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Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazineW Kruis, P Fricˇ, J Pokrotnieks, M Luka´sˇ, B Fixa, M Kasˇcˇa´k, M A Kamm, J Weismueller, C Beglinger,M Stolte, C Wolff, J Schulze. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gut 2004;53:1617–1623. doi: 10.1136/gut.2003.037747 Background and aim: Evidence exists for the pathogenic role of the enteric flora in inflammatory boweldisease. Probiotics contain living microorganisms which exert health effects on the host. We compared theefficacy in maintaining remission of the probiotic preparation Escherichia coli Nissle 1917 and establishedtherapy with mesalazine in patients with ulcerative colitis.
Patients and methods: In total, 327 patients were recruited and assigned to a double blind, double dummy trial to receive either the probiotic drug 200 mg once daily (n = 162) or mesalazine 500 mg three . . . . . . . . . . . . . . . . . . . . . . .
times daily (n = 165). The study lasted for 12 months and patients were assessed by clinical and endoscopic activity indices (Rachmilewitz) as well as by histology. The primary aim of the study was to confirm equivalent efficacy of the two drugs in the prevention of relapses.
Results: The per protocol analysis revealed relapses in 40/110 (36.4%) patients in the E coli Nissle 1917 group and 38/112 (33.9%) in the mesalazine group (significant equivalence p = 0.003). Subgroup analyses showed no differences between the treatment groups in terms of duration and localisation ofdisease or pretrial treatment. Safety profile and tolerability were very good for both groups and were not Conclusions: The probiotic drug E coli Nissle 1917 shows efficacy and safety in maintaining remission equivalent to the gold standard mesalazine in patients with ulcerative colitis. The effectiveness of probiotic . . . . . . . . . . . . . . . . . . . . . . .
treatment further underlines the pathogenetic significance of the enteric flora.
Ulcerativecolitis(UC)isachronicrelapsingdisease.The good clinical practice (GCP) guidelines. The study was aims of treatment are induction of remission and prevention of relapses. Guidelines1 2 recommend ami- Nordrhein, Germany, as well as by the local ethics nosalicylates for maintenance treatment. Aminosalicylates committees of the participating centres. All patients received exert various effects on leukotrienes, cytokines, and oxygen material in their own language and gave written informed radicals.3 Their mode of action in UC remains unclear. It is consent. Patients were included in the study if aged 18– suggested that the sum of their anti-inflammatory activities 70 years and diagnosed with UC in remission (clinical constitutes their therapeutic principle. Thus maintenance activity index (CAI) (4, endoscopic index (EI) (4, and no treatment with aminosalicylates is only effective when signs of acute inflammation on histological examination). In inflammation starts, but not in the non-inflamed gut.
addition, inclusion criteria comprised at least two acute Growing evidence exists for a role of the intestinal attacks of UC prior to the study and a duration of the current microflora in the pathogenesis of inflammatory bowel disease remission of no longer than 12 months. Exclusion criteria (IBD). Findings from genetically engineered animal models were: active UC; proctitis with up to 10 cm proximal spread; as well as clinical observations have elucidated the impor- Crohn’s disease; infectious colitis; severe accompanying tance of commensal bacteria.4–6 Antibacterial treatment illnesses or major colonic surgery; use of antibiotics, showed some beneficial effects7 8 but the use of antibiotics sulphonamides, steroids, or other therapies for UC at entry is limited. Therefore, treatment with probiotics has been into the trial; administration of EcN within the previous six months before trial entry; as well as known intolerance to Probiotics are viable non-pathogenic microorganisms that confer health benefits to the host by improving the microbialbalance of the indigenous microflora.9 Apart from anecdotal experience, two controlled studies with the probiotic bacterial The investigational drug was a bacterial preparation for oral strain Escherichia coli Nissle 1917 (EcN) in UC already use containing non-pathogenic Escherichia coli of strain Nissle exist.10 11 These trials showed no difference between the 1917 (serotype O6:K5:H1). Capsules were enteric coated to relapse preventing effects of EcN and standard mesalazine.
protect the microorganisms from gastric juice and contained However, some criticism was raised as to the validity of these 2.5–256109 viable bacteria (Mutaflor 100 mg; Ardeypharm studies.12 13 The present study was undertaken to confirm that GmbH, Herdecke, Germany). The control preparation was the relapse preventing effects of probiotic therapy with EcN mesalazine, consisting of eudragit L coated 5-aminosalicylic and standard mesalazine are equivalent.
