A protocol for systematic review and meta-analysis

Background: Diabetic peripheral neuropathy is a common complication of diabetes and the main cause of disability. At present, there is no specific therapeutic regimen. Mecobalamin is often used as a neurotrophic drug, and its long-term effects are not satisfactory when used alone. Clinical practice indicates that traditional Chinese medicine injection with mecobalamin has a therapeutic advantage in treating diabetic peripheral neuropathy while it lacks evidence-based medicine. In this scheme, the efficacy and safety of traditional Chinese medicine injection with mecobalamin in treating diabetic peripheral neuropathy has been studied. Methods:Computers were used to search the English database (PubMed, the Cochrane Library, Embase, Web of Science), and Chinese database (CNKI, Wanfang, CBMDISC, VIP). Besides, manual searching was conducted to search for Baidu Scholar, CHICTR, Google Scholar. During the establishment of the database to November 2020, a randomized controlled trial on traditional Chinese medicine injection with mecobalamin in treating diabetic peripheral neuropathy was conducted. There were 2 researchers independently conducting data extraction and quality evaluation of literature on the included studies, RevMan5.3 was performed for meta-analysis on the included literature. Results: In this study, the efficacy and safety of traditional Chinese medicine injection with mecobalamin in treating diabetic peripheral neuropathy was evaluated by the total effective rate, motor nerve conduction velocity, sensory nerve conduction velocity, adverse reactions, and glucose metabolism level. Conclusion: This study can provide an evidence-based basis on the clinical applications of traditional Chinese medicine injection with mecobalamin in the treatment of diabetic peripheral neuropathy. Ethics and dissemination: The study does not involve patient privacy or rights and does not require approval from an ethics committee. The results may be published in peer-reviewed journals or disseminated at relevant conferences. OSF Registration number: DOI 10.17605/OSF.IO/KPW5E. Abbreviations: CBMDISC = China Biology Medicine disc, CHICTR = Chinese Clinical Trial Register, CI = confidence interval, CMB = Chinese Biological and Medical database, CNKI = China National Knowledge Infrastructure, DPN = diabetic peripheral neuropathy, FPG = fasting blood glucose, GRADE =Grading of Recommendation Assessment, Development and Evaluation., OSF = open science framework, PRISMA-P = Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols, RCTs = randomized controlled trials, RR = Relative risk, SMD = standard mean difference, WMD = weighted mean difference.


Introduction
Functional constipation (FC) is a common disease in clinical practice.It is characterized by infrequent bowel movements and other associated symptoms of difficult defecation, hard and lumpy stools, feeling of tension, a sensation of incomplete evacuation. [1,2]8][9][10] It also causes serious harm to the mental and psychological health of the patients. [11]FC affects over 14% of adults globally and has become one public health issue. [12]here are 3 therapies for FC currently: nonpharmaceutical, pharmaceutical, and surgical. [13][16][17] Surgical treatment is not widely used in clinic practice because of its disadvantages such as large injury and uncertain clinical efficacy. [18]At present, the clinical treatment of FC mostly adopts laxatives and gastrointestinal prokinetic drugs. [19]In the short term, the frequency of spontaneous bowel movements can be increased, but the long-term efficacy is not good, and there are some toxic and side effects. [20]Therefore, effective complementary and alternative therapies with few side effects for FC are important for patients.
Acupoint catgut embedding therapy is a therapeutic method established and developed on the basis of traditional acupuncture.Traditional acupuncture methods can only retain filiform needles for a short time, but acupoint catgut embedding has a long-term and lasting stimulation on acupoints for about 30 days.And catgut embedding needle is thicker than filiform needle, so it can produce stronger needle sensation.Some studies have found that continuous stimulation of catgut to related acupoints can enhance the contractility and excitability of intestinal smooth muscle and promote intestinal peristalsis.The clinical application of this approach achieved stable curative effects and satisfactory results in the treatment of chronic FC. [21][22][23][24] Nowadays, acupoint catgut embedding is widely applied in the clinical practice of functional constipation, but there is no systematic review and meta-analysis that provides persuasive evidence of its effect on FC.This study will summarize the current evidences and conduct a systematic review and meta-analysis to assess the efficacy and safety of acupoint catgut embedding for patients with FC.

