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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. References

Background:

Rectally administered mesalazine (5-aminosalicylic acid) is a recognized therapy for distal ulcerative colitis. It is frequently applied as a liquid enema. However, there are reasons (acceptability to the patient, more uniform topical dispersion and effective adhesion) to prefer a foam-based enema.

Aim:

This study compared a foam enema (2 g mesalazine per day, Claversal Foam) with a standard liquid enema (4 g mesalazine per day, Salofalk enema).

Methods:

Patients with active distal ulcerative colitis, diagnosed according to standardized criteria, were treated for 4 weeks. The primary goal was clinical remission; endoscopic remission, histological changes, global assessment and standard safety measures were also analysed. A major subset of the patients also provided quality-of-life data.

Results:

Both foam and liquid enema gave good rates of clinical and endoscopic remission. The foam enema was shown to be as efficacious as the reference, even though the daily dose in the foam treatment contained only half as much active drug as in the reference treatment. Minor regional differences in efficacy were seen. The tolerabilities of the two formulations were comparable.

Conclusions:

The foam enema offers a safe, efficacious and acceptable treatment for distal ulcerative colitis.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. References

Ulcerative colitis is a chronically recurrent inflammatory disease of the large intestine; its aetiology is unknown. The inflammation is limited to the mucosa and submucosa. This disease is always related to the rectum; it may, however, spread to the entire colon. Inflammation up to the splenic flexure is termed distal or left-sided ulcerative colitis. The principal symptom of this disease is diarrhoea, with bloody-mucous faeces and abdominal spasms.

Because of the unknown cause of this disease, therapy is symptomatic and is aimed at general inflammatory mechanisms. For active mild to moderate ulcerative colitis, treatment with mesalazine (5-ASA) is recommended as a first-line therapy;1 in order to maximize the amount of drug applied to the inflamed area of the gut, and to minimize systemic absorption, rectal formulations have also been developed. 5-ASA enemas have a well-documented efficacy in the treatment of distal ulcerative colitis.2–8 The mechanism of its action is not yet fully understood. It has antioxidative properties, an inhibition of 5-lipoxygenase activity (leading to a decreased release of leucotriene B4) and has an inhibitory effect on NFκB, which all appear to play a part.

5-ASA liquid enemas are the treatment of choice for active distal ulcerative colitis; their large volume ensures that the drug is brought to the inflamed mucosa as far as the splenic flexure. However, a major disadvantage of these enemas is insufficient retention because of their fluid consistency and large volume. A foam enema should overcome this disadvantage, being more adhesive to the mucosa, and thus reducing incontinence and urgency (impulse to defecate) after administration. Furthermore, 5-ASA is more finely dispersed on the mucosa by a foam, so that a wider, more uniform spreading of the substance and a longer retention in the bowel can be obtained.9 Thus, a foam may be expected to give a more sustained topical effect than a liquid enema. This was indeed demonstrated in a pharmacokinetic study [`A cross-over study to investigate the systemic absorption of a 2 g 5-ASA non-CFC foam enema in comparison with a 4 g 5-ASA liquid retention enema in healthy volunteers. Study Number 33862/062: unpublished results] in which the administration of 2 g 5-ASA in a rectal foam led to the same plasma 5-ASA level as 4 g 5-ASA in the liquid enema (Salofalk). Moreover, the efficacy of a CFC-containing 5-ASA foam enema has been demonstrated in a clinical study7 and this product has received marketing approval in the UK.

In the clinical study described here, the efficacy and safety of a non-CFC 5-ASA foam enema (Claversal Foam) with 2 g 5-ASA per day was compared with those of a standard therapy, the liquid enema (Salofalk) containing 4 g 5-ASA per day, with clinical remission as primary efficacy variable. The dosage of 2 g 5-ASA/120 mL foam was chosen because the clinical efficacy of 2 g 5-ASA in a similar (but CFC-containing) rectal foam in patients with acute distal ulcerative colitis has been demonstrated in a comparison with prednisolone foam.7 The spreading of this foam in the intestine was investigated in patients with ulcerative colitis in remission: it was found that more than one-third of the applied foam had spread through the descending colon, so that the foam appears to be ideal for treatment of distal ulcerative colitis.10

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. References

Study design

To compare the 5-ASA foam enema with the corresponding liquid enema in patients with active distal ulcerative colitis, a Phase-II study was conducted at 61 centres in Germany, Poland and the Baltic states, according to a randomised, active-controlled, parallel-group design. Since the difference between the rectal application forms precluded a double-blind design, an investigator-blinded design was chosen. Patients who gave their written informed consent were assigned by a centralized randomization procedure to one or other treatment, in equal-sized groups.