Abbreviations: UC, ulcerative colitis; IBD, inflammatory bowel disease; EcN, Escherichia coli Nissle 1917; GCP, good clinical practice; CAI, clinical activity index; EI, endoscopic index; ITT, intention to treat Declaration (revised version of Hong Kong) and adhered to population; PP, per protocol population; 5-ASA, 5-aminosalicylic acid acid (Salofalk500 mg; Dr Falk Pharma GmbH, Freiburg, Germany). The test group received one capsule of Mutaflor 100 mg once daily and one tablet of placebo three times daily At trial entry and at the end of the study, patients from day 1 to day 4, and two capsules of Mutaflor 100 mg once daily and one tablet of placebo three times daily from Endoscopic activity was assessed using a four point index14: day 5 to the end of the study. The control group received one granularity, vascular pattern, vulnerability of mucosa, and capsule of placebo once daily and one tablet of Salofalk mucosal damage. All biopsies were examined by a single 500 mg three times daily from day 1 to day 4, and two capsules of placebo once daily and one tablet of Salofalk Secondary efficacy variables were the physician’s and 500 mg three times daily from day 5 to the end of the study.
patient’s assessment of general well being and calculation No concomitant medication for UC was allowed through- of a quality of life index.16 Additionally, time to relapse, CAI, EI, and histological findings were documented.
Laboratory assessments, including erythrocyte sedimenta- tion rate, C reactive protein, orosomucoids, blood counts, This was a randomised, double blind, double dummy trial liver enzymes, creatinine, serum iron, and serum albumin comparing the relapse preventing effects and safety of a were performed at trial entry and at the end of the study.
bacterial preparation containing viable EcN and mesalazine Incidence and severity of adverse events were reported for 12 months in patients with UC in remission. The study according to GCP for clinical trials of medication in the was conducted in 60 hospitals and private settings in 10 European Community (91/507/EWG, CPMP/ICH/135/95).
European countries (see list of participating investigators in Tolerance of the study medication was assessed on a four point scale (very good, good, fair, poor), and patient Randomisation was carried out in a double blind manner compliance was ascertained by pill counting.
in blocks of four patients using 1:1 allocation to the twotreatment groups. Only complete blocks of random numbers were used for each centre. If patients were eligible for study The aim of the study was to statistically confirm one sided entry, they were assigned to random numbers ( = patient equivalent efficacy of EcN and mesalazine in preventing numbers) in ascending order within each centre according to relapses of UC. Relapse rates were compared using the one the chronological order of their randomisation and were sided test of Farrington and Manning17: this tests the null given the corresponding study medication.
hypothesis that the difference between treatment groups isgreater than or equal to the upper equivalence margin D of 20% versus the alternative that the true difference is less than Clinic visits were required at the start and end of the study as 20% (a = 0.05; upper confidence limit 95%). Assuming a well as after 1, 2, 3, 6, and 9 months of treatment.
12 month relapse rate of 30% under mesalazine treatment The primary objective of the study was to compare the and 35% under EcN treatment, to reach a statistical power of number of patients experiencing a relapse of UC during the 80% at least n = 127 patients were required in each treatment 12 month observation period between the two treatment group according to the sample size term for comparative groups. Patients were classified as suffering a relapse when binomial trials with the null hypothesis of non-zero risk all three of the following criteria were met: CAI .6 or an difference.17 Two sets of patients were analysed: an intention increase in CAI of at least 3 points with CAI = 4 being to treat population (ITT), including all patients who took at exceeded at the same time; EI .4; and histological signs of least one dose of the study medication, and a per protocol Table 1 Demographic data and prestudy clinical characteristics Treatment before study (single/combined therapy) UC, ulcerative colitis; EcN, Escherichia coli Nissle 1917; ITT, intention to treat population; PP, per protocolpopulation.
