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ORIGINAL ARTICLE
Boswellia serrata extract for the treatment of collagenous
colitis. A double-blind, randomized, placebo-controlled,
multicenter trial
Ahmed Madisch & Stephan Miehlke & Otto Eichele &
Jenny Mrwa & Birgit Bethke & Eberhard Kuhlisch &
Elke Bästlein & Georg Wilhelms & Andrea Morgner &
Bernd Wigginghaus & Manfred Stolte
Accepted: 3 July 2007 / Published online: 2 September 2007
#
Springer-Verlag 2007
Abstract
Background and aims The objective of this study was to
investigate the effect of Boswellia serrata extract (BSE) on
symptoms, quality of life, and histology in patients with
collagenous colitis.
Materials and methods Patients with chronic diarrhea and
histologically proven collagenous colitis were randomized to
receiveeitheroralBSE400mgthreetimesdailyfor6weeksor
placebo. Complete colonoscopy and histology were performed
before and after treatment. Clinical symptoms and quality of
life were assessed by standardized questionnaires and SF-36.
The primary endpoint was the percentage of patients with
clinical remission after 6 weeks (stool frequency ≤3soft/solid
stools per day on average during the last week). Patients of the
placebo group with persistent diarrhea received open-label
BSE therapy for a further 6 weeks.
Results Thirty-one patients were randomized; 26 patients
were available for per-protocol-analysis. After 6 weeks, the
proportion of patients in clinical remission was higher in the
BSE group than in the placebo group (per protocol 63.6%;
95%CI, 30.8–89.1 vs 26.7%, 95%CI, 7.7–55.1; p=0.04;
intention-to-treat 43.8% vs 26.7%, p=0.25). Compared to
placebo, BSE treatment had no effect on histology and
quality of life. Five patients discontinued BSE treatment
prematurely. Discontinuation was due to adverse events (n=
1), unwillingness to continue (n=3), or loss to follow-up for
unknown reasons (n=1). Seven patients received open-label
BSE therapy, five of whom achieved complete remission.
Conclusions Our study suggests that BSE might be clinical-
ly effective in patients with collagenous colitis. Larger trials
are clearly necessary to establish the clinical efficacy of BSE.
Keywords Microscopic colitis
.
Collagenous colitis
.
Boswellia serrata extract
Introduction
Collagenous colitis (CC) is a form of microscopic colitis
with an incidence of 0.6 to 5.2/100,000 person years and a
prevalence of 10 to 15.7/100,000 in Europe [1–3]. The
Int J Colorectal Dis (2007) 22:1445–1451
DOI 10.1007/s00384-007-0364-1
A. Madisch (*)
:
S. Miehlke
:
J. Mrwa
:
A. Morgner
Medical Department I, Technical University Hospital,
Fetscherstrasse 74,
01307 Dresden, Germany
e-mail: ahmed.madisch@uniklinikum-dresden.de
O. Eichele
Pharmacist,
Koblenz, Germany
B. Bethke
:
M. Stolte
Institute for Pathology, Klinikum Bayreuth,
Bayreuth, Germany
E. Kuhlisch
Institute of Medical Informatics and Biometry,
Technical University Hospital,
Dresden, Germany
Present address:
E. Bästlein
Cologne, Germany
Present address:
G. Wilhelms
Goslar, Germany
Present address:
B. Wigginghaus
Osnabrück, Germany
disease is clinically characterized by chronic watery
diarrhea and few or no endoscopic abnormalities [4, 5].
The diagnosis of CC relies on histopathologic examination
of biopsy specimens from the colorectal mucosa, with a
typical feature being diffuse thickening of the subepithelial
collagen layer (≥10 μm) beneath the basement membrane
and a nonspecific chronic inflammatory infiltrate of the
lamina propria [6–10]. The etiology of CC is unknown.
Several hypotheses have been suggested. Autoimmunity
may play an important role arising from a poorly regulated
epithelial immune response to luminal antigens [11–14].
There is also an increasing evidence for specific drugs to
cause or worsen collagenous colitis [15].