Patients were to apply their study medication for 4 weeks, or for 2 weeks if both clinical and endoscopic remission were established after 2 weeks' treatment.

Patients

The sample size calculated on the basis of assumed rates of clinical remission (≈ 60%) and premature withdrawal (≈ 15%) was 125 patients in each treatment group. Males and females of age 18–75 years were recruited. They were diagnosed as having recurrent, active distal ulcerative colitis according to established criteria (histologically and endoscopically confirmed ulcerative colitis, with infection microbiologically excluded; blood in stools, stool frequency > 18 in the week before the start of medication). They were to have a clinical activity index (CAI1–4, see below) of at least 4 and mucosal inflammation extending for at least 12 cm, but not above the splenic flexure. Patients with first appearance of colitis, severe ulcerative colitis/toxic megacolon, radiation- or drug-induced or bacterial colitis were excluded, as were patients treated with immunosuppressives (≤ 90 days before study treatment) or with antibiotics against colitis (≤ 30 days before study treatment). Patients receiving oral maintenance treatment with 5-ASA or sulfasalazine at entry to the study were allowed to continue, as long as the dosage was not changed within the 4 weeks before the study or during the study itself.

Study medication

The test medication was a foam enema in a pressurized canister suitable for rectal application and containing sufficient medication for 1 week's treatment. The propellant was a mixture of propane and butane, which are regarded as safe. A single actuation of the canister valve released 1 g of 5-ASA in a volume of about 60 mL foam. The study medication was supplied by Merckle GmbH, Ulm, Germany. The reference medication was the commercially available liquid enema Salofalk, containing 4 g 5-ASA per 60 mL liquid. With compliance in mind, single daily dosing was chosen for both treatment groups. Patients were required to administer a single 60-mL liquid enema (reference therapy) or two metered 60-mL applications of foam enema (test therapy) every evening, if possible after defecation.

Procedures

Patients attended the study centres three times: at screening (patients included in the study began treatment at once), at mid-study (14 ± 2 days after inclusion) and for a concluding examination (28 ± 2 days after inclusion).

At the first visit, the patient was informed about the study and gave written informed consent. Vital signs, demographic data, medical history and CAI variables were documented and a physical examination was carried out. Study-related examinations were performed (coloscopy, biopsy sampling for histological diagnosis, microbiological examination of stool, blood-sampling for haematological and chemical tests, urinalysis, body temperature, weight) and relevant information was elicited from the patient; this included the patient's history of ulcerative colitis, the duration of the active disease, urgency, tenesmus, and a rating of the patient's quality of life (QoL). The patient was issued with a diary and the randomised, investigator-blinded study medication. At the second and third visits, vital signs and weight were measured; the CAI variables, urgency and tenesmus were assessed. Adverse events and the use of concomitant medication were recorded. Changes in concomitant symptoms and the global efficacy and tolerability of the treatment were assessed, and the patient's diary was reviewed. At the third visit, concluding examinations were also performed, including physical examination, sigmoidoscopy, biopsy sampling, blood sampling, urinalysis and QoL rating.

