Chinese herbal medicine for advanced pancreatic cancer

Notes

Editorial note

This protocol will not be progressed to a review because there has been no progress with the review in 10 years, and the topic is no longer considered a priority.

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the effectiveness and safety of Chinese herbal medicine, alone or with chemotherapy, radiotherapy, or both, for the treatment of advanced pancreatic cancer.

Background

Description of the condition

Pancreatic cancer is one of the most fatal types of cancers and also one of the few types of cancers where survival has not improved substantially during the last 30 years (Jemal 2010). The American Joint Comittee on Cancer (AJCC) have developed a system called staging to determine how far cancer has developed in the body. Staging is based on three variables, the initial tumor, spread to lymph nodes and metastasis. Staging helps a doctor determine treatment, and predict prognosis (AJCC 2010). In the US, the 5‐year relative survival for primary, regional and metastasized pancreatic cancer is 22.5%, 8.8% and 1.9% respectively (Altekruse 2010). Mortality is closely related to incidence because pancreatic cancer is difficult to diagnose at an early stage (Hariharan 2008). Histologically, approximately 90% of all pancreatic cancers are ductal adenocarcinomas, and the remaining 10% is represented by acinar cell neoplasms and pancreatoblastoma. A computerized tomography (CT) scan and biopsy are commonly used to diagnose and stage pancreatic cancer (Cascinu 2010).

Description of pancreatic cancer can be found in the "Yellow Emperor's Internal Classic" (Chinese name in pinyin "Huang Di Nei Jing"), a classical literature from the Han Dynasty (25 to 220 AD). According to the theory of traditional Chinese medicine (TCM), carcinoma in the digestive system, including pancreatic cancer, was believed to be caused by a deficiency of healthy qi; which leads to retention of pathological factors in the organs located in the abdominal area. "Qi" is literally translated as gas or breath. TCM theory holds the opinion that every living thing is formed by qi, which also can be understood as vital energy. In the human body, qi functions similarly with immunity and vitality, as strengthening qi will enable the body with positive functions against diseases. Today, TCM holds the view that pancreatic cancer is caused by deficiency of spleen qi and stagnation of pathogenic factors such as "damp", "heat" and "toxicity" in the spleen. Therefore, clinical practices focuses on dispelling heat‐ and damp‐toxicity while at the same time strengthening the spleen and regulating qi (Jin 2005; Liu 2008; Long 2009; Zhao 2009).

Description of the intervention

There is no curative treatment for advanced pancreatic cancer. Chemotherapy, with Gemcitabine (GEM) and 5‐flurouracil (5‐FU), is the current standard in the treatment of locally advanced and metastatic pancreatic cancer (Cascinu 2010). Chemotherapy is usually given to improve survival, quality of life and to reduce pain and other common symptoms among patients with advanced pancreatic cancer (Li 2004). Side‐effects of these drugs include nausea, vomiting, loss of appetite, loss of hair, mouth sores and a reduced blood cell count. Depending on the drug used, side‐effects such as nephropathy and neuropathy can also occur.

In China, Western medicine and traditional Chinese medicine are regarded as equal. A patient may choose to seek treatment at a Western medicine hospital or a Chinese medicine hospital. In 2009 there were 2728 TCM hospitals, 245 integrative medicine hospitals. 191 ethnomedicine hospitals, and other specialized hospitals in China, in addition almost all general hospitals have departments for TCM. TCM therapies are also adopted in cancer treatment at integrated treatment hospitals (China Health Statistics Yearbook 2010). Chinese herbal medicine is one of several methods of treatment based on TCM theory. Intervention using Chinese herbal medicine involves decoction of herbs, and there are different ways of preparing a herbal medicine, for example doctor‐prescribed decoction, classical decoction described in classical works of Chinese medicine, hospital patent formula, Chinese patent medicine and herbal extract injection. A decoction is the resulting fluid proceeded by boiling herbs together with water, and which is taken orally as the most usual form of herbal medicine. People drink the decoction instead of taking the raw herbs as it is believed that by immersing (usually 20 to 30 minutes) and boiling (usually 10 to 20 minutes) with water, the essence of herbs gets into the decoction.