The treatment of CC has been purely empirical in the past
and remains a challenge. The first randomized placebo-
controlled trial suggested that treatment with bismuth sub-
salicylate has a positive effect on clinical symptoms and
histopathology in patients with collagenous and lymphocytic
colitis. However, because the number of patients in that study
was rather small (n=9), these data may need confirmation by
larger trials [16]. Recently, budesonide capsules have been
shown to be effective for induction of remission in
collagenous colitis in three placebo-controlled trials [17–
19]. The majority of patients treated with budesonide
capsules experience a rapid induction of clinical remission,
a significant improvement of quality of life and histology
[20, 21]. However, a considerable clinical relapse rate after
cessation of treatment has been described [17, 22]. Thus,
alternative treatment modalities for acute and long-term
treatment of CC are needed.
Due to their anti-inflammatory properties, Boswellia
serrata extract (BSE) has been used in various inflamma-
tory disorders, such as bronchial asthma, chronic polyar-
thritis, and inflammatory bowel diseases [ 23 – 28 ].
This led us to hypothesize that BSE might also be effective
in collagenous colitis. The aim of this study was therefore to
evaluate the clinical and histologic effects of oral BSE in
patients with CC in an appropriate study design.
Materials and methods
Study desig n and recruitment of patients
The clinical trial was conducted in a randomized, placebo-
controlled, double-blind fashion performed at several
centers in Germany.
Patients, aged between 18 and 80 years were eligible for
the study if they had at least five liquid or soft stools per
day on average per week, a complete colonoscopy
performed within the last 4 weeks before randomization,
and a histologically confirmed diagnosis of collagenous
colitis.
Exclusion criteria included treatment with budeson ide,
salicylates, steroids, prokinetics, antibiotics, ketoconazole,
or non-steroidal anti-inflammatory drugs within 4 weeks
before randomization, other endoscopically or histological-
ly verified causes for diarrhea, infectious diarrhea, preg-
nancy or lactation, previous colonic surgery, and known
intolerance to BSE.
The study protocol and consent form were approved by
the Ethics Committee of the University Hospital Dresden in
accordance with the revised Declaration of Helsinki.
Written informed consent was obtained from all patients
before inclusion in the trial.
Randomization and therapy
Eligible patients were randomized by groups of four
patients according to a central computer-generated random-
ization list to receive either BSE 400 mg or placebo given
three times daily with meals for 6 weeks (Fig. 1).
Physicians, patients, and pathologist were blinded to the
treatment group. Study medication was provided in identi-
cal-looking white boxes labeled with consecutive numbers
corresponding to the randomization list. In addition, the
placebo containers were prepared from the inside to mimic
the typical scent of incense to prevent unblinding by the
typical odor of BSE.
For each box of study medication, a sealed white
envelope was available to be opened only in case of
emergency for unblinding.
Concomitant use of loperamide was allowed for the first
3 weeks but was not allowed for the last 3 weeks of the
study. Patients were allowed to use butylscopolamine in
case of abdominal pain.
Patients who did not respond to treatment after 6 weeks
were individually unblinded. If they were in the active
treatment group, they were judged as treatment failure. If
they were in the placebo group, crossover therapy with
open-labeled BSE 400 mg, given orally three times daily
was offered.
Study medication
The preparation used in this study contained 400 mg of
BSE per capsule (80% Boswellia acid). High performance
liquid chroma tography (HPLC) analysis of individual
Boswellia acids revealed the following results: 21. 2 mg
11-k eto-β-boswellia acid, 27.3 mg α-boswellia acid,
50.9 mg β-boswellia acid, 11.3 mg acetyl-11-keto-β-
boswellia acid, 9.8 mg acetyl-α-boswellia acid, and
28.7 mg acetyl-β-boswellia acid. The study medication
was prepared and delivered by a local pharmacist in
Western Germany (O.E.) associated with a hospital for
naturopathy.
1446 Int J Colorectal Dis (2007) 22:1445–1451
Clinical symptoms, safet y, and compliance
Stool frequency and c onsistency, intake of study medica-
tion, adverse events, and any intake of allowed concomitant
medication were assessed by standardized questionnaire.