Efficacy and safety variables

The primary efficacy variable was clinical remission of the disease after 4 weeks of treatment, defined on the basis of the CAI according to Rachmilewitz11 which covers clinical symptoms for 1 week, and comprises the following seven variables: number of stools per week, presence of blood in stools, abdominal pain, cramps, the investigator's global assessment of the symptoms, fever due to colitis, extra-intestinal manifestations, and laboratory values (ESR and haemoglobin). The first three of these were noted daily in the patient's diary and were summed by the physician to give a weekly score. The total score was calculated at the beginning and end of the study. However, the sum of the first four variables (CAI1–4; each calculated as in ref. 11) is more suited to the documentation of the course of clinical symptoms, as the patients only rarely have fever, and the extra-intestinal symptoms do not change in any relevant manner within 4 weeks. Therefore, the course of disease was defined by CAI1–4, with a value `CAI1–4 ≥ 4' for entry and `CAI1–4 ≤ 2' defining clinical remission. (In this paper, the term CAI always refers to the standard 7-variable index, and the 4-variable index is termed CAI1–4.) Further efficacy variables were clinical improvement after 4 weeks (also assessed by CAI1–4), endoscopic remission, histological changes, symptom improvement based on the patient's diary, urgency, tenesmus, global assessment of efficacy by the patient and the investigator, and (in Germany only) QoL.

The endoscopic findings were graded according to the endoscopic index of Rachmilewitz.11 This considers granulation (scattering of reflected light), vascular pattern, vulnerability of the mucosa and mucosal damage (mucus, fibrin, exudate, erosions, ulcer). The investigators were trained appropriately, and all endoscopic procedures for a given patient were performed by the same (treatment-blinded) investigator. A histological analysis was performed on mucosal samples from the middle parts of the sigmoid and rectum. Evaluation was performed centrally by one blinded pathologist.

The patients' general condition was assessed daily by a 10-cm VAS (0=very good, 10=very poor).

To assess the patients' quality of life, the standard 32-question Inflammatory Bowel Disease Questionnaire (IBDQ) was employed. This has been validated in English12 and Dutch.13 Because of the cultural similarity between Germany and the Netherlands, it was considered that a German translation would be valid for German patients. However, the questionnaire was not used in Eastern Europe, as the risk of confounding cultural factors was considered too great.

Safety variables were the frequency of adverse events, clinically relevant changes in laboratory values (central analysis), and the overall tolerability, as assessed by the patient and the investigator.

Statistical analysis

The primary purpose of this study was to show equivalence between the two treatments, with clinical remission as primary variable; the confirmatory statistical analysis was based on the per-protocol population. To test the null hypothesis of equivalence (i.e. non-inferiority) of test vs. reference medication an exact overall and a stratified odds-ratio analysis were performed. The odds ratio θ was defined as [πfoam/ (1 –πfoam)]/[πliquid/(1 –πliquid)], where π is the rate of clinical remission. The stratification factor in the stratified analysis was the part of Europe (Germany vs. Eastern Europe). The null hypothesis of better efficacy of the reference medication `θ ≤ 0.4444' was to be rejected if the lower limit of the two-sided 95% confidence interval for the odds ratio was> 0.4444 (one-sided equivalence test with α=0.025). This is in accordance with an equivalence limit of 20% at a remission rate of 60%, corresponding to the requirements of the FDA guideline on the clinical development of anti-infective drug products.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. References

Demographic and baseline data

Of 400 patients screened for inclusion in this study, 134 were found to be unsuitable (principal reasons were first appearance of disease, remission, proctitis/pancolitis or patient's refusal of endoscopy). All the remaining 266 patients were randomised, but two were not treated. The safety population thus comprised 264 patients (225 in Germany and 39 in Eastern Europe); of these, 133 were treated with foam enema and 131 with liquid enema. The corresponding intention-to-treat treatment groups numbered, respectively, 128/128 patients, and the per-protocol treatment groups 111/118 patients.

There were only minor differences, if any, between the treatment groups in respect of age distribution, alcohol, time from first diagnosis of ulcerative colitis (more than 2 years for about 80% of the patients), histological findings and extent of inflammation.

The extent of the diseased colon was between 15 and 65 cm for 96% of the patients (overall range: 12–100 cm). The severity of the disease was comparable in the two groups, with CAI values (mean ± s.d.) of 7.2 ± 2.0 (foam) and 7.3 ± 2.0 (liquid). CAI1–4, the primary efficacy variable, was, respectively, 6.8 ± 1.6 and 7.0 ± 1.7. The endoscopic index was 8.2 ± 2.3 and 8.5 ± 2.3. Smoking has a beneficial influence on ulcerative colitis; 8.3% and 9.9%, respectively, were smokers.