Registration of the review
Our protocol for this systematic review has been registered on the open science framework (OSF), the registration number is DOI 10.17605/OSF.IO/XTKE2 (https://osf.io/xtke2),and the protocol is designed strictly follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols (PRISMA-P) statement guidelines.

Inclusion and exclusion criteria 2.2.1. Types of studies.
Randomized controlled trials comparing acupoint catgut embedding for FC with no treatment, placebo, or conventional drugs (eg, laxative agents) will be included.All eligible trials will be included regardless of language and publication types.Articles of the following research types will be excluded: case series, qualitative studies, case-control studies, observational studies, animal experiments, experiences, review articles.There are no restrictions on study area, race, patient age, and gender.

Types of participants.
Participants with FC over the age of 18 years will be considered in this study.The diagnosis of FC needs to be consistent with Rome III or IV criteria rather than other clinical research guidelines.Studies with participants that include pregnant women, lactating women, addicts, strokes will be excluded.

Types of interventions.
In the intervention group, patients received acupoint catgut embedding without restrictions of points and treatment courses.The trials that the intervention group is acupoint catgut embedding combines with other therapies should not be included.In the control group, patients received conventional drugs (eg, laxative agents), no treatment, sham or placebo acupoint catgut embedding, and etc. Sham acupoint catgut embedding or placebo will be classified into a category as inert control.
2.2.4.Types of outcome measures.The primary outcomes will be the improvement in mean spontaneous bowel movements, complete spontaneous bowel movements at the end of all sessions and the Bristol Stool Form Scale, the Cleveland Clinic Score, Patient Assessment of Constipation symptom.
The secondary outcomes involved Patient Assessment of Constipation Quality of Life Questionnaire, Self-rating Anxiety Scale, Self-rating Depression Scale and Transit time measurement (radiopaque markers), functional rectoanal evaluation (proctoscopy, anorectal manometry, defecography, cinedefecography), or electromyography.And the number and types of adverse events will be assessed safety evaluation.

Data sources and search strategy
We will systematically search electronic database from inception to December 2020, including PubMed, EMBASE OVID, CINAHL,OVID MEDLINE, Web of Science, the Cochrane Central Register of Controlled Trials, Cochrane library, Scopus, CNKI,VIP, Wan Fang Database, CBM and other resources from inception to December 2020.The search terms will include intervention methods, diseases and research types: ('acupoint catgut embedding' or 'acupoint catgut embedding therapy' or 'acupoint therapy' or 'thread-embedding acupoint ligation' or 'acupoint ligat thread embed') and ('functional constipation' or 'FC' or 'outlet obstruction constipation' or 'OOC' or 'slow transit constipation' or 'STC' or 'mixed functional constipation') and ('clinical trial' or 'randomized controlled trial' or 'randomized' or 'trial').To avoid missing ongoing clinical trials, we will search the following two trial registration centers to identify relevant studies: China Clinical Trial Registry (www.chictr.org.cn/index.aspx), The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov),The World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch).Besides, we will screen the references of included studies to identify other potential clinical trials.The search strategy for PubMed is shown in Table 1.This search strategy will be slightly modified and used in several other databases.
2.4.Data collection and management 2.4.1.Data selection.First, use the EndNote X9 software to exclude duplicate references from different databases.Then, two reviewers (Fumin Wang and Man Jin) will evaluate the titles and abstracts of each clinical trial to identify the eligible studies independently.Finally, read the full text to assess eligible studies.If there is a disagreement, it will be resolved through discussions with the third reviewer (Xiaoen Cheng).Figure 1 shows the flow of this systematic review and meta-analysis.

