 1996 and July 1998. Mildly or moderately active proctitis, proctosigmoiditis, or left sided ulcerative colitis, preferably with a disease history of at least 3 months, was confirmed at baseline endoscopically, histologically, and microbiologically, to exclude pathogenic microorganisms. In accordance with Rachmilewitz, patients with left-sided ulcerative colitis had to have a Clinical Disease Activity Index (CAI) of > 4 and an Endoscopic Index (EI) of ≥ 4 on admission.11 Patients with proctitis or proctosigmoiditis had to have a Clinical Disease Activity Index of ≥ 3, an Endoscopic Index of ≥ 4, and at least occasionally have blood in stools in the week before admission. Female patients had to have a negative human chorionic gonadotropin (HCG) pregnancy test at baseline.
Patients with macroscopic lesions not just distal but also proximal to the splenic flexure, infectious bowel disease, or any other severe concomitant disease of an acute or chronic nature were excluded. Moreover, patients requiring systemic corticosteroids or who had been taking glucocorticosteroids chronically for 1 month, immunosuppressants for 3 months, or non-steroidal anti-inflammatory drugs (NSAIDs) for 2 weeks before study start were excluded. Other disallowed concomitant medications included antibiotics (i.e. metronidazole, ciprofloxacin, ofloxacin), psyllium-containing drugs, bile-acid products, loperamide, other enema or foam products, and oral mesalazine, olsalazine, or sulfasalazine. Treatment of other diseases already existing was to be continued throughout the study, wherever possible.
Patients in whom mesalazine was contraindicated, e.g. in renal failure or liver disease, and those with known intolerance of mesalazine and/or 5-ASA-releasing drugs were also excluded. Participation in another clinical study during the preceding 30 days and alcohol or drug abuse were additional exclusion criteria.
At study entry, all patients underwent a physical examination, and their demographics and medical history were recorded. The Clinical Disease Activity Index was calculated by creating a sum score from seven disease-specific clinical findings.11 Disease activity was also assessed endoscopically by creating a sum score (Endoscopic Index) for four disease-specific endoscopic findings, using the Rachmilewitz point scale.11 Severity of the disease was classified as mild if the baseline Clinical Disease Activity Index was 8 or less, and as moderate if the Clinical Disease Activity Index was higher than 8. Biopsy specimens from both healthy and affected mucosa were examined microscopically by local pathologists blinded to the treatment to determine the Histological Index (HI) according to Floren et al.12
To monitor disease activity during the study, the Clinical Disease Activity Index was also determined at visits 2 and 3 (i.e. after 2 and 4 weeks of treatment). Determination of the Endoscopic Index and Histological Index was repeated at the end of the 6-week study (visit 4).
Both the patients and investigators evaluated the global efficacy of study medication at visits 2, 3, and 4. Evaluation by the patient was based on a 5-point scale ranging from ‘much better’ to ‘much worse’. Global assessment of the therapeutic effect was made by the same investigator at each visit and was based on a 6-point scale, ranging from complete relief of symptoms to worsening of symptoms.13 At the final visit, patient preference of formulations, if they had had any previous experience with a liquid enema formulation, was established.
Treatment failure was defined as an increase in the Clinical Disease Activity Index by > 4 from baseline, a worsening or lack of improvement of symptoms, or development of a fever due to colitis which exceeded 39 °C and persisted for at least 3 days. This led to the immediate withdrawal of the patient from the study.
At each visit, physical examination, vital sign measurements, and laboratory tests, including haematological and biochemical assessments as well as urinalysis, were performed. Adverse events and tolerability of the study medication as assessed by both the patients and investigators were recorded at visits 2, 3, and 4. Concomitant medications and diseases were reported at the same time points.
The number of bowel movements, consistency of stools, rectal bleeding, abdominal pain or cramps, general state of health, and regular use of study medication and (if applicable) of other medications were recorded daily by the patients. The patient diaries were checked by the investigator at each visit.
Mesalazine and placebo foam enemas were supplied by Dr Falk Pharma GmbH, Freiburg, Germany. Spray cans of identical appearance containing foam enema, with or without the active ingredient, sufficient for 14 actuations were manufactured at a central location, and labelled and randomized in blocks of four according to a randomization list generated by the randomization program ‘Random’, based on SAS software. The propellant gas was a mixture of propane and butane.
