Traditional Chinese medicine combination therapy for patients with steroid-dependent ulcerative colitis: study protocol for a randomized controlled trial
Zheng et al. Trials
Traditional Chinese medicine combination therapy for patients with steroid- dependent ulcerative colitis: study protocol for a randomized controlled trial
Kai Zheng 0 2
Hong Shen 0
Jia Jia 1
Yuelin Lu 0
Lei Zhu 3
Lu Zhang 3
Zhaofeng Shen 3
0 Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine , Nanjing, Jiangsu 210029 , China
1 Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine , Nanjing, Jiangsu , China
2 First Clinical Medical College, Nanjing University of Chinese Medicine , Nanjing, Jiangsu , China
3 Division of Scientific Research, Affiliated Hospital of Nanjing University of Chinese Medicine , Nanjing, Jiangsu , China
Background: Approximately 20% of patients with ulcerative colitis become steroid dependent. Azathioprine is recommended in steroid-dependent ulcerative colitis, but its side effects limit its use. Chinese herbal medicine has been widely used to treat ulcerative colitis in China. However, its effectiveness in steroid-dependent patients has not been evaluated. This study aims to investigate the efficacy of traditional Chinese medicine combination therapy with 5-aminosalicylic acid in patients with steroid-dependent ulcerative colitis. Methods/Design: This is a parallel, multicenter, randomized controlled trial. One hundred and twenty eligible patients will be randomly assigned to a traditional Chinese medicine group or azathioprine group. All patients will be given basic treatment, which includes steroids and 5-aminosalicylic acid. Patients allocated to the traditional Chinese medicine group will receive basic treatment plus Chinese herbal medicine granules, while patients in the azathioprine group will receive basic treatment plus azathioprine. The whole study will last 24 weeks. The primary outcome measure is the steroid-free remission rate. Secondary outcome measures are health-related quality of life, efficacy of endoscopic response, degree of mucosal healing, and inflammation indicators. Discussion: Results from this study may provide evidence for the effectiveness of traditional Chinese medicine combined with 5-aminosalicylic acid in patients with steroid-dependent ulcerative colitis. The findings will provide a basis for further confirmatory studies. Trial registration: Chinese Clinical Trial Register, ChiCTR-IPR-15005760. Registered on 2 January 2015.
5-aminosalicylic acid; Azathioprine; Chinese herbal medicine; Steroid-dependent ulcerative colitis; Study protocol
Ulcerative colitis is a form of inflammatory bowel disease
characterized by a chronic relapsing clinical course.
Intermittent rectal bleeding, diarrhea, and abdominal pain are
often symptoms of ulcerative colitis. 5-Aminosalicylic acid
is usually used in mild cases of ulcerative colitis. Steroids
are another effective therapy for inducing remission in
patients with moderate and severely active ulcerative colitis.
Approximately 20–34% of patients with ulcerative colitis
have chronic active disease requiring several courses of
steroids to achieve remission [1, 2]. Many patients initially
benefit from steroid treatment but relapse shortly after
treatment cessation or after dose reduction. Up to 20% of
patients with ulcerative colitis become steroid dependent
. The European Crohn’s and Colitis Organisation
guidelines define “steroid-dependent” patients as those who are
unable to reduce steroids below the equivalent of
prednisolone 10 mg/day within 3 months of starting steroid use,
without recurrent active disease, or who have a relapse
within 3 months of stopping steroid use . The risks of
long-term steroid therapy include osteoporosis,
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pathological fractures, cataracts, metabolic changes,
psychological disturbances, and infection. Moreover,
steroids have not been shown to be effective for the
maintenance of remission.
The American College of Gastroenterology and
European Crohn’s and Colitis Organisation guidelines
recommend that patients with steroid-dependent disease
should be treated with azathioprine or 6-mercaptopurine
[5, 6]. Azathioprine is significantly more effective than
5-aminosalicylic acid at achieving clinical and
endoscopic remission in the treatment of steroid-dependent
ulcerative colitis. In a single-center retrospective cohort
study, 64 Asian patients with steroid-dependent
inflammatory bowel disease were assessed, and 61% of patients
were able to maintain clinical remission after 5 years of
azathioprine therapy . Toxicity induced by
azathioprine and 6-mercaptopurine in patients with
inflammatory bowel disease includes bone marrow suppression,
drug-induced hepatitis, pancreatitis, and infection.