Spontaneous reports of adverse events were documented at
the time of onset. The documentation sheets were collected
at the end of the treatment period.
Compliance was assessed by pill count. Patients who took
less than 80% of the prescribed pills were considered to be
non-compliant and excluded from the per-protocol analysis,
but were included in the intention-to-treat analysis.
The primary endpoint of the study was the percentage of
patients with clinical remission after 6 weeks. Histology
and quality of life served as secondary endpoints of the
study. Clinical remission was defined as stool frequency
equal to or less than three soft or solid stools per day on
average during the last week of treatment.
Quality of life
Quality of life was assessed by using SF-36 at baseline and
after 6 weeks of treatment. The SF-36 consists of four
domains of physical health (physical functioning, role
limitation-physical, bodily pain, general health) and four
domains of mental health (role limitation-emotional, vital-
ity, mental health, social functioning).
Endoscopy and histology
A complete colonoscopy including in spection of the
terminal ileum was performed at baseline and after 6 weeks,
i.e., at the end of therapy. At each colonoscopy, at least two
biopsy specimens each from the ileum, ascending colon,
transverse colon, descending colon, sigmoid colon, and
rectum were taken for histological examination. Biopsy
specimens were fixed in 10% formalin and embedded in
Boswellia serrata Extract
n = 16
Intention-to-treat set
n = 16
Adverse event
n = 1
Unwillingness to continue
n = 3
Lost of follow-up
n = 1
Completed study
n = 11
Screened patients
n = 48
Not eligible
n = 17
Randomized
n = 31
Placebo
n = 15
Intention-to-treat set
n = 15
Completed study
n = 15
Open-label Therapy
n = 7
Fig. 1 Trial profile
Int J Colorectal Dis (2007) 22:1445–1451 1447
paraffin. Hemato xylin and eosin stain and van Gieson stain
were performed. On well-oriented sections, in which at
least three adjacent crypts were cut in the vertical plane, the
following three parameters were assessed: thickness of the
collagen band (μm), inflammation of the lamina propria
(semiquantitative score 0–3), and degeneration of surface
epithelium (present/absent). The diagno sis of CC was made
when the subepithelial collagen layer on at least one well-
oriented section of mucosa exceeded 10 μm.
For each individual patient, the values of each parameter
at the various biopsy sites were pooled and the mean was
calculated.
Statistical analysis
For statistical analysis, the Banard’s exact test, Fisher’s
exact test, and the Mann–Whitney test were used when
appropriate. Less than 0.05 p values were c onsidered to
indicate statistical significance. The sample size of n=23
per group was required that a Fisher’s exact test with a 0.05
two-sided significance level will have 80% power to detect
the difference in the response rate between the active group
of 60% and the placebo group of 20%.
Statistical analyses were performed utilizing the software
package SPSS 13.0 for windows and StatXact-4.
Results
Study population
Between October 2002 and April 2005, a total of 31
patients (16 BSE group) were enrolled. In May 2005, the
study was prematurely stopped due to insufficient recruit-
ment. The baseline characteristics of the two groups were
similar (Table 1). Eight patients (25.8%) of the study
population reported concomitant autoimmune-like disorders
such as diabetes, thyroid disease, or fibromyalgia. A total of
seven pati ents (22.5%; 4 patients BSE group; 3 patients of
placebo group) received concomitant medications that are
reportedly associated with microscopic colitis, such as
aspirin, NSAIDs, and lisinopril. Patients c ontinued their
concomitant medications during the entire study.
A total of four patients discontinued treatment prema-
turely either due to adverse events (one BSE group) or due
to unwillingness to continue (three BSE group, 2 weeks
after starting treatment with persistent diarrheal symptoms).
One patient of the BSE group was lost to follow-up for
unknown reason. Thus, a total of 26 patients (83.8%) were
available for per protocol analysis.
Efficacy of treatment
After 6 weeks, the rate of clinical remission was significantly
higher in the BSE group than in the placebo group (per
protocol 63.6%; 95%CI, 30.79–89.07 vs 26.7%; 95%CI, 7.7–
55.1) p=0.04); intention-to-treat, 43.8% vs 26.7%, p=0.25).