Patients inserted two actuations of mesalazine foam (each actuation containing 1 g of mesalazine in approx. 30 mL of foam) or placebo foam rectally at night, if possible after defaecation, for 6 weeks.
Sample size calculation was based on estimates of a 30% response in the placebo group and a ≥ 55% response in the mesalazine group. In each group, 55 patients were needed to assure 80% power with a P-value of 0.05.
The primary efficacy parameter, i.e. clinical remission at the end of the study, was analysed by Fisher’s exact test (one-sided test for difference). This was the only confirmatory test, with all other tests serving a descriptive purpose only. Both an intention-to-treat analysis and a per protocol analysis were performed. The intention-to-treat population (n=111) included all patients who had received at least one dose of study medication. The per protocol population (n=80) excluded all patients with major protocol violations (n=31).
Clinical remission was defined as a Clinical Disease Activity Index score of ≤ 4, associated with a decrease of least 2 points from baseline. In the intention-to-treat analysis of the main efficacy variable, i.e. clinical remission at study end, the last observation on treatment was carried forward for patients who terminated the study prematurely.
To account for adequate interpretation of the results, variables were cross-checked for homogeneity between the two groups with respect to baseline. For both the Clinical Disease Activity Index and the localization of disease within the intestine, comparability was defined as an individual P-value of ≥ 0.2 in the inter-group test on the difference.
For all secondary efficacy variables, the two study groups were compared by Fisher’s exact test (one-sided), with P-values calculated for descriptive purposes only. Secondary measures of efficacy included the Clinical Disease Activity Index after 2 and 4 weeks (visits 2 and 3), the changes in baseline scores of the Endoscopic Index and Histological Index after 6 weeks (visit 4), and global assessment of efficacy by the patients and investigators after 2, 4, and 6 weeks of treatment. Patient preference was assessed at the end of the study.
Safety data were analysed descriptively. Safety variables included the recording of adverse events, laboratory values, and vital signs at each visit, as well as assessment of overall tolerability by the patients and investigators after 2, 4, and 6 weeks of treatment. The safety population included all patients who had received at least one dose of study medication and for whom at least one follow-up value was available.
A total of 111 patients were allocated to randomized treatment (54 to mesalazine foam, 57 to placebo foam). There were no significant differences between the groups with respect to demographic variables, general medical history, concomitant medications, vital signs, laboratory data, and history and extent of ulcerative colitis (Table 1). Similarly, the number of patients who had abnormal baseline findings in the various organ systems at baseline were comparable in the two study groups. Furthermore, there were no significant differences between the groups in baseline disease activities, as assessed by the Clinical Disease Activity Index, Endoscopic Index, and Histological Index.
Of the 54 patients receiving mesalazine foam, 48 (89%) took the study medication in compliance with the protocol. In the placebo group, 53 out of 57 (93%) patients were compliant. Overall, 44 major violations were reported for 31 patients. These patients were excluded from the intention-to-treat analysis.
The rate of clinical response based on the Clinical Disease Activity Index (Last Observation Carried Forward values, intention-to-treat population) in patients receiving mesalazine foam was 65%, compared with 40% in those receiving placebo foam (Table 2). The difference was highly statistically significant (P= 0.0082; Fisher’s exact test, one-sided). In the per protocol population, mesalazine foam was still superior to placebo foam, albeit somewhat less markedly (67% vs. 45%; P=0.040).
Clinical remission was also analysed by disease location and severity (Table 3).
The superior effect of mesalazine foam on the Clinical Disease Activity Index score at the end of the study was already apparent after 2 and 4 weeks of treatment. Although both study groups exhibited a trend towards progressively reduced Clinical Disease Activity Index scores from baseline to the end of the study, the reduction was more marked in the mesalazine group at each control visit ( Figure 1). At the end of the study, Clinical Disease Activity Index scores were reduced by 4.7 points in the mesalazine group and by 3.5 points in the placebo group. If the Last Observation Carried Forward values were used, values for Clinical Disease Activity Index decreased from baseline by 2.5 and 1.0 points in the mesalazine and the placebo groups, respectively.