Complementary and alternative medicine use is
common in patients with inflammatory bowel disease. The
single most commonly used modality in most surveys is
traditional Chinese medicine (TCM) . Chinese herbal
medicine is useful in improving symptoms, such as
abdominal pain and diarrhea, and reducing inflammation
in patients with ulcerative colitis. Many
steroiddependent patients are dissatisfied with conventional
therapies, including azathioprine’s side effects; thus, they
turn to TCM. However, it is not clear whether Chinese
herbal medicine is effective for patients with
steroiddependent ulcerative colitis. Therefore, the primary aim
of our study is to evaluate the clinical efficacy of TCM
treatment among patients with steroid-dependent
ulcerative colitis. Health-related quality of life in
steroiddependent patients will be a secondary aim.
This is a multicenter, randomized controlled trial with
two parallel groups and a 24-week follow-up. The
centers include the Affiliated Hospital of Nanjing University
of Chinese Medicine, Beijing Hospital of Chinese
Medicine, Guangdong Province Hospital of Chinese
Medicine, Longhua Hospital affiliated to Shanghai University
of Chinese Medicine, the First Affiliated Hospital of
Henan University of Chinese Medicine, Nanjing Drum
Tower Hospital of Nanjing University of Medical School,
Shengjing Hospital of China Medical University, the
Hospital of Shanxi University of Chinese Medicine, the
First Affiliated Hospital of Heilongjiang University of
Chinese Medicine, and Nantong Hospital of Chinese
Medicine. The study began in January 2015 and will last
until October 2017. Trained researchers enroll
participants. One hundred and twenty patients who meet the
eligibility criteria will be recruited and allocated into two
groups, with 60 individuals per group. This study has
been approved by the Institutional Review Board of
Human Research of the Affiliated Hospital of Nanjing
University of Chinese Medicine (approval number:
2014NL073-03). Participants must provide written informed
consent to participate in the study. All participants will
continue their initial steroid and 5-aminosalicylic
therapy, and will be randomly assigned to receive either
Chinese herbal medicine or azathioprine. The overall
flow of the trial is shown in Fig. 1.
Participants will be considered for enrollment if they:
range in age from 18 to 65 years; have a confirmed
diagnosis of steroid-dependent ulcerative colitis; agree to
participate in this clinical trial; and sign the informed
Patients will be excluded from the study if they:
experience complications such as intestinal obstruction,
intestinal perforation, toxic megacolon, or colorectal
cancer; are pregnant, breast-feeding, or preparing for
pregnancy; have an alanine aminotransferase level above
the twice upper limit of normal; have a serum creatinine
level above the upper limit of normal; have a platelet
value of less than 50 × 109/l; have a leukocyte count of
less than 3.0 × 109/l; have a known history of alcohol or
drug abuse; or are enrolled in other clinical trials.
The remission rate for ulcerative colitis by azathioprine
ranges from 59.1% to 87% [9, 10], and the average rate is
about 73%. This is a noninferiority trial. For a two-sided
significance level of 0.05 and power of 80% (α = 0.05, β
= 0.2, δ = 0.15), the sample size is calculated using the
Considering a 10% loss to follow-up, the sample size is
120 cases (n = 60 in each group).
A randomization sequence was generated using SAS
9.4 (SAS Institute Inc., Cary, NC, USA). An
independent person (Dr. Jiandong Zou) who is not involved
in observation or assessment of the patients possesses
the computer-generated randomization sequence. The
researchers are blinded to the randomization sequence.
The randomization procedure will be conducted by
research assistants using an online computerized
randomization system (https://sci.njpdkj.com/pdsci/). Eligible
participants will be randomly assigned to either the TCM
group or azathioprine group.
Fig. 1 Flow chart of the trial. 5-ASA, 5-aminosalicylic acid; AZA, azathioprine
All eligible steroid-dependent patients will continue
their initial steroid and 5-aminosalicylic therapy.