Although Chinese herbal medicine is widely used in China for pancreatic cancer, no clinical guideline or systematic reviews are available on this topic.

The clinical application of TCM in the treatment of pancreatic cancer falls roughly into three categories. Firstly, herbal prescriptions, based on a patient’s syndrome differentiation, are given to patients too weak or unable to receive conventional Western medicine or, after conventional treatment to improve quality of life and relieve future cancer‐related symptoms. Secondly, Chinese herbal medicines are integrated with conventional treatment to relieve side‐effects from surgery or chemoradiotherapy, to improve the effectiveness of conventional treatment, to further relieve cancer‐related symptoms, and to prevent metastasis or relapse. Lastly, herbal medicine is used as an alternative to morphine based preparations or to reduce the dose of pain‐killers (Sun 2007).

How the intervention might work

There are two main principles of TCM treatment for pancreatic cancer, treatment based on pattern differentiation or on disease differentiation. According to TCM theory, treatment based on disease differentiation concentrates on the deficiency of spleen qi and stagnation of damp, heat or toxicity of pancreatic cancer, including the therapeutic method of strengthening the spleen, dissipating dampness and clearing heat and so on. These types of treatment are meant to adjust the TCM pathogenesis of pancreatic cancer, in order to control tumor growth and prolong survival. On the other hand, patients will show different TCM syndromes which are defined as some inter‐related syndromes and clinical signs at different cancer stages. For example, postoperative patients always manifest with deficiency of qi and blood, but resistant "blood stasis" can often occur in advanced pancreatic cancer (Sun 2007). Treatment based on pattern differentiation concentrates on each patient's individual pattern defined by TCM diagnosis methods: observing the tongue and facial complexion, asking about the patient's disease condition, smelling and listening and examining the pulse. The application of Chinese herbal medicine, based on TCM theory and TCM diagnosis, is believed to relieve the TCM syndromes, and thus relieve clinical symptoms and improve the patient's quality of life in the later stage of pancreatic cancer. These two types of treatment principles are usually combined in the clinical application of Chinese herbal medicine for the treatment of pancreatic cancer.

Existing studies shows that Chinese herbal medicines with the intention of clearing heat, expelling "superficial evil" and invigorating the spleen to eliminate dampness can prolong survival, relieve symptoms, improve quality of life and stabilize the tumour condition in patients with advanced pancreatic cancer (Liu 2003). Animal and laboratory studies suggest that Chinese herbal medicine suppress pancreatic cancer growth in vivo and improve immune functions (Chen 2007; Liang 2006; Yao 2010; Zhang 2008). Some herbal decoctions may inhibit the proliferation of cancer in vivo, possibly by reducing the serum cytokines, regulating the oncogene and its relevant signal transduction, or by regulating the protein synthesis in cancer cells (Ouyang 2010; Shen 2005). However, further studies on the effectiveness and biological mechanisms of Chinese herbal medicine for the treatment of pancreatic cancer are needed.

Why it is important to do this review

Chinese herbal medicine is widely used in China for the treatment of advanced pancreatic cancer. Animal studies, clinical reports on Chinese herbal products, such as Cinobufacini Injection and Qingyi Huaji Fang (clearing the pancreas and dispelling stagnation decoction), and clinical studies on the use of Chinese herbal medicine alone or integrated with conventional medicine, suggest that Chinese herbal medicine has an effect in the treatment of advanced pancreatic cancer (Meng 2007; Ouyang 2010; Shen 2006; Shen 2009; Zhu 2008). However, no systematic reviews have been published.

Objectives

To assess the effectiveness and safety of Chinese herbal medicine, alone or with chemotherapy, radiotherapy, or both, for the treatment of advanced pancreatic cancer.

