This protocol is developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols (PRISMA-P) statement guidelines[25]. The PRISMA Extension Statement is used to ensure all aspects of methods and findings are reported.
Eligibility criteria
Inclusion criteria
There will be no restrictions on the length of treatment and duration of follow-up. This systematic review will include high-quality RCTs in English or Chinese that evaluated the therapeutic effect and safety of CG combined with desloratadine in the treatment of CU. Without any date of dissemination or restriction of publication type. To RCTs, it should report adequate randomization methods, eligible diagnosis, eligible outcome measurement, and statistical methods description. Blinding will not be a part of the inclusion criteria because of the particularity of acupuncture manipulation.
Exclusion criteria
1) controlled (non-randomized) clinical trials, case reports, observational study, retrospective studies, animal mechanism studies, self-controlled, random crossover studies;
2) Studies with overlapping data;
3) Studies missing raw data.
Participants
Regardless of gender, age, ethnicity, education, and economic status, patients with CU who meet the following diagnostic criteria (eg, EAACI/GA2LEN/ EDF/WAO guidelines, Chinese Medical Association clinical treatment guidelines. Skin disease and STD Volume, Practical Dermatology, Clinical dermatology.).[1]
Intervention and comparators
The intervention group was mainly treated with CG combined with desloratadine.
A comparison of the following processing will be performed:
- CG combined with desloratadine compared with no treatment.
- CG combined with desloratadine compared with placebo or sham drugs therapy.
- CG combined with desloratadine compared with a separate desloratadine therapy.
- CG combined with desloratadine compared with other active therapies.
Outcomes
Primary outcomes
The primary outcomes will be the total effective rate. According to the severity of clinical symptoms using 4 scores; the total score is the sum of the individual scores. Symptom Score Reducing Index (SSRI)=(total score before treatment-total score after treatment)/total score before treatment×100%.
Secondary outcomes
- Itching score: The degree of itching was evaluated by Visual Analogue Scale (VAS).
- The related inflammatory factors, such as interleukin-interferon, immunoglobulin E (IgE), were observed
- Quality of life, using the chronic urticaria quality of life questionnaire (CU-Q2oL).
- Response rate.
- Adverse events. Usually the last observation score change from baseline to follow-up.
Information sources
A literature search strategy using medical subject headings and text words has been developed. We will search MEDLINE (OVID interface), EMBASE (OVID interface), and the Cochrane Central Register of Controlled Trials (Wiley interface).
To ensure the capture of all relevant trials, all selected studies will also undergo an ancestry search, in addition to citation search using SCOPUS. OpenGrey will be interrogated for unpublished relevant literature.
Search strategy
The systematic review will search all randomized controlled trials (RCTs) by searching the following database: PubMed, EMBASE, Web of Science, Cochrane Controlled Trials Register (CENTRAL), China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), Chinese Science Journal Database (VIP Database) and Wanfang database with a language limitation of English and Chinese until January 14, 2020. In addition, The related reference lists of identified publications, meeting minutes, gray literature, and unpublished literature for eligible studies which will be searched by us.
Study selection
All potential relevant clinical studies will be screened according to their titles, abstracts, keywords by 2 reviewers (QYW and XXH) at the same time independently after removing duplicates and nonclinical trials. And then the intensive reading of full text could authenticate for further assessment if there are studies that could not be clearly included based on both titles and abstracts. Once any disagreement occurs, a decision will be resolved through discussion among the 2 reviewers (QYW and XXH), or argument will be adjudicated by a third reviewer (PSH). Details of entire study selection procedure are summarized in the flow chart (Fig. 1).
Data extraction and management
Before data extraction, a standard data extraction form containing specified outcomes will be created according to the inclusion. Two reviewers (QYW and ML) will extract data independently from each trial: article general information, participants’ characteristics (such as age, sex, race, disease history), number of participants on each group, intervention measure of trial and control group, outcomes measures. Any disagreements will be resolved through discussion or consultation between the 2 reviewers if necessary, final determination from a third reviewer (PSH) will be sought. When certain dates don’t be provided in the paper, we will contact the original author for the needed information.
Risk of bias (quality) assessment
Two reviewers (QYW and ML) will evaluate the risk of bias according to the risk of bias (ROB) tool[26] to assess the bias risk of all included studies. We will assess the risk of bias in the following areas: random sequence generation, concealment of allocation sequences, the blindness of participants and staff and their result evaluators, incomplete outcome data, selective outcome reports, and other sources of bias. This review will use L, U, and H as the key to these assessments, where L (low) indicates a lower risk of bias, U (unclear) indicates an uncertain risk of bias, and H (high) indicates a higher risk of bias. All reviewers will resolve their differences through discussions. The information contained in the study on the risk of biased assessments will be summarized in a tabular format with a critical discussion of results and impacts. If the information is unclear, we will try to contact the author. For republished articles, we only select the original text.