Withdrawal of steroids occurs along with clinical remission. If
there is clinical remission, a taper dose will be initiated
with 5 mg taper weekly until a 20 mg daily dose is
reached. Then tapering should proceed by 2.5 mg per
Chinese herbal medicine granules
Patients in the TCM group will be treated with basic
treatment plus granules. The granules include Radix
Astragali (Huangqi) 20 g, Rhizoma Atractylodis
Macrocephalae (Baizhu) 10 g, Semen Coicis (Yiyiren) 20 g,
Rhizoma Dioscoreae (Shanyao) 20 g, Rhizoma Coptidis
(Huanglian) 6 g, Radix Scutellariae (Huangqin) 10 g,
Radix Pulsatillae (Baitouweng) 10 g, Rhizoma Smilacis
Glabrae (Tufuling) 15 g, Radix Angelicae Dahuricae
(Baizhi) 12 g, Radix Paeoniae Alba (Baishao) 20 g,
Pericarpium Citri Reticulatae (Chenpi) 12 g, Radix
Saposhnikoviae (Fangfeng) 12 g, Radix Aucklandiae (Muxiang)
6 g, Radix Sanguisorbae (Diyu) 10 g, Radix Arnebiae
(Zicao) 10 g, Radix et Rhizoma Rubiae (Qiancao) 20 g,
Fructus Alpiniae Oxyphyllae (Yizhi) 10 g, Rhizoma
Zingiberis Preparata (Paojiang) 6 g, and Radix et Rhizoma
Glycyrrhizae (Gancao) 6 g. All ingredients are
manufactured as a Chinese herbal granule with a weight 27.5 g
(Jiangyin Tianjiang Pharmaceutical Co., Ltd, Jiangyin,
China). Patients will take one Chinese herbal medicine
granule per day. The course of treatment is 24 weeks
unless there is a loss of follow-up.
The control group will take basic treatment plus
azathioprine. Azathioprine treatment can be initiated at a
dosage of 1 mg/kg per day [12, 13]. The course of treatment
will be in accordance with the TCM group.
Primary outcome measure
The primary outcome measure of this study is the
steroid-free remission rate in patients with
steroiddependent ulcerative colitis. Remission is defined as a
Mayo disease activity index score of 0–2, with no
individual subscore exceeding 1 . The withdrawal time
of steroids will also be recorded. The outcome measure
will be evaluated at the end of 24 weeks. If there is no
statistical significance between the steroid-free remission
rate of the TCM group and the azathioprine group, then
the mean withdrawal time from steroids will be
Secondary outcome measures
The key secondary aim is to investigate the effect of
Chinese herbal medicine granules on health-related
quality of life in steroid-dependent patients compared
with azathioprine, as measured by the inflammatory
bowel disease questionnaire. Other secondary outcome
measures include the efficacy of endoscopic response,
which is defined as a decrease from baseline in a Mayo
disease activity index endoscopy subscore by at least 1
. The degree of mucosal healing is defined as a Mayo
disease activity index endoscopy subscore of 0 or 1 .
Improvements in inflammation indicators include fecal
calprotectin, C reactive protein, and erythrocyte
During the study, all adverse events, including toxicity
and side effects, such as drug allergies, liver damage,
renal failure, bone marrow suppression, and pancreatitis,
will be reported and recorded in the case report form in
detail. The researcher will report serious adverse events
to the Institutional Review Board of Human Research of
the Affiliated Hospital of Nanjing University of Chinese
Data management and statistical analysis
Data recorded in printed case report forms are kept in
locked cabinets. Data will be double-entered on
electronic case report forms by two persons. Frequency,
median, and mean ± standard deviation of the steroid-free
remission rate and the mean withdrawal time of steroids
will be used for descriptive statistics. Student’s t test and
analysis of variance will be employed using continuous
variables with a normal distribution. The
Mann–Whitney U test and Kruskal–Wallis test will be used for
continuous variables with abnormal distributions, such as
health-related quality of life and inflammation markers.