Methods

Criteria for considering studies for this review

Types of studies

Any available randomized controlled trials, both published and unpublished, in any language. 

Types of participants

Patients diagnosed with advanced pancreatic cancer, defined as patients with unresectable pancreatic tumour or patients diagnosed with stage III and IV, or patients with relapse or metastasis after surgery with curative intent.

Types of interventions

Intervention

All Chinese herbal medicines based on traditional Chinese medicine theory, including traditional Chinese medicine doctor‐prescribed herbal prescription, standardized herbal prescription, Chinese patent medicine, herbal extracts, and single herb decoction/extraction. Chinese herbal medicine can also include animal extracts and minerals. In addition, we will include studies using pure animal or mineral extracts because these preparations can be found in volume 1 of the 2010 version of Pharmacopoeia of the People's Republic of China, which contains information about Chinese herbal medicine.

Administration types

Oral herbal medicine, decoction, intramuscular or intravenous injection and external application.

Comparison

Chinese herbal medicine and conventional medicine, including chemotherapy, radiotherapy or combined chemoradiotherapy compared with conventional medicine alone and/or placebo and/or no treatment.

Chinese herbal medicine compared with conventional medicine and/or placebo and/or no treatment

Types of outcome measures

Primary outcomes

• Survival

• Improvement of quality of life

Secondary outcomes

• Remission of clinical symptoms, including tumor size.

• Adverse events

Search methods for identification of studies

Electronic searches

We will search the following electronic databases

• China National Knowledge Infrastructure (CNKI) from 1949 to present (Appendix 1; Appendix 2)

• Chinese Scientific Journal Database (VIP) from 1989 to present (Appendix 2)

• Chinese BioMedical Literature Database (CBM) from 1949 to present (Appendix 2)

• Wanfang Database from 1949 to present (Appendix 2)

• The Cochrane Registry of Controlled Clinical Trials (CENTRAL), current issue (Appendix 3)

• MEDLINE (Appendix 4)

• EMBASE (Appendix 5)

Searching other resources

We will scan the reference lists in relevant published systematic review articles and trials for potential references to include in our review. If an article has the potential to be included, we will try to retrieve the paper manually in journals, or contact the original author(s) for the full paper.

We will search for conference proceedings and dissertation papers by searching the CNKI and Wanfang databases.

Data collection and analysis

Two review authors (NYH and LX) will independently select the papers according to the selection criteria. Decisions will be made by discussion if there is a disagreement.

Selection of studies

In order to determine studies to be included in our systematic review, we will extract citations from databases to the reference managing software “NoteExpress” version 2.6.1.1512.

How we will contact the study authors

First, we will try to contact the contact author, if contact information is available. If it is not, we will contact the first author. If we fail to contact the contact or first author after three attempts, we will try to contact the second author and so forth.

Data extraction and management

Two review authors (LX and NYH) will independently extract data using a data extraction form (Appendix 6) which was made following the criteria in the Cochrane Handbook for Systematic Reviews of Intervention table 7.3a (Higgins 2011). If necessary, additional information will be gathered by contacting the study author. If there are disagreements, these will be resolved by discussion between the two review authors. If no consensus is reached, then a third person (LJP) will resolve the disagreement.

For dichotomous outcomes, we will extract the number of incidences and the total number participants in each group. For continuous outcomes, we will extract the mean and the standard deviation for each group, as well as P value and confidence interval.

One review author will enter data into Review Manager (RevMan 2011), then the other author will double check the correctness of the inserted data.

A backup hard copy of each study and data extraction form will be kept.

Assessment of risk of bias in included studies

Risk of bias will be assessed using criteria described in the Cochrane Handbook for Systematic Reviews of Intervention version (Higgins 2011). Two review authors (LX, NYH) will independently assess the risk of bias in the included studies.

We will access risk of bias according to the different methodology aspects as followed (the judgment of ‘Yes, No and Unclear’ is the judgment in Review Manager 'Risk of bias' assessment).