*Partly combined with steroids.
No significant differences between treatment groups.
Maintaining therapy with E coli Nissle 1917 in ulcerative colitis study at the time of clinical visits and at population (PP). According to generally accepted standardsfor equivalence and non-inferiority trials,18 primary analysis of the main objective (difference in relapse rates) was based on the PP population. Assuming 25% protocol violators, a total number of 160 patients in each treatment group was Baseline comparability and statistical analysis of secondary objectives was assessed using Fisher’s exact test (two sided; a = 0.05). In addition, Kaplan-Meier curves were plotted. If no CAI or other parameter was documented at the individual study end, the ‘‘last observation carried forward’’ method was applied. Results are given as mean (SD). Statistical tests were executed using SPSS software package version 10.0under the Microsoft Windows NT operating system. For Figure 2 Proportion of patients experiencing a relapse of ulcerative exploratory comparisons (tables 2, 3), the Student’s t test was colitis in the Escherichia coli Nissle 1917 (EcN) and mesalazine groups.
25.9% and 25.5% of EcN and mesalazine patients, respec- tively. All 327 randomised patients received at least one dose of the study medication and thus were included in the ITT In total, 327 patients were enrolled and randomised to either the EcN preparation (n = 162) or mesalazine (n = 165). The Before unblinding the study, a steering committee assessed two patient groups were matched with regard to demo- protocol violations in 105/327 (32.1%) patients. Major graphic, clinical, and pretreatment characteristics (table 1).
protocol deviations comprised violation of inclusion criteria The time gap between the end of the last relapse before the (CAI (4, EI (4, and no signs of acute inflammation on study and entry into the study was not longer than four histological examination) (32 patients in both groups), weeks in 11.1% of patients receiving EcN and in 9.1% premature discontinuation of the study without relapse (see receiving mesalazine, and not longer than three months in below), and unknown or not unequivocally assessed end Table 2 Reasons for premature discontinuation of the study Deterioration of disease (relapse not included) Newly emerged exclusion criterion during study *Multiple reasons possible.
EcN, Escherichia coli Nissle 1917.
group could not be calculated due to the large number of late censorings. In the mesalazine group it was 386 days.
ITT analysis confirmed these results, showing a relapse rate of 45.1% in the EcN group and 37.0% in the mesalazine group (significant equivalence p = 0.013). The upper limit of the 95% confidence interval for the difference in treatment was All subgroup analyses were performed in the ITT population.
CAI increased in all patients by 1.8 (3.4) points over the study period, showing a slightly larger increase in the EcN group (2.4 (3.7)) than in the mesalazine group (1.2 (3.0)). Nodifferences were observed in EI or histology between the start Figure 3 Probability of remaining in remission in the Escherichia coli and end of the study (fig 4). Table 3 lists relapse rates with Nissle 1917 (EcN) and mesalazine groups.
regard to duration, localisation, and pretrial treatment. Therewere no significant differences between the treatment groups point (EcN 29 patients, mesalazine 24 patients). Accordingly, for any of these characteristics. Quality of life scores on the PP analysis set comprised 222 patients (EcN 110, admission were 24.5 (3.9) in the EcN group and 24.4 (4.0) in mesalazine 112). Mean duration of the study observation the mesalazine group. Respective values after 12 months period was 250 (144) (median 357) days in the EcN group were 24.3 (5.2) and 25.1 (3.9). No significant changes and 287 (125) (median 360) days in the mesalazine group.
occurred during the 12 month observation period.
The number of patients in the study at the scheduled visits isshown in fig 1. Premature discontinuation of the study for reasons other than relapse of disease occurred in 39/327 As rated by the patients, overall tolerance was very good or (11.9%) patients (in 19/162 (11.7%) patients in the EcN good in the EcN group in 80.0% and in the mesalazine group group and in 20/165 (12.1%) patients in the mesalazine in 86.0%. According to the physician’s assessment, the group) (table 2). Newly emerged exclusion criteria during respective values were 85.1% and 90.3%.