A chi-square test or Fisher’s exact test will be used for
categorical variables, including the efficacy of endoscopic
response and the degree of mucosal healing. Results will
be analyzed as per intention-to-treat. All data will be
analyzed by an independent statistician using SAS 9.4. For
all analyses, P < 0.05 is considered statistically significant.
To summarize the present study protocol, please see
Additional file 1 for an overview of enrollment,
interventions and assessments, and Additional file 2 for
an overview of the Standard Protocol Items:
Recommendations for Interventional Trials (SPIRIT) checklist.
Ulcerative colitis is a chronic inflammatory bowel
disease characterized by a relapsing-remitting course owing
to recurrent intestinal inflammation. Steroids are often
prescribed for moderate to severe ulcerative colitis
patients. Although steroids are usually effective, long-term
steroid use should be avoided because of its severe side
effects. Patients who initially respond to steroids but
then relapse after tapering or shortly after
discontinuation, and require reintroduction of steroids to induce
remission are defined as steroid dependent. The
therapeutic objective of steroid-dependent patients is to
achieve steroid-free remission.
In view of the side effects of steroids, different drugs
are used in the management of steroid-dependent
ulcerative colitis. Drugs used include established agents,
such as thiopurines, methotrexate, infliximab,
adalimumab, vedolizumab, and golimumab. If common
treatments fail, colectomy may be performed . Current
guidelines recommend thiopurines as first-line therapy
to spare steroids in steroid-dependent ulcerative colitis
[3, 6]. Therefore, the thiopurine agents azathioprine
and 6-mercaptopurine are used to sustain steroid
withdrawal in patients with steroid-dependent ulcerative
colitis . Azathioprine is a purine analog that
competitively inhibits the biosynthesis of purine
ribonucleotides . Azathioprine is the main therapy for
steroiddependent patients in China, because vedolizumab and
golimumab are not available, and adalimumab is not
indicated for use in patients with ulcerative colitis.
Furthermore, cessation of infliximab is still considered in
clinical practice because of its high cost and fear of
long-term side effects . There is also a reduced
response to infliximab, which may reach approximately
13% per year with uninterrupted scheduled
maintenance therapy . Fraser et al. reported that the
remission rate was 87% in 346 ulcerative colitis patients who
received more than 6 months of azathioprine treatment
. Another study demonstrated that the steroid-free
remission rate was 59.1% in patients with
steroiddependent or steroid-resistant ulcerative colitis treated
with azathioprine . The most common adverse event
of azathioprine is leukopenia, which occurs in 3.8% of
patients . Other adverse events include hepatitis,
infection, pancreatitis, and hair loss. Once absorbed
into the plasma, azathioprine is nonenzymatically
converted to 6-mercaptopurine. 6-Mercaptopurine can
be metabolized to 6-methylmercaptopurine by the
enzyme thiopurine methyltransferase (TPMT), to
6thiouric acid by the enzyme xanthine oxidase, and to
the active metabolites of 6-thioguanine nucleotide.
6Thioguanine nucleotide is the active ribonucleotide of
6-mercaptopurine; it functions as a purine antagonist,
resulting in immunosuppression and
lymphocytotoxicity. A deficiency in TPMT may lead to preferential
6mercaptopurine metabolism into 6-thioguanine nucleotide,
resulting in myelosuppression . An apparent genetic
polymorphism of TPMT is associated with TPMT enzyme
deficiency. Despite a lower frequency of variant TPMT
observed in Asian populations , lower starting doses of
azathioprine are recommended in Asian populations than
in white populations, along with close monitoring of
complete blood count and liver function .
Chinese herbal medicine is a type of complementary
and alternative medicine, and is often used in patients
with inflammatory bowel disease , especially in China.
Dai et al.  analyzed 247 patients with ulcerative
colitis. The Sutherland Disease Activity Index scores for
patients treated with TCM and those treated with
integrated TCM and Western medicine were
significantly lower for both groups after treatment (P < 0.01).
Sugimoto et al. used the Chinese herbal medicine
QingDai to treat 20 patients with moderate ulcerative colitis.