For the majority of patients who responded to therapy, clinical remission was observed after 2 weeks of treatment (62% of responders in the mesalazine group, 69% of responders in the placebo group). Thus, the time of first remission was similar in the two study groups, although the total number of responders in the mesalazine group at the end of the study was clearly higher than in the placebo group (37 vs. 26 responders).
Endoscopic remission was defined as a an Endoscopic Index score of ≤ 3 at the final visit (after 6 weeks of treatment). As shown in Table 2, the frequency of patients with endoscopic remission was statistically significantly higher in the mesalazine group than in the placebo group (P=0.047). The superior effect of mesalazine foam over placebo foam on the Endoscopic Index was also reflected in the lower mean Endoscopic Index scores at the end of the study ( Figure 1). Moreover, an improved Endoscopic Index at the end of the study vs. baseline was apparent in 70% of patients in the mesalazine group but in only 46% of patients in the placebo group.
The Histological Index was considered improved if the score at the last visit was reduced by at least 1 point compared with the baseline score. After 6 weeks of treatment, the Histological Index was improved in 59% of patients in the mesalazine group and in 41% of patients in the placebo group (Table 2; P=0068).
In the investigator’s global assessment of efficacy after 2, 4, and 6 weeks of treatment, the therapeutic success achieved with mesalazine foam was greater than that with placebo for all visits (Table 4). Differences between treatment groups were more pronounced after 2 and 6 weeks than after 4 weeks, although the differences did not reach statistical significance. In contrast, a statistically significantly higher percentage of patients experiencing a therapeutic benefit after 2 weeks of treatment was seen in the mesalazine group (75% vs. 55%; P=0.028).
Treatment failure rates were low in both study groups (17% in the mesalazine group, 21% in the placebo group). The slightly higher failure rate in the placebo group did not warrant formal testing because of the small number of patients involved.
During the study, 78 adverse events were reported (26 in the mesalazine group, 52 in the placebo group) by 40 (36%) patients. Only five adverse events reported by four patients were of severe intensity, with all other events mild or moderate. In total, six (11%) patients in the mesalazine group and 11 (19%) patients in the placebo group, had at least one adverse event which was assessed by the investigator as treatment-related.
Overall, six serious adverse events occurred in five patients (one in the mesalazine group, four in the placebo group). All five cases resulted in hospitalizations for deterioration of ulcerative colitis, and for one case (placebo group), additionally for decompensation of diabetes mellitus. Only one patient in each study group prematurely terminated the study because of an adverse event (mesalazine group: hallucinations; placebo group: diarrhoea and abdominal cramps).
No clinically relevant changes in laboratory parameters and vital signs were noted during the study.
Among the 55 patients who had previous experience with liquid enema formulations of mesalazine, 24 (44%) preferred the new foam formulation, 23 (42%) patients had no preference, and only eight (15%) patients preferred the enema formulation.
Mesalazine foam enema (mesalazine 2 g o.d.) was clearly superior to placebo foam with respect to the Clinical Disease Activity Index after 6 weeks of treatment, with statistically significantly higher remission rates noted both in the intention-to-treat and per protocol analyses. Endoscopic remission at the end of the study was in good agreement with the Clinical Disease Activity Index scores. The Clinical Disease Activity Index scores exhibited a progressive reduction during the study in both study groups, but the degree of reduction was more marked in the mesalazine group than in the placebo group, at all time points. This trend was also apparent for the numbers of defaecations per week, which were lowest in the final study week.
The superiority of mesalazine foam enema over placebo was more pronounced in patients with mild colitis than those with moderate colitis, where the response rate in patients receiving placebo foam appeared to be somewhat higher than in those receiving mesalazine foam. This finding was, however, not considered representative because of the small number of patients with moderate disease participating in the study (n=16).
In all three subgroups of patients defined according to disease location, response rates were higher in the mesalazine group than in the placebo group, with this superiority most marked in the patients with proctosigmoiditis.
The global assessment of efficacy by the investigators revealed that the majority of patients derived a therapeutic benefit from treatment with mesalazine, with more than 50% of patients experiencing therapeutic success after 6 weeks of treatment. In congruence with this finding, most patients in the mesalazine group considered their symptoms to be improved at the end of the study.
