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.
. . . . . . . . . . . . . . . . . . . . .
UK: Leeds General Infirmary, Leeds: ATR Axon; St Mark’s
W Kruis, Evangelisches Krankenhaus Kalk, University of Cologne,GermanyP Fricˇ, Ustrˇedna´ vojenska´ nemocnice, II internı´ oddeˇlenı´, Praha, Czech
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B Fixa, 2nd Department of Medicine, Charles University Prague,
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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.
Currently, we are interested in finding contributors with an interest inthe following clinical areas:Altitude sickness; Autism; Basal cell carcinoma; Breast feeding; Carbon monoxide poisoning;Cervical cancer; Cystic fibrosis; Ectopic pregnancy; Grief/bereavement; Halitosis; Hodgkinsdisease; Infectious mononucleosis (glandular fever); Kidney stones; Malignant melanoma(metastatic); Mesothelioma; Myeloma; Ovarian cyst; Pancreatitis (acute); Pancreatitis(chronic); Polymyalgia rheumatica; Post-partum haemorrhage; Pulmonary embolism;Recurrent miscarriage; Repetitive strain injury; Scoliosis; Seasonal affective disorder;Squint; Systemic lupus erythematosus; Testicular cancer; Varicocele; Viral meningitis; Vitiligo
However, we are always looking for others, so do not let this list discourage you.
N Appraising the results of literature searches (performed by our Information Specialists) to
identify high quality evidence for inclusion in the journal.
N Writing to a highly structured template (about 2000–3000 words), using evidence from
selected studies, within 6–8 weeks of receiving the literature search results.
N Working with Clinical Evidence Editors to ensure that the text meets rigorous
epidemiological and style standards.
N Updating the text every eight months to incorporate new evidence.
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 (email@example.com).
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 www.clinicalevidence.com or contact ClaireFolkes(firstname.lastname@example.org).
DUKES AVENUE PRACTICE CHOLESTEROL AND CARDIOVASCULAR RISK ADVICE Your cholesterol should be measured as part of a RISK ASSESSMENT for cardiovascular disease (heart disease, stroke, TIA and peripheral arterial disease). Heart disease is a condition in which the blood vessels of the heart become narrowed or blocked by the build up of fat. Stroke is when the blood supply to the brain is cut off,
CONTRATO GENERAL DE COMISION PARA LA REALIZACION DE OPERACIONES BURSATILES Y CUSTODIA DE A TRAVES DE BCT VALORES, PUESTO DE BOLSA, S. A. Celebrado en __________ el día ___________del mes ___________ del año 2012 entre: BCT VALORES PUESTO DE BOLSA, S.A. cédula de persona jurídica número tres-ciento uno-cero veintiocho seiscientos noventa y tres, representado en este acto por su Gerente Gen