Sequence generation

Low risk of bias: for the judgment of ‘Yes’. Adequate description of the detailed methods such as referring to a random number tale, using a computer random number generator, coin tossing, throwing dice, drawing of lots and shuffling cards or envelopes.

High risk of bias: for the judgment of ‘No’. Non‐random component in the sequence generation process such as sequence generated by odd or even date of birth, by some rule based on date of admission, or by some rule based on hospital or clinic record number. Other methods such as allocation by judgment of the clinician, allocation by preference of the participants, allocation based on the results of a laboratory test or a series of tests and allocation by availability of the intervention are also regarded as high risk of bias, and will be excluded from our review.

Moderate risk of bias: for the judgment of ‘Unclear’. Only stating the sequence generation method as “randomized” without description. We will contact the authors by letter, email or telephone for detailed information. If no information is obtained, we will regard the trial’s sequence generation as unclear, and classify it as moderate risk of bias.

Allocation concealment

Low risk of bias: for a judgment of ‘Yes’. Adequate allocation concealment methods such as central allocation (including telephone, website‐based, and pharmacy‐controlled randomization). Sequentially numbered drug containers of identical appearance, and sequentially numbered, opaque, sealed envelopes.

High risk of bias: for the judgment of ‘No’, such as allocation based on using an open random allocation schedule (e.g. a list of random numbers), assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered), alternation or rotation, date of birth, case record number and any other explicitly unconcealed procedure.

Moderate risk of bias: for the judgment of ‘Unclear’, there is insufficient information for the allocation concealment, or concealment is inadequately stated in the paper, as randomization is stated, and we fail to contact the original authors.

Blinding of participants, personnel and outcome assessors

Low risk of bias: For a judgment of ‘Yes’. 1) No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding such as surgery. 2) Participants and the physicians were blinded. 3) Participants or the physicians were blinded, and the outcome assessors were also blinded, and the blinding methods for participants and physicians are clearly stated in the paper, and unlikely that the blinding could have been broken.

High risk of bias: for the judgment of ‘No’, no blinding or incomplete blinding was implemented.

Moderate risk of bias: for the judgment of ‘Unclear’. 1) The blinding was implemented on outcome measurers or statistics analyzers, or both but not participants or physicians when lack of blinding is likely to bring obvious bias. 2) Insufficient information to permit judgment of ‘Yes’ or ‘No’, or the study did not address this outcome, and we also fail to contact the authors for the details.

Incomplete outcome data

Low risk of bias: criteria for the judgment of ‘Yes’. 1) If in the paper the number of participants is the same before and after the treatment, and we suspect that there are missing participants, we will contact the authors to confirm whether there were any data underreported. If the original authors confirm that no participant was missing, then we will regard it as of low risk of bias. 2) if the reason(s) for missing outcome data in every group, such as withdrawals, lost to follow‐up or drop‐out, are clearly stated, and unlikely to be related to the true outcome. 3) missing outcome data are balanced in numbers across intervention groups, with similar reasons for missing data across groups. 4) missing data have been imputed using appropriate methods such as intention‐to‐treat (ITT) analysis.

High risk of bias: for the judgment of ‘No’. 1) Reason for missing outcome data is likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups. 2) The authors fail to provide the missing data in the paper after contacting the authors.

Moderate risk of bias: for the judgment of ‘Unclear’. There was insufficient information for us to make a ‘Yes’ of ‘No’ judgment. The study did not address the issue of missing outcomes and we fail to contact the authors for the details.

Selective outcome reporting

Low risk of bias: for the judgment of ‘Yes’. The published reports include all expected outcomes, including those that were pre‐specified.

High risk of bias: for the judgment of ‘No’. Not all of the study’s pre‐specified primary outcomes have been reported, and we fail to get complete information by contacting the authors.

Moderate risk of bias: for the judgment of ‘Unclear’. Insufficient information to permit judgment of ‘Yes’ or ‘No’.