Notably, there were fairly high rates of remission and considerable improvement of symptoms in the placebo group in this study. This phenomenon confirms that spontaneous remission in ulcerative colitis can occur without specific drug treatment.
Rectal self-administration of mesalazine foam enema proved to be safe and well-tolerated. Both the investigators and patients rated the global tolerability of study medication as very good, good, or fair, with no clear difference between the two study groups apparent. Most of the adverse events matched the known side-effects profile of mesalazine and occurred with only mild or moderate intensities. Colitis-related symptoms were seen more frequently in the placebo group than in the mesalazine group, thus reflecting the beneficial effect of mesalazine on the activity of ulcerative colitis.
Generally, the findings reported here are in good agreement with data in the literature. Lee et al.10 reported a clinical remission rate of 52% in 149 ulcerative colitis patients receiving mesalazine foam enema (2 g per day) for 4 weeks, with sigmoidoscopic and histological remission rates somewhat lower. Moreover, mesalazine foam enema was significantly more effective than prednisolone foam enema used as the comparator. In another randomized, comparative trial, the onset of the effect of mesalazine foam enema was more rapid than that of prednisolone foam, an aspect of considerable importance in the treatment of acute relapses of distal ulcerative colitis.14 These findings were confirmed in a meta-analysis comprising 33 clinical trials.15 The authors concluded that mesalazine is superior to rectal corticosteroids in the clinical management of distal ulcerative colitis.
In a study comparing mesalazine foam and liquid enemas in 87 patients with active distal ulcerative colitis, both mesalazine formulations were effective, with similar clinical remission rates and histological improvements seen.9 However, endoscopic remission in patients receiving the foam was markedly higher than in those receiving the liquid enema.
Although the spread of mesalazine foam was not assessed in this study, good distribution of mesalazine was apparent from the activity in all subgroups of patients classified according to the location of disease. Campieri et al.16 compared the spread and distribution of mesalazine foam with those of liquid enema in 10 patients with ulcerative colitis and found a more uniform distribution and prolonged persistence in the descending and sigmoid colon for the foam formulation. Equivalent or a better spread and distribution of Salofalk foam vs. liquid mesalazine enema were also found in a recent unpublished scintigraphic study in healthy volunteers and ulcerative colitis patients, with the superiority of foam more pronounced in patients than in healthy volunteers (Dr Falk Pharma, Internal Report, 1998).
The rectal administration of mesalazine foam enema (Salofalk foam) at a dose of 2 g of mesalazine given for 6 weeks was well-tolerated and more effective than placebo in the treatment of patients with distal ulcerative colitis.
Financial support for this trial was provided by Dr Falk Pharma GmbH (Freiburg, Germany).
We thank Mr Stephan Köhne (Chrysalis Clinical Pharmacology Services GmbH [former BioClin], D-40217 Düsseldorf, Germany) for the statistical analysis of the trial.
The members of the Salofalk Foam Study Group are the following: Central Military Hospital, Warsaw (Poland): Prof. P. Zaborowski, Dr S. Batowski; Pomeranian Medical Academy, Szczecin (Poland): Prof. K. Marlicz, Dr M. Wielondek; Medical Academy of Latvia, Riga (Latvia): Prof. A. Danilans, Prof. J. Pokrotnieks; Kaunas Medical Academy, Kaunas (Lithuania): Prof. L. Kupcinskas, Dr V. Petrenkiene, Dr R. Petroniene; Vilnius 3rd Clinical Hospital, Vilnius (Lithuania): Prof. D. Kalibatiene, Dr R. Vanagaitiene, Dr A. Jablonskis; Medical University, Wroclaw (Poland): Prof. L. Paradowski, Dr J. Cader; G. Narutowicz District Hospital, Krakow (Poland): Dr P. Hydzik, Dr W. Szczygiel; Tallinn Central Hospital, Tallinn (Estonia): Dr B. Margus, Dr A. Koldits; University Medical School, Lublin (Poland): Prof. L. Szczepanski, Dr D. Chudzik; Wojewodzki Szpital Specjalistyczny im. Ludwika Rydygiera, Krakow (Poland): Dr J. Marecik.