In the per-protocol analysis, the median stool frequency
per day was reduced from 6.5 (range, 4–15) to 3 (range, 1–7)
in the BSE group and from 5 (range, 4–10) to 4 (range, 1–9)
in the placebo group after 6 weeks of treatment (Fig. 2).
Change of stool consistency after treatment is depicted in
Fig. 3. After 3 weeks of treatment, clinical remission rates
were not significantly different between the two groups
(p=0.18). None of the patients used any antidiarrheals or
butylscopolamine during the entire study perio d.
Seven patients of the placebo group with persistent
diarrhea after 6 weeks of treatment agreed and received an
open-label BSE therapy for further 6 weeks. Of those, five
patients (71,4%) achieved clinical remission at the end of
cross-over BSE treatment.
Effect on histopathology
The thickness of the collagen layer was patchy distributed
through the entire the colon ranged between 0 to 15 μm.
The diagnosis of CC was made when the subepithelial
collagen layer on at least one well-oriented section of
mucosa exceeded 10 μm.
Table 1 Baseline characteristics of patients
BSE group
(n=16)
Placebo group
(n=15)
Characteristics
Age (year), median 64,5 53
Sex (female %) 87,5 80
Body weight (BMI), median 25 28
History of weight loss, (%) 39 40
Stool frequency/day, median
(range)
6,5 (4–15) 5 (4–9)
Time between onset of diarrhea
and diagnosis, %
<1 year 61.4 66.3
1–2 years 6,5 0
>2 years 32 33
Abdominal pain, n (%) 12 (75) 13 (86)
3
6,5
4
5
0
5
10
Baseline After 6 weeks of treatment
Boswellia serrata extract Placebo
Median Stool frequency per day
p = 0.062
Fig. 2 Median stool frequency at baseline and after 6 weeks of
treatment (per-protocol; p=0.062 vs placebo)
1448 Int J Colorectal Dis (2007) 22:1445–1451
At baseline, the mean of the collagen band thickness was
10.1 μm in the BSE group and 8.8 μm in the placebo
group. The corresponding inflammatory scores were 2.3
and 1.9, respectively. There was no significant difference
between both groups at baseline. After 6 weeks of
treatment, there was only a small reduction of collagen
band thickness and inflammation score without statistical
significance compared to baseline or between the groups.
Effect on quality of life
Complete SF-36 assessments at baseline and after 6 weeks
were available in 26 patients. At baseline, the mean scores
of all eight domains in the entire study population were
markedly lower in patients with collagenous colitis com-
pared to normal controls. After 6 weeks of treatment, there
were no statistical significant changes of quality of life in
the two groups compared to baseline and between groups.
Adverse events
BSE therapy was well tolerated, and no serious adverse
events were reported. Two patients of the BSE group did
experience some side effects. One of them withdrew after
3 weeks of treatment because of dizziness, hypoglycemia
(not judged as a severe adverse event by the local
investigator and protocol committee), and lack of appetite
and recovered to normal after cessation of treatment. The
second patient completed the 6-week treatment with
persistent diarrhea and newly diagnosed bacterial enteritis.
In the placebo group, one patient experienced adverse
events (eczema and Coxsackie virus infection) but still
completed the treatment.
Discussion
At present, this is the second largest randomized, placebo-
controlled trial investigating medical intervention in collag-
enous colitis. Although our study failed to show a
statistically significant difference between Boswellia ser-
rata extract and placebo, the per-protocol analysis indicates
that Boswellia serrata extract may be clinically effective
and safe in the treatment of collagenous colitis.
The clinical course of collagenous colitis is variable with
spontaneous improvement or exacerbation of symptoms.
Thus, therapeutic trials of patients with collagenous colitis
require a placebo-controlled, randomized study design to
eliminate the effect of spontaneous improvement or other
sources of bias. Recently, budesonide capsules have been
proven effective for induction of remission in collagenous
colitis in three placebo-controlled trials [17–19]. A recent
Cochrane review of these trials has calculated a number
needed to treat of two patients [29]. The same Cochrane
review included preliminary data from the present study
[30] and concluded that there was a trend towards clinical
improvement in patients receiving BSE treatment compared
to placebo and that there may have been a lack of power
given the small numbers of patients in each group [29].