Measures of treatment effect

Survival data will be summarized using hazard ratio. For other variables, the effect measure of choice for dichotomous data will be risk ratio (RR) with 95% confidence interval (CI). For continuous data, we will use difference in means (MD) with 95% CI. If difference in means is not applicable, we will use standardized means (SMD).

Unit of analysis issues

For trials with multiple treatment groups, we will include the comparisons we are interested in the meta‐analysis, if more than one comparison from the same trial are included in the same meta‐analysis, we will split the sample size in the shared group so that the weight from the trial will not be doubled.

For cross‐over trials, we will only include data from the first period.

For cluster randomized trials, we will reduce the trial sample size to the effective sample size by 1 + (M – 1) ICC (ICC = 0.02) (intraclass correlation) before including the data in the meta‐analysis (Higgins 2011).

Dealing with missing data

In general, if relevant data are missing, the review author(s) (LX, XY) will contact the original investigators to request the missing data.  

If participants are missing from the original study, and the original authors are not able to provide or explain why data are missing, we will perform an ITT analysis and compare this with the results from the original study, and if possible, we will also conduct a meta‐analysis based on the ITT analysis results, see Sensitivity analysis.

If included studies have missing summary data, we will perform sensitivity analyses to explore how meta‐analysis results change if these were excluded. The potential implication of these studies will be addressed in the discussion section.

Assessment of heterogeneity

We will include comparisons with the same experimental interventions and the same control interventions for each group in one meta‐analysis. 'Same interventions' means that 1) same combination (if any) with same types of treatments, i.e. Chinese medicine plus chemotherapy versus chemotherapy alone, 2) each intervention is same. For example, if there are two trials that both have an intervention comparison as Chinese medicine plus radiotherapy versus radiotherapy, the Chinese medicine should be the same. Trials applying Chinese herbal decoction and those applying Chinese patent medicine, for example, will not be combined in the meta‐analysis; in that case, we will implement sub‐group analysis. For trials applying Chinese herbal decoctions with different prescriptions, if the prescription is formed based on the same basic formula or with minor herbal modifications, we will include them in meta‐analysis.If the prescriptions are based on different basic formulae, we will then include them in a sub‐group analysis.

Studies will be considered heterogeneous if the P value for Chi² test is < 0.10 or if the I² statistic is > 50% in the forest plot.

If heterogeneity is detected, we will check again to see if the data we inserted into RevMan 2011 are correct.

Assessment of reporting biases

If at least 10 studies are included in the review, we will make a funnel plot to assess “small‐study effect”, publication‐ and reporting bias. To support visual inspection of the funnel plot, we will include contour lines as proposed by Peters 2008. This will enable us to see “milestones” of statistical significance (P = 0.01, P = 0.05, P = 0.1 etc) (Higgins 2011).  

If we detect funnel plot asymmetry via visual inspection, we will discuss different sources that can cause funnel plot asymmetry, as can be found in table 10.4.a of the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). The conclusion of this discussion will be written in the discussion part of the review.

Data synthesis

Statistical synthesis of study results will be done using the newest available edition of RevMan 2011. We will look at all the Chinese herbal medicine studies together and compare these with conventional and other interventions. The Mantel–Haenszel method will be used. We will perform a fixed‐effect meta analysis for synthesis of study results and perform a random‐effects meta‐analysis for sensitivity anaylses.

When meta‐analysis is not possible, we will describe our findings verbatim.

Subgroup analysis and investigation of heterogeneity

We will perform subgroup analysis if data are available and if there are sufficient numbers of studies.

Relevant subgroups might include: A specific herbal interventions such as Chinese herbal medicine versus conventional therapy, Chinese herbal medicine plus conventional therapy versus conventional therapy and Chinese herbal medicine versus placebo and Chinese herbal medicine versus no treatment. The different variants of Chinese herbal medicine used in the interventions such as individual‐tailored decoction, modified standard decoction, herbal extract injection and Chinese patent medicine.