the study were start of concomitant medication in four Discontinuation of the study medication due to adverse patients on EcN. One patient on mesalazine became afraid of events (relapse included) occurred in 22 (6.7%) patients (11(6.8%) in the EcN group and 11 (6.9%) in the mesalazine 5-aminosalicylic acid (5-ASA) and another patient under- group). Most frequent reasons were gastrointestinal disorders such as bloody stools, nausea, diarrhoea, mucous secretion(EcN 4.3%, mesalazine 4.2%), and abdominal pain (EcN PP analysis revealed relapse in 40/110 (36.4%) patients in the Generally, no unexpected drug reactions occurred during EcN group and in 38/112 (33.9%) patients in the mesalazine the study. No deaths but 17 serious adverse events were group (fig 2), resulting in significant equivalence between the reported in 13/327 (4%) patients (EcN 7, mesalazine 6). Each two groups (p = 0.003). The corresponding one sided upper serious adverse event occurred only once.
95% confidence limit for the difference in treatment was Adverse events were reported in 68/162 (42.0%) patients 12.8% (that is, within the equivalence range of 20%).
treated with EcN and in 58/165 (35.2%) patients treated with Figure 3 depicts the probability of remaining in remission mesalazine. Many adverse events reflect symptoms common by Kaplan-Meier curves. Median time to relapse in the EcN for active UC such as bloody stools (4.6%), diarrhoea (5.8%), Maintaining therapy with E coli Nissle 1917 in ulcerative colitis Table 3 Relapse rates according to clinical characteristics (intention to treat population) UC, ulcerative colitis; EcN, Escherichia coli Nissle 1917.
*Partly combined with steroids.
No significant differences between treatment groups.
and abdominal pain (8.5%). The most frequent non- identification of the antigenic stimuli has not been deter- intestinal adverse events were viral infections (EcN 4.9%, mined, the intestinal microflora represents a likely cul- mesalazine 4.2%), nausea (3.1%, 3.0%) and headache (1.9%, prit.4 21 22 To manipulate the resident gut bacteria therefore 0.6%). Laboratory tests showed no significant alterations.
seems to offer a rational approach to maintaining remissionin IBD. One way of doing this, which has gained credence over recent years, is by using probiotics.23 Most controlled trials are designed to test differences in Mechanisms which may account for probiotic activity efficacy. In contrast, our trial was aimed at proving include production of antimicrobial agents, inhibition of equivalence. Indeed, we demonstrated that the probiotic adhesion of pathogens, and influence on mucosal barrier EcN provides significantly equivalent efficacy in preventing function.13 It was reported that inhibition of nuclear factor kB relapses of UC and is not inferior to the established gold could be mediated by probiotic microorganisms.24 The standard mesalazine. This result was not only confirmed by properties of EcN are well characterised25 and its genome statistical analysis of the PP population, which is preferred in has been extensively analysed.26 It carries non-pathogenic equivalence studies,18 but also by ITT analysis.
adhesion molecules. A specific lipopolysaccharide renders it Therapeutic efficacy is usually demonstrated by superiority immunogenic without showing any immunotoxic proper- in a placebo controlled trial. In serious disease however when ties.27 Immunomodulating activity was demonstrated for effective therapy exists that has already been tested by specific immune responses as well as for induction of non- comparison with placebo, additional placebo controlled trials specific natural immunity in preterm infants.28 EcN develops may be considered unethical.18 A meta-analysis19 reviewed 16 antagonistic activity against enterobacteria such as Salmonella studies of maintenance therapy involving 2341 patients with enteritidis, Shigella dysenteriae, Yersinia enterocolitica, and Vibrio UC. In four of these 16 trials, preparations containing 5-ASA cholerae.29 30 It prevents invasion of Salmonella typhimurium were compared with placebo; in the remaining 12 studies into intestinal cells,31 inhibits adhesion and invasion of sulphasalazine was compared. 5-ASA was observed to be adherent invasive E coli,32 and reduces concentrations of significantly more effective than placebo in all dosage mucosa associated colonic microflora constituents in UC.33 subgroups (,1 g/day, 1–1.9 g/day, >2 g/day). A dose depen- EcN is safe. Molecular genetics as well as functional dent trend was not observed.19 Indeed, some studies analyses have revealed that EcN does not produce any comparing at least two doses were performed showing virulence factors or carry any genes for pathogenicity traits.34 mainly negative or conflicting results20: Pentasa 3 g/day was It does not bear genes for antibiotic resistance, transferable not superior to 1.5 g/day; balsalazide 4 g/day was better than genes or plasmids, and does not take up foreign pathogenic 2 g/day; balsalazide 6 g/day was better than 3 g/day in one DNA. No formation of enterotoxins, cytotoxins, or haemo- study but in another trial was similarly effective; and two lysins has been observed and there is no serum resistance.25 26 29 studies with olsalazine reached different conclusions. Thus Clinical studies have demonstrated a favourable safety superior efficacy of doses higher than 1.5 g/day has not been profile for EcN compared with placebo,35 36 mesalazine,10 11 established.20 It can be stated that mesalazine 1.5 g/day and lactulose.37 Our study confirms this excellent safety and presently reflects the standard in the prevention of UC relapses and thus it qualifies as a control in an equivalence There are other controlled studies with different probiotics.