A slight baseline inhomogeneity was detectable in respect of the use of oral remission-maintaining therapy (5-ASA, sulfasalazine). In the foam group the number of patients receiving such therapy (54/111, 48.6%) was slightly greater than in the liquid-enema group (51/118, 43.2%), presumably indicating that in the foam group the average status of the disease at entry was more severe.

Efficacy results: primary analysis

The overall clinical remission rate in the per-protocol population after 4 weeks of treatment revealed a considerable improvement of the patients' ulcerative colitis (Table 1). Equivalence of the two treatments was demonstrated, as the clinical remission rate of the foam enema was not statistically different from that of the liquid enema. As the odds ratio was the statistical metric used, the two-sided 95% confidence interval (CI) for the unstratified odds ratio ranged from 0.449 to 1.462, i.e. the lower confidence interval was above 0.444, which means that neither treatment was significantly worse than the other. The result obtained for the intention-to-treat population was similar (CI 0.450–1.311). A qualitatively similar result (CI 0.468–1.422) is also seen for the per-protocol population stratified by region (Germany or Eastern Europe). Clinical remission was achieved by 64.9% of the patients in the foam group and by 69.5% in the enema group; this small difference is of no clinical relevance.

Table 1.  . Clinical remission after 4 weeks of treatment (per-protocol population) Thumbnail image of

For the population stratified by region, by remission-maintaining therapy and by patient's sex, the same general result was seen for clinical remission (Table 1), with minor differences, as follows.

The clinical remission rate stratified by region showed comparable results for the foam group in Germany and Eastern Europe. However, in Germany the remission rates were better for the liquid-enema group than for the foam group, whereas in Eastern Europe the outcome for the foam group was better. The result of the enema group in Eastern Europe was almost identical to the value of 60% used in the sample size estimation, whereas the result in Germany was above original expectations. An explanation for the differences might be that patients in Germany were already accustomed to the enema and withdrew prematurely if there were any difficulties with administering the foam, whereas for patients in Eastern Europe, both study medications were new.

Higher clinical remission rates were seen for patients without remission-maintaining therapy. The slight baseline inhomogeneity in respect of remission-maintaining therapy was in favour of the enema group, in which more patients without this therapy were included (in the per-protocol population: 57/111=51% foam vs. 67/118=57% liquid enema). Obviously, patients without the need for a remission-maintaining therapy responded better to treatment. Nevertheless, patients needing a remission-maintaining therapy achieved clinical remission slightly more often with the foam (34/54=63%) than with the enema (31/51=61%). Therefore, it is possible that patients with a somewhat more severe disease—i.e. patients needing remission-maintaining therapy—respond better to the foam than to the liquid enema.

The supporting intention-to-treat analysis gave a result similar in all respects to that of the per-protocol analysis. Stratified analyses revealed no potentially statistically significant trends.

Efficacy results: Secondary analysis

For CAI1–4, more than 85% of the patients showed a clinical improvement, and in only four patients in the foam group and five patients in the enema group was a worsening in the score seen. The effect of treatment on CAI1–4 is shown in Table 2.

Table 2.  . Clinical Improvement: shift in CAI1–4 after 4 weeks of treatment (per-protocol population) Thumbnail image of

During the study, patients were asked to document in diaries their stool consistency, mucus in stool, abdominal pain, stool incontinence and their general condition. These records show an improvement for all of these, in both treatment groups. Differences between the foam and the enema groups were small and clinically insignificant. For example, after 4 weeks of treatment no or only mild abdominal pain or cramps were mentioned in 89% of entries (foam) against 88% (liquid), while 8% (foam) and 9% (liquid) mentioned moderate or severe pain. The patients' general condition (10 cm VAS) at the start of the study was rather worse in the foam group (mean=4.9 cm; average over first study week) than in the enema group (4.6 cm), but in both groups the improvement in the mean was 1.3 cm (average for last study week minus average for first study week), indicating a generally positive course of the disease during treatment.

Endoscopic remission was considered to be achieved if the endoscopic index after treatment was 2 or less. Results are summarized in Table 3. In both treatment groups the overall remission rate was about 38%. As already seen for the clinical remission rate, the endoscopic remission rate was greater for patients who needed no remission-maintaining therapy, but differences between the two treatment groups were not detected.