Strategy for data synthesis
Data analysis and quantitative data synthesis will be performed using RevMan V.5.3. For continuous data, if there is no heterogeneity, we will use mean difference (MD) or standard MD (SMD) to measure the therapeutic effect of 95% CIs. If significant heterogeneity is found, a random-effects model will be used. For the two-category data, we will use the 95% CIs hazard ratio (RR) for analysis. We will include data from parallel-group design studies for meta-analysis. Only the first phase of the data will be included in the random crossover trial. In these trials, participants were randomly divided into two intervention groups and individual measurements for each outcome of each participant were collected and analyzed. The result will be expressed as the RR of the binary data and the SMD of the continuous data.
Dealing with missing data or unclear information.
Referring to the Cochrane handbook for systematic reviews of intervention, if there are insufficient details or missing data in relation to the characteristics of the studies, 2 reviewers (QYW and XXH) will attempt to contact both senior and/or corresponding author of articles through email or telephone for further information about any missing data or unclear information. If it is not possible to contact the original authors or obtain sufficient information, we will exclude such studies and only analyze the available data and describe it in the discussion. The potential impact of insufficient data on the review results will be taken into account in the discussion section.
Data synthesis and assessment for heterogeneity
We will use RevMan V.5.3. for all statistical analyses. The forest map is used to illustrate the relative strength of the effect. The funnel plot is used to illustrate the bias because the number of trials exceeds 10. If a significant difference is detected, a random-effects model will be used. If the I² test is less than 50%, a fixed-effect model is used for data synthesis. If the I² test is between 50% and 75%, a random-effects model is used for data synthesis. If the I² test is higher than 75%, we will investigate the possible causes from a clinical and methodological perspective and provide a descriptive analysis or a subgroup analysis.
When there are enough studies, we will conduct a sensitivity analysis of the main results according to the sample size, heterogeneous quality and statistical model (random or fixed effect model) to explore the robustness of the conclusions. Sensitivity analysis will be conducted by removing low-quality studies. If heterogeneity still exists after subgroup analysis, a meta-analysis will be performed again after excluding low-quality tests according to the STRICTA checklist. The results of these meta-analyses will be compared and discussed in terms of their sample size, the strength of the evidence, and their impact on the size of the merger effect. However, if there is a high risk of bias in all included studies, we will not conduct sensitivity analysis.
In terms of grading the quality of evidence, we will assess the evidence quality and credibility of the major findings (major outcomes and adverse events) of the studies included in our review, based on recommendations, assessments, development and grading of assessment (grade) guidelines[26]. The quality of evidence will be classified as "very low", "low", "medium" or "high". Any differences will be resolved by consensus or with the third review author (PSH).
Patient and public involvement
This systematic review and meta-analysis will be based on published studies; therefore, primary patient data will not be collected. Patients and the public will not be involved in the study design, recruitment, and data analysis.
Ethics and dissemination
The systematic review and meta-analysis don’t require to pass the ethics approval. Because we include published articles rather than directly adopt interventions in participants. Ultimately, we will publish the results at a peer-reviewed journal follow as our study is completed.
Table 1
Search strategy used in PubMed
No
|
Search items
|
1
|
Randomised controlled trial. pt
|
2
|
Controlled clinical trial. pt
|
3
|
Randomised. ti, ab
|
4
|
Randomly. ti, ab
|
5
|
Placebo. ti, ab
|
6
|
Trial. ti, ab
|
7
|
Groups. ti, ab
|
8
|
1 or 2-7
|
9
|
Compound, ti. ab
|
10
|
Glycyrrhizin. Mesh
|
11
|
Glycyrrhizic Acid, ti. ab
|
12
|
Acid, Glycyrrhizic, ti. ab
|
13
|
Glycyrrhizinic Acid, ti. ab
|
14
|
Acid, Glycyrrhizinic, ti. ab
|
15
|
Glycyrrhizin, ti. ab
|
16
|
Zinc Glycyrrhizate, ti. ab
|
17
|
Glycyrrhizate, Zinc, ti. ab
|
18
|
Diammonium Glycyrrhizinate, ti. ab
|
19
|
Glycyrrhizinate, Diammonium, ti. ab
|
20
|
Dipotassium Glycyrrhizinate, ti. ab
|
21
|
Glycyrrhizinate, Dipotassium, ti. ab
|
22
|
10 or 11-21
|
23
|
Desloratadine. Mesh
|
24
|
descarboethoxyloratadine, ti. ab
|
25
|
SCH-34117, ti. ab
|
26
|
SCH 34117, ti. ab
|
27
|
Clarinex, ti. ab
|
28
|
Neoclarityn, ti. ab
|
29
|
Aerius, ti. ab
|
30
|
23 or 24-29
|
31
|
chronic urticaria. Mesh
|
32
|
Urticaria, Chronic, ti. ab
|
33
|
Chronic Urticarias, ti. ab
|
34
|
Chronic Hives, ti. ab
|
35
|
Hives, ti. ab
|
36
|
31 or 32-35
|
37
|
8 and 9 and 22 and 30 and 36
|