Sensitivity analysis

We will perform sensitivity analyses to see if the results of the meta‐analysis change under different assumptions such as:

1. comparing the results of the meta‐analysis with ITT analysis results;

2. excluding studies with high risk of bias;

3. imputing best‐case/worst‐case scenario for missing data.

What's new

Date	Event	Description
28 July 2022	Amended	Editorial note added.

History

Protocol first published: Issue 5, 2012

Date	Event	Description
13 December 2012	Amended	Added statement to contributions of authors.

Appendices

Appendix 1. Databases searched by CNKI

We will search the sub‐databases including China Academic Journal Network Publishing Database, China Doctoral Dissertations Full‐text Database, China Master Theses Full‐text Database, China Proceedings of Conference Full‐text Database, China Core Newspapers Full‐text Database, Chinese Science and Technology Achievements Database,

Appendix 2. Chinese database search strategies

Chinese terms:（胰腺癌 OR（胰 AND 恶性）OR （胰 AND 肿瘤））AND （中医 OR 中药 OR 草药 OR 中成药 ）

Chinese pinyin: (yi xian ai OR (yi AND e xing) OR (yi AND zhong liu)) AND (zhong yi OR zhong yao OR cao yao OR zhong cheng yao)

Translation of the Chinese terms: pancreatic cancer OR (pancreas AND malignant) OR (pancreas AND tumor) AND (Chinese medicine OR Chinese herbal medicine OR herbal medicine OR Chinese patent medicine)

Appendix 3. CENTRAL search strategy

1. Pancreatic Neoplasms/

2. Carcinoma, Pancreatic Ductal/

3. (carcin$ or cancer$ or neoplas$ or tumour$ or tumor$ or cyst$ or growth$ or adenocarcin$ or malig$).mp.

4. (pancrea$ or ductal or acinar cell).mp.

5. 3 and 4

6. pancreatoblastoma*.tw.

7. or/1‐2,5‐6

8. Medicine, Chinese Traditional/

9. (herb* adj2 (medicin* or prescript* or medicat* or inject* or treatment* or therap*)).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

10. Plants, Medicinal/

11. Drugs, Chinese Herbal/

12. (herbal adj2 (extrac* or decoct*)).mp.

13. or/8‐12

14. 7 and 13

Appendix 4. MEDLINE search strategy

1. Pancreatic Neoplasms/

2. Carcinoma, Pancreatic Ductal/

3. (carcin$ or cancer$ or neoplas$ or tumour$ or tumor$ or cyst$ or growth$ or adenocarcin$ or malig$).mp.

4. (pancrea$ or ductal or acinar cell).mp.

5. 3 and 4

6. pancreatoblastoma*.tw.

7. or/1‐2,5‐6

8. Medicine, Chinese Traditional/

9. (herb* adj2 (medicin* or prescript* or medicat* or inject* or treatment* or therap*)).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

10. Plants, Medicinal/

11. Drugs, Chinese Herbal/

12. (herbal adj2 (extrac* or decoct*)).mp.

13. or/8‐12

14. 7 and 13

15. randomized controlled trial.pt.

16. controlled clinical trial.pt.

17. randomized.ab.

18. placebo.ab.

19. drug therapy.fs.

20. randomly.ab.

21. trial.ab.

22. groups.ab.

23. or/15‐22

24. exp animals/ not humans.sh.

25. 23 not 24

26. 14 and 25

Appendix 5. EMBASE search strategy

1. pancreas tumor/

2. pancreas carcinoma/

3. (carcin$ or cancer$ or neoplas$ or tumour$ or tumor$ or cyst$ or growth$ or adenocarcin$ or malig$).mp.

4. (pancrea$ or ductal or acinar cell).mp.

5. 3 and 4

6. pancreatoblastoma*.tw.