The rates of clinical response, clinical remission, and
mucosal healing were 72%, 33%, and 61% at week 8,
respectively . Qing-Dai stimulates mucosal type 3
innate lymphoid cells to generate interleukin-22, which
induces antimicrobial peptide and tight junction
production, suggesting a therapeutic mechanism for mucosal
healing . Our study using Chinese herbal medicine
plus 5-aminosalicylic in patients with steroid-dependent
ulcerative colitis aims to observe improvements in the
primary outcome of steroid-free remission rate, and the
secondary outcomes of health-related quality of life,
endoscopic response, mucosal healing, and inflammation
indicators. We expect that the steroid-free remission
rate of the TCM group will be improved over that of the
azathioprine group. The mean withdrawal time of
steroids in the TCM groups should be less than that of the
azathioprine group, which would reduce the risks of
steroid therapy. We anticipate that the results will show
that Chinese herbal medicine is effective for patients
with steroid-dependent ulcerative colitis.
There are several limitations to our study. First, this is
an open-label randomized controlled trial without
double blinding. Because of the lack of placebo control
groups, our findings will be interpreted with caution.
Another limitation to this study is the lack of TPMT and
6-thioguanine nucleotide testing. Some patients do not
respond to azathioprine because of lower 6-thioguanine
nucleotide levels. Although a lower frequency of variant
TPMT is observed in Asian populations, TPMT and
6thioguanine nucleotide testing may assist dose
optimization of azathioprine to achieve response and
avoid drug-induced toxicity. Both TPMT and
6thioguanine nucleotide testing will be determined in
corollary studies. The last limitation is of first-choice
therapy in steroid-dependent ulcerative colitis. The Toronto
consensus in 2015 recommends anti-TNF therapy to
induce and maintain complete steroid-free remission in
patients with steroid-dependent ulcerative colitis .
The consensus group also recommends that anti-TNF
plus azathioprine therapy is the preferred choice for
steroid-dependent patients rather than monotherapy to
induce complete remission [26, 27]. However,
azathioprine is still the most practicable therapy for
steroiddependent patients in China, because anti-TNF agents
are not widely used. Combination therapy with anti-TNF
agents will be available in the future. Notwithstanding
its limitations, this study will suggest whether Chinese
herbal medicine can be an effective complementary and
alternative medicine in patients with steroid-dependent
Additional file 1: Schedule of enrollment, interventions, and
assessments. (DOC 148 kb)
Additional file 2: SPIRIT 2013 Checklist: recommended items to address
in a clinical trial protocol and related documents. (DOC 133 kb)
This study is supported by the Special Scientific Research for TCM of State
Administration of Traditional Chinese Medicine of China (no. 201407001),
and the National Natural Science Foundation of China (no. 81403343).
KZ and HS contributed to the design of the study protocol. KZ, HS, YL, LZ,
LZ, and ZS participated in the project development. KZ and JJ prepared the
initial draft of the manuscript. KZ was involved in designing the statistical
methods of the study design. KZ and JJ will be involved in the statistical
analysis. HS is the project leader. All authors were responsible for the
manuscript drafting and approved the final version.
Ethics approval and consent to participate
Ethical approvals for this 10-center study were obtained from the
Institutional Review Board of Human Research of the Affiliated Hospital of Nanjing
University of Chinese Medicine (Approval number: 2014NL-073-03), the ethics
committee of Beijing Hospital of Chinese Medicine, the ethics committee of
Guangdong Province Hospital of Chinese Medicine, the ethics committee of
Longhua Hospital affiliated to Shanghai University of Chinese Medicine, the
Institutional Review Board of Human Research of the First Affiliated Hospital
of Henan University of Chinese Medicine, the ethics committee of Nanjing
Drum Tower Hospital of Nanjing University of Medical School, the ethics
committee of Shengjing Hospital of China Medical University, the ethics
committee of the Hospital of Shanxi University of Chinese Medicine, the
ethics committee of the First Affiliated Hospital of Heilongjiang University of
Chinese Medicine, and the Institutional Review Board of Human Research of
Nantong Hospital of Chinese Medicine. Informed consent will be obtained
from all study participants. This study is registered with the Chinese Clinical
Trial Registry, number ChiCTR-IPR-15005760.
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