Table 3.  . Endoscopic remission after 4 weeks of treatment (per-protocol population) Thumbnail image of

The histological analysis also showed the effectiveness of the study medications. Overall, in both treatment groups an improvement was observed for the majority of patients, with a slightly greater improvement in the liquid-enema group (remission 46% in the foam group and 50% in the enema group), while for patients with a high-grade active inflammation, the improvement was greater in the foam group. The numbers of patients who had a high-grade inflammation in the sigmoid colon at study start and who reached remission under treatment were: foam=5/7 and enema=5/14; the corresponding numbers for high-grade inflammation of the rectum were: foam 5/7 and enema 4/11.

The numbers of patients who left the study after only 2 weeks of treatment because they showed both clinical and endoscopic remission were small, and very similar, in the two treatment groups (foam, 9.0%; liquid enema, 9.3%). The small numbers in both treatment groups support the assertion that a 4-week treatment is necessary to obtain satisfactory results.

Efficacy was rated globally by the investigator as `very good', `good', `moderate' or `poor'. Respective percentages (per-protocol) were for the foam-enema group 27.3%, 43.4%, 21.2% and 8.1%, and for the liquid-enema group 21.9%, 46.7%, 28.6% and 2.9%. Thus, no substantial difference was seen.

Results of the QoL questionnaire, which was only used in Germany, are presented in Table 4. The magnitude of the changes found were clinically significant. Irvine et al.12 found that a change of one point in IBDQ is clinically significant, while a change of 0.5 points is not. Table 4 shows that a change of 1.06 took place during treatment with foam and a change of 0.93 during treatment with enema. Therefore, a slightly greater improvement was obtained in the foam group than in the enema group; the statistical significance of this small difference was not tested. The four subscores `emotional function', `bowel symptoms', `social function' and `systemic symptoms' were analysed; the results were in favour of the foam treatment for all except `bowel symptoms', for which no difference between treatment groups was observed. As expected, the increase in QoL score showed a strong positive correlation with the achievement of clinical remission; the patients with clinical remission showed an increase in score of 1.21 (foam) and 1.17 (enema), while those without clinical remission showed increases of 0.82 (foam) and 0.39 (enema). The difference between the last two values is in agreement with the trends of the subscores, in which the patients in the foam group showed better results than those in the enema group, with the single exception of the score `bowel symptoms', which reflects most closely the clinical remission. Thus, patients treated with the foam profited from a slight improvement in quality of life, even though they were not yet free of clinical symptoms.

Table 4.  . Global quality-of-life score (per-protocol population) Thumbnail image of

Safety and tolerability

A total of 69 adverse events (AEs) were reported by 43 patients. The percentage of patients reporting AEs, as well as the total number of AEs, was higher in the foam group than in the enema group. The greatest number of AEs were associated with the gastro-intestinal system (flatulence, nausea, abdominal pain or diarrhoea), which may have been caused by the underlying disease and occurred comparably often in the two treatment groups. Four patients (3 foam, 1 liquid) experienced SAEs; of these, none were fatal and all were unrelated to the study medication.

The number of AEs with a possible or probable relationship to the study medication was higher in the foam group (14 AEs) than in the liquid-enema group (4 AEs). Again, gastrointestinal symptoms were the most prominent (mainly flatulence), and they were probably due to incorrect application of the foam by some patients.

The global judgement of tolerability of both treatments, by patients and investigators, was positive for the majority. The investigators in Eastern Europe rated the tolerability of the foam better than that of the enema (`very good' or `good' 81% for the foam, 67% for the enema) while the investigators at German sites preferred the enema. The same was true for the patients, which may reflect the fact that the Germans were used to the enema. The higher number of ratings of `moderate' or `poor' in the foam group reflects the higher number of AEs recorded for this group. The laboratory values used to assess inflammation (leukocytes, ESR and C-reactive protein) indicated a comparably good efficacy of the foam and liquid-enema treatments. The analysis of the safety laboratory values gave no indication of any differences of clinical relevance between the treatment groups.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. References