7. or/1‐2,5‐6

8. Chinese medicine/

9. (herb* adj2 (medicin* or prescript* or medicat* or inject* or treatment* or therap*)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

10. medicinal plant/

11. herbaceous agent/

12. (herbal adj2 (extrac* or decoct*)).mp.

13. or/8‐12

14. 7 and 13

15. random:.tw.

16. placebo:.mp.

17. double‐blind:.tw.

18. or/15‐17

19. 14 and 18

Appendix 6. Data extraction form

Data extractor:

Date of data extraction:

Source

Study ID

Citation

Contact details

Country of study

Study eligibility

Fill out if study is excluded

Study eligibility

Reason for exclusion

 Fill out if study is included

Methods

Study design (parallel or cross‐over RCT)

Total study duration (months/year)

Follow up duration (months/year) (date of study)

 Risk of bias

Sequence generation (table, computer, dice etc)

Allocation sequence concealment (centre randomisation generation, opaque envelop, pharmacy controlled randomization) what does this mean?

Blinding (patient, doctor, outcome measure or data analyser)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other bias

  Participants

Items	Treatment group	Control group
Total number
Setting (outpatients?)
Diagnostic criteria
Participant inclusion criteria
Participant exclusion criteria
Age
Sex
Country
Co‐morbidity
Socio‐demographics
Ethnicity

 

Interventions

Total number of intervention groups

Specific intervention

Intervention details (prescription, dose, method of admin, duration of treatment)

 

Control

Specific control

control details (prescription, dose, method of admin, duration of treatment)

 

Results

Number of participants allocated to each intervention group.

 

For each outcome of interest (add cell within table)

Sample size

Missing participants*

Summary data for each intervention group (e.g. 2×2 table for dichotomous data; means and SDs for continuous data)

[Estimate of effect with confidence interval; P value].

[Subgroup analyses]

 

Miscellaneous

Funding source.

Key conclusions of the study authors.

Miscellaneous comments from the study authors.

References to other relevant studies. Correspondence required.

Miscellaneous comments by the review authors.

Notes

 

Outcomes and results
Summary of reported outcomes:	1. 2. 3.
Include units of measurement where applicable	Outcome description*	Number of participants CHM (n/N)	Control (n/N)	Other group (n/N)	P value

*If relevant, include diagnostic criteria and outcome definition. Scales: upper and lower limits, time points and whether high or low score is good.

Contacting the author(s)

Reason for contacting the authors

Interview time (fill out detailed information)

Contact methods: e‐mail or by phone

Rules for contacting the authors

First we will contact the “contact author”, if unavailable we will contact the first author. If we fail to contact the contact/first author after three times, we will try to contact the second author and so forth.

Contributions of authors

Xun Li and Yi Hu Ni contributed equally to the development of the protocol.

Item	Ni, Yi Hu	Li, Xun	Xu, Yun	Liu, Jian Ping
Conceiving the review	X	X		X
Designing the review	X	X	X	X
Coordinating the review	X
Data collection for the review	X	X
Designing search strategies	X	X		X
Undertaking searches	X	X
Screening search results	X	X
Organising retrieval of papers	X	X
Screening retrieved papers against inclusion criteria	X	X
Appraising quality of papers	X	X
Extracting data from papers	X	X
Contacting authors of papers for additional information		X	X
Providing additional data about papers		X	X
Obtaining and screening data on unpublished studies		X	X
Data management for the review	X
Entering data into RevMan	X	X
Analysis of data	X	X
Interpretation of data	X	X	X	X
Providing a methodological perspective				X
Providing a clinical perspective	X		X	X
Providing a policy perspective			X	X
Providing a consumer perspective			X	X
Writing the review	X	X
Providing general advice on the review				X
Securing funding for the review	X			X
Performing previous work that was the foundation of the current study				X

Sources of support

Internal sources

• No sources of support provided

External sources

• National Research Centre in Complementary and Alternative Medicine (NAFKAM), Norway

  Research funding.

Declarations of interest

None.

Edited (no change to conclusions)