Several clinical studies suggest an effect of Boswellia
serrata extract in patients with Crohn’s disease, ulcerative
colitis, and nonspecific colitis [26–28]. In a randomized,
double-blind, parallel group study, Gerhardt et al. [26] have
shown that Boswellia serrata extract was not inferior to
mesalazine in maintenance therapy of patients with Crohn
disease. In another study, Boswellia serrata extract was
effective in patients with ulcerative colitis [27].
Thus, the rationale of our study was to investigate
Boswellia serrata extract in patients with collagenous
colitis in a randomized, placebo-controlled tri al. Unfortu-
nately, the study had to be stopped prematurely due to
insufficient recruitment. We speculate that the meanwhile
widely distributed acceptance of budesonide as first-line
treatment of collagenous colitis in Germany has contr ibuted
to a declining willingness of patients to participate in this
trial. Despite the low patient number, the per-protocol
analysis suggests a clinical effect of BSE with a therapeutic
gain of 37% over placebo. The clinical benefi t was further
supported by the observation that five out of seven patients
responded to crossover BSE.
The study was powered under the assumption of a
placebo response rate of 20%, but the placebo response rate
actually observed was far g reater (26,7%) compared to
other placebo controlled trials [17–
19]. Possible explan-
ations for the high placebo response may be the spontane-
ous course of disease or aggravation of the placebo effect
by the odor of incense of the placebo container. Thus, the
high placebo response combined with the low patient
number may have obscured statistical separation between
BSE and placebo regarding the secondary study endpoints.
Quality of life, assessed by SF-36, was markedly
reduced in the present population with collagenous colitis
when compared to normal controls, which confirms
previous data of our study gr oup using GILQI [20].
However, in contrast to our previous study, we did not
0
5
0
10
3
3
6
0
0
5
10
Liquid to solid Liquid to soft Soft to solid no change
Boswellia serrata extract Placebo
Change of stool consistency after treatment
Number of patients
Fig. 3 Change of stool consistency after 6 weeks of treatment (per-
protocol; p>0.05 for all vs placebo)
Int J Colorectal Dis (2007) 22:1445–1451 1449
observe a significant change in quality of life comparing
both groups after therapy, which may be due the low patient
number or due to the short treatmen t period.
Treatment with Boswellia serrata extract was well
tolerated and safe. Only two p atients reported side effects.
One of them discontinued treatment prematurely because of
self-reported side-effects. Therefore, Boswellia serrata
extract might be considered as a useful therapeutic option
for patients with collagenous colitis.
The mode of action of BSE has been investigated in
several experimental studies showing that Boswellia acids
inhibit production of 5-lipooxygenase and synthesis of
leucotrienes [32–35]. Furthermore, Boswellia acids are
catalytic inhibitors of human topoisomerase I and IIα [36].
In contrast to our previous clinical trial [18], we did not find
a significant influence on the histopathology in the present
study as would be expected based upon the anti-inflamma-
tory effect of BSE. A possible explanation could be again
that the treatment period of 6 weeks may have been too
short to improve histolology. The possible slow mode of
action was further supported by the observation that most of
the patients experienced clinical benefit only after 6 weeks
of BSE treatment. In contrast, budesonide treatment leads to
rapid induction of clinical remission [21].
In conclusion, our study suggests that oral Boswellia
serrata extract might be a clinically effective and safe
treatment modality for patients with collagenous colitis.
However, we strongly recommend to further investigate
BSE in larger clinical randomized trials before definite
conclusions can be drawn.
Acknowledgement We thank R. Beckmann for assistance in data
collection. We also thank M. Stewart for critical reviewing the
manuscript. We are grateful to the following colleagues for recruiting
patients to the study: R. Abuagela, H.-P. Bartram, P. Dietz, M.
Dornberg, D. Fuchs, E. Grüger, C Haferland, J. Keymling, E. Meier, J.
Morgenthaler, P. Rohde, G. Stegemann-Özdemir, and H. Wollmann.
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