The therapeutic equivalence of the foam enema (2 g 5-ASA per day) and the liquid enema (4 g/day) is supported by the following observations: (i) in the primary analysis, the null hypothesis that the foam enema is inferior to the liquid enema was rejected. (ii) The shifts of CAI1–4 indicated similar rates of clinical improvement in the two treatment groups. (iii) The endoscopic remission rates were also very similar. (iv) Symptoms recorded by the patients (stool consistency, mucus in stool, abdominal pain, stool incontinence, urgency, general condition) showed improvement in both treatment groups, with only small and clinically insignificant differences. A similar result was found for (v) histological analysis, (vi) global judgement of efficacy by the investigator, and (vii) inflammation-related laboratory values (leucocytes, ESR, C-reactive protein).

It should be noted that the largely similar results from the two rectal application forms were obtained in spite of the fact that the 5-ASA dosage in the foam enema (2 g/day) was only half that in the liquid enema (4 g/day). As discussed below, this foam, with 2 g/day 5-ASA, may yield slightly higher clinical remission rates than treatment with another foam formulation with 4 g/day 5-ASA.8 Thus, the clinical efficacy is determined not only by the amount of active drug, but also by whether the galenic formulation allows the drug to reach the inflamed areas of the intestine and to remain in contact with them for a sufficiently long time.

In two recent clinical studies of patients with proctosigmoiditis or distal ulcerative colitis, foam formulations of 5-ASA were investigated, with clinical remission defined by the complete CAI. The respective remission rates for 5-ASA foam enema were found to be 62% (remission defined as CAI < 4, with 4 g/day 5-ASA;8) and 65% (remission defined as CAI ≤ 4, with 2 g/day 5-ASA;14). With these definitions, the foam used in the present study would clearly have shown higher remission rates than in the two studies cited: with the remission criterion `CAI < 4' the remission rate would have been 69%, and with `CAI ≤ 4' it would have been as high as 82%. These results suggest that the rectal foam used in the present study is clinically more effective than the foams used in earlier studies. Rates of clinical improvement and endoscopic remission in the present study were well-comparable with those found in previously published trials (e.g.2, 15, 16).

None of the more detailed analysis revealed any trends with potential statistical significance. Some minor trends call for comment:

1 The outcome was, as expected, generally better for patients who needed no concomitant oral remission-maintaining therapy (Tables 1 and 3, and as these patients were more strongly represented in the liquid-enema group, this will have conferred a slight advantage upon response rates in this group.

2 There was general similarity between clinical response rates in Germany vis-à-vis Eastern Europe (Table 1). A slightly higher rate of clinical remission was seen for the liquid enema in Germany; this was presumably because German patients (unlike those in Eastern Europe) were already accustomed to the use of this administration, while the foam, with its new mode of application, was unknown to the patients in both regions. This trend was not reflected in the rates of endoscopic remission (Table 3), which were nearly the same in each region. This supports the contention that the two therapies are of equal efficacy, as endoscopic healing is not influenced by subjective factors that could influence the remission of clinical symptoms. The decisive factor in the avoidance of recurrence, and thus long-term freedom from symptoms, is mucosal healing, which was equally good in the two groups.

3 In the present study, the Inflammatory Bowel Disease Questionnaire (used in Germany only, as explained above) showed slightly better QoL results in the foam group, in spite of the fact that in Germany the clinical remission rate was slightly higher for the liquid-enema group. This supports the impression that the observed minor differences between the treatment groups were without clinical relevance, as confirmed by the equal rates of endoscopic remission. This positive result also confirms the acceptability of the foam to the patients, which is intended to be more comfortable, more practical, easier to retain and less disruptive of evening routine than the liquid.

Some of the 14 AEs with a causal relationship to the foam may have been caused by an incorrect administration of the foam. It is essential to apply the foam enema very slowly, as otherwise the foam is released very rapidly and generates a high pressure in the intestine, which may cause unwanted effects. After the first patients had withdrawn from the study because of such AEs, special care was taken to explain the correct application of the foam; in this way, further AEs of this type were avoided. The assessment of tolerability was positive for the majority of the patients. This judgement was influenced by the AEs, and the tolerability rating reflected this by more ratings of `moderate' or `poor' tolerability in the foam group. Analysis of laboratory values gave no indication of any differences of clinical relevance between the treatment groups.