Data extraction. Two reviewers (Fumin Wang and
Man Jin) will independently examine eligibility for inclusion in the study and use Microsoft Excel to encode and extract data based on pre-designed data extraction forms after reaching a consensus.The data will include the first author, country, year of publication, characteristics of participants, randomization, allocation concealment and blinding methods, interventions, acupoint selection, outcome measures, main outcomes, secondary outcomes, study duration, adverse effects, main conclusions, funding source, and conflicts of interest.Particularly, the third reviewer (Xiaoen Cheng) will take part in the discussion and decide to select the controversial search or not.

2.4.3.
Management of missing data.We will contact the researchers for the missing data by Email.If the missing data cannot be obtained, it will be excluded.

Assessment of risk of bias and reporting of study quality
Two review authors (Fumin Wang and Man Jin) will independently evaluate each included study and will follow the domain-based evaluation as developed by the Cochrane Handbook for Systematic Reviews of Interventions.They will assess the following domains: selection bias (random sequence generation and allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessment); attrition bias (incomplete outcome data); reporting bias (selective reporting); other bias (such as presample size estimation, early stop of trial).Each domain will be divided into three categories: low risk, high risk, or unclear risk.

Measures of treatment effect
We will analyze the data with RevMan software (Version 5.3).Mean difference (MD) or standardized mean difference (SMD) with 95% confidence interval (95% CI) will be used to analyze continuous data.Risk ratio with 95% CI will be used to analyze dichotomous data.

Unit of analysis issues
The analysis will focus on patients in randomized controlled trials.If more than 1 objective is used, we will conduct separate multiple meta-analyses for each treatment arm.If multiple non-acupoint catgut embedding control groups are included, pooled analyses of the control groups against the intervention group will be used.

Assessment of heterogeneity
We will test the heterogeneity of data by calculating the value of I 2 statistics and x 2 test.I 2 values of 25% is considered low levels of heterogeneity, 50% indicated moderate levels, and 75% indicated high levels.Since low or moderate heterogeneity (P > .1,I 2 < 50%) suggests little variability among these studies, the data will be analyzed in a fixed-effects model.When significant heterogeneity occurs among the studies (P < .1,I 2 > 50%), a random-effect model will be performed to analyze the data.At this very moment, the subgroup stratification analysis will be further carried out to explore the possible sources of heterogeneity. [25,26]9.Assessment of reporting biases Funnel plots is used to assess reporting biases.If funnel plot asymmetry is detected, the reasons will be analyzed.

Data synthesis
For continuous data, we will use mean difference or standard mean difference SMD to measure the therapeutic effect of 95% CIs.If significant heterogeneity is found, we will use the randomeffects model instead.For dichotomous data, we will denote the outcomes as relative risks with 95% CIs.If the I 2 test is < 50%, the fixed-effects model will be used for data synthesis.If the I 2 test is between 50% and 75%, the random-effects model will be conducted for data synthesis.If the I 2 test is higher than 75%, we will investigate possible reasons from both clinical and methodological perspectives, and provide a descriptive analysis or conduct subgroup analysis.

Subgroup or sensitivity analysis
Subgroup analysis will be conducted to evaluate the specific influence of intervention type, study quality, study location, treatment duration on pooled results.If the data is insufficient, qualitative synthesis will be conducted instead of quantitative synthesis.In addition, sensitivity analysis will be performed to examine the robustness of the results by eliminating low quality trials.

Sensitivity analysis
A sensitivity analysis will be performed according to the following criteria: sample size, heterogeneity qualities, and statistical model (random-effects or fixed-effects model).
Table 1 The search strategy in PubMed.

Grading the quality of evidence
We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines to assess the overall quality of evidence.The overall quality of the evidence for each outcome will be determined after considering each of these factors and graded as: high, moderate, low, very low.

Discussion
FC is a common health problem causing significant physical and emotional distress to patients and affects their quality of life.Acupoint catgut embedding therapy has been used in many diseases including FC as an adjuvant therapy at present.Our study will assess current evidence related to the effectiveness and safety of acupoint catgut embedding therapy in FC.