Relapse prevention with Lactobacillus GG tested negatively for Previous studies on EcN were criticised12 13 for several maintenance therapy in surgically induced remission of reasons—for example, short observation period10 or hetero- Crohn’s disease38 but a small study showed positive results geneity of patients and outcome parameters.11 The present when Saccharomyces boulardii was added to mesalazine.39 trial considered this critique and followed actual standards.
Inflammation of the ileal pouch constructed after proctocol- The observation period was 12 months, only patients with UC ectomy and ileoanal anastomosis in patients with UC is of in remission were included, and the clinical outcome was particular interest because bacterial growth seems to be of assessed by well established endoscopic and histological pivotal pathophysiological significance. Cases successfully activity indices resulting in a low relapse rate for the treated with EcN have been reported.40 A formulation mesalazine group comparable with previous publications.19 comprising eight different probiotic bacteria demonstrated A total of 327 patients were included to achieve a statistical convincing therapeutic effects in primary prevention41 and power sufficient to test for equivalence in a one sided set.
chronic pouchitis.42 In an uncontrolled study, this preparation Most likely, IBD is caused by an unrestrained inflamma- was able to colonise the gut and maintain remission in tory response to as yet undefined agents. Although precise In conclusion, the use of probiotics in IBD is in accordance Slovak Republic: Comenius University Hospital, Bratislava: with its pathogenesis. They may prevent induction of M Huorka; City Hospital, Trencı´ne: M Kasˇc inflammatory reactions. EcN shows therapeutic efficacy and safety in maintaining remission in UC. It can be considered Sweden: Sabbatsberg Naersjukhuset, Stockholm: P Benno; Switzerland: Kantonsspital-University, Basel: Ch Beglinger.
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Clinical Evidence—Call for contributors Clinical Evidence is a regularly updated evidence based journal available worldwide both asa paper version and on the internet. Clinical Evidence needs to recruit a number of newcontributors. Contributors are health care professionals or epidemiologists with experience inevidence based medicine and the ability to write in a concise and structured way.
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N Expanding the topic to include new questions once every 12–18 months.
If you would like to become a contributor for Clinical Evidence or require more informationabout what this involves please send your contact details and a copy of your CV, clearlystating the clinical area you are interested in, to Claire Folkes (
Clinical Evidence also needs to recruit a number of new peer reviewers specifically with aninterest in the clinical areas stated above, and also others related to general practice. Peerreviewers are health care professionals or epidemiologists with experience in evidence basedmedicine. As a peer reviewer you would be asked for your views on the clinical relevance,validity, and accessibility of specific topics within the journal, and their usefulness to theintended audience (international generalists and health care professionals, possibly withlimited statistical knowledge). Topics are usually 2000–3000 words in length and we wouldask you to review between 2–5 topics per year. The peer review process takes placethroughout the year, and our turnaround time for each review is ideally 10–14 days.
If you are interested in becoming a peer reviewer for Clinical Evidence, please complete the peer review questionnaire at or contact ClaireFolkes(


Cholesterol and cardiovascular risk advice leaflet july 201

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