All in all, the results are of clinical relevance and do not indicate any restricted generality due to the criteria by which patients were selected.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. References

The new 5-ASA foam enema Claversal Foam, at a dosage of 2 g 5-ASA/day, proved to be an effective treatment for active distal ulcerative colitis. Equivalence to the reference therapy, a liquid enema with 4 g 5-ASA/day (Salofalk), was demonstrated in the primary statistical analysis. Both treatments produced a considerable improvement in all symptoms without any indication of clinically relevant treatment differences; a small difference in favour of the foam may be inferred from the quality-of-life investigation. The safety profile of the foam enema was comparable to that of the liquid enema.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. References

This study was sponsored by Merckle GmbH, Germany. We wish to thank Dr U. Steder-Neumann (Leverkusen, Germany) for translating the inflammatory bowel disease questionnaires into German, Prof. M. Stolte (Klinikum Bayreuth, Germany) for performing the histological analysis and Prof. C. Luley (University of Magdeburg, Germany) for conducting the laboratory tests.

Members of the CLAFOAM group participating as investigators were: for Germany: Dr H. Ahrens (Paderborn), Dr F. Bannout (Augsburg), Dr J. Bauer (Leipzig), Dr R. Burlefinger (München), Dr D. Bojanovski (Hannover), Dr H. Brinkhoff (Stuhr), Dr A. Brom (Grebenhain), Dr H. Daake (Wiesbaden), Dr U. Diete (Magdeburg), Dr B. Dirr (Hechingen), Dr F. Eller (Neuburg), Dr Ch. Fritze (Jena), Dr Ch. Gerasch (Hannover), Dr E. Gozdowsky (Berlin), Dr H. Grümmer (Potsdam), Dr J. Hagel (Schwabach), Dr H. Hagmann (Berlin), Dr G. Hirschmann (Berlin), Dr E. Hommel (Stuttgart), Dr H. Horstkotte (Hannover), Dr W. Kerzel (Forchheim), Dr B. Klesser (Ulm), Dr H-G. Kühn (Hamburg), Dr K. Landendinger (Vilsbiburg), Dr B. Lischewski (Berlin), Dr T. Lutfi (Bottrop), Dr A. Lütke (Koblenz), Prof. H. Malchow (Leverkusen), Dr D. Marheineke (Neuwied), Dr J. Narro (Köln), Dr P. Prause (Göttingen), Prof. A. Raedler (Hamburg), Dr A. Ryschka (Berlin), Dr H. Schalk (Worms), Dr J. Schenk (Erlangen), Dr U. Schink (Mainz), Dr W. Schneider (Halle), Prof. H. Schönekäs (Nürnberg), Dr E. Schütz (Regensburg), Dr P. Tippmann (Esslingen), Dr T. Tibroni (Coesfeld), Dr K. Uhlig (Berlin), Dr R. Vogt (Mannheim), Prof. L. Witzel (Berlin), Dr G. Wolf (Köln), Dr R. Wack (Berlin), Dr K. Ziegler (Berlin), Dr W. Zink (Nürnberg); for Eastern Europe: Prof. J. Dzieniszewski (Warsaw, Poland), Dr A. Kaufmanis (Riga, Latvia), Prof. L. Kupcinskas (Kaunas, Lithuania), Dr J. Leszcyszyn (Wroclaw, Poland), Dr B. Margus (Tallinn, Estonia), Prof. L. Paradowski (Wroclaw, Poland), Prof. J. Pokratnieks (Riga, Latvia), Dr G. Simulionis (Klaipeda, Lithuania), Prof. L. Szczepanski (Lublin, Poland), Prof. P. Zaborowski (Warsaw, Poland).

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSION
  8. ACKNOWLEDGEMENTS
  9. References
  • 1
    DGVS. (2001) Diagnostik und Therapie der Colitis ulcerosa – Ergebnisse einer evidenzbasierten Konsensuskonferenz der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten. Z Gastroenterol 2001; 39: 1972.
  • 2
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