This meta-analysis has been prospectively registered in the PROSPERO database (CRD42021252806 Available from: https://www.crd.york.ac.uk/prospero/display_record.php? RecordID=252806). The protocol is prepared based on the the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols(PRISMA-P) statement(29, 30) (Additional file 1). The study started on 27 April 2021 and is scheduled to be completed by 15 September 2022.
Types of studies. Only randomized controlled trials(RCTs) will be included. Other types of clinical trials and animal trials is not eligible in this study.
Types of participants. The participants were in accordance with the diagnosis of IPF regardless of age, severity, and duration of the diseases, which meet the diagnostic criteria of the consensus of Chinese experts by Chinese Medical Association Respiratory Society or ATS/ERS/JRS/ALAT Clinical Practice Guideline on the diagnosis and treatment of IPF. Patients with other respiratory disease like asthma, bronchiectasia, chronic obstructive pulmonary disease (COPD), and severe liver, kidney, heart disease will be excluded.
Types of interventions. The control group was treated with conventional western medicine treatment modalities, including oxygen therapy, infection control, rehabilitation, and antifibrotic drugs, etc. Patients use acupuncture or other TCM treatment are excluded. Interventions in the experimental group are Chinese patent medicine combine with the same treatment option as the control group. The dosage form and treatment course of Chinese patent medicine are not limited, such as tablet, pill, and injection. Other therapies of TCM like acupuncture, massage, Qigong, are not included in the study.
Types of outcome measures. We will include studies that reported at least one of the
following outcomes. IPF is characterized by the deterioration of respiratory functions due to fibrosis of the lung interstitium(1). Progressive deterioration of lung function in patients with IPF is associated with poor prognosis, as lung function declines, QOL follows(31, 32). We therefore chose Lung function and life quality as main outcomes, besides, 6-min walking distance (6MWT), blood gas analysis, clinical symptom, adverse events, acute exacerbation (AE), all-cause mortality, and respiratory-specific cause of death or IPF-related mortality as additional outcomes:
We will include publications and studies reported in the English and Chinese languages.
Information sources and search methods
We will perform an all-round search in the following electronic databases from their inception to April 29, 2021: PubMed, EMBASE, Cochrane Central, Web of Science, Chinese Biomedical Database (SinoMed), Chinese National Knowledge Infrastructure (CNKI), Chongqing VIP information (CQVIP), and Wanfang database. Search was also carried out on ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP) and the Chinese Clinical Trials Register (ChiCTR) in order to find potential RCTs or data not yet published. If any, references of literature included and previous published systematic reviews and meta-analysis related to TCM and idiopathic pulmonary fibrosis will also be checked. If necessary, We will contact the author to provide additional information. Studies with unavailable data will be excluded. Search is limited to English and Chinese languages. The search will include the following search terms, such as “idiopathic pulmonary fibrosis”, “pulmonary fibrosis”, “Chinese patent medicine”, “Chinese medicine”, “traditional medicine”. A draft search strategy for PubMed is provided in Additional file 2.
All identified records through the performed search will be imported into Endnote X9, and duplicate data will be removed.
Selection of studies
Two independent reviewers (F Sun and ZC Wu) will remove irrelevant articles by reading the title and abstract, and then evaluate the trials to determine if they are appropriate for inclusion by reading the full text. Any disagreement will be resolved by discussion with the third team members (FL Jiang). Full-text articles of eligible studies will be analyzed in detail, and then reviewers will decide which studies to include and explain the reasons for excluding the study. The selection process will be recorded in detail, and the PRISMA flow diagram and tables will be filled in with the characteristics of the included and excluded studies.[17,18]The whole selection process will be presented in a PRISMA flow diagram (33)(Fig. 1).
Data extraction will undergo a process with independent abstraction by the two reviewers (F Sun and ZC Wu), the final decisions will be made by consensus process. We will check the consistency of information (M Huang) and disagreements will be resolved by discussion or a third senior reviewer(FL Jiang). Extracted data will include first author, publication year, countries and regions，participants (age, sex, number of subjects, course of disease，baseline Information), study design (randomization, allocation concealment, blinding,), trial size, criteria used to screen for IPF diagnosis, interventions and controls (dosage, frequency and duration), outcomes, duration of follow-up, reasons and number of patients who dropped out or lost during follow-up, type and source of financial support and publication status. If required information is incomplete or unclear, we will try to contact the corresponding author of the studies.
Risk of bias assessment
We will use the Cochrane collaboration’s tool to assess the risk of bias of the included studies, which covers: sequence generation, allocation concealment, blinding, incomplete outcome data (e.g. dropouts and withdrawals) and selective outcome reporting. Two reviewers(JE Wang, WL Sun) will independently assessed risk of bias based on the criteria. Disagreements will be resolved first by discussion and then by consulting a third reviewer(F Sun) for arbitration.
Data synthesis and analysis
The RevMan (V.5.4.1) software will be used for the meta-analysis. For dichotomous variables, risk ratio (RR) with 95% confidence interval (CI) is implemented for statistical analysis. Meanwhile, continuous results will be presented as the weighted mean difference (WMD) or the standardized mean difference (SMD) with 95% CIs. Under the heterogeneity of the included studies, a random-effects or fixed-effects model will be used. The heterogeneity between the studies will be measured by the I² tests. If the statistical heterogeneity between the results of each study does not exist or is negligible (I²<50%, P>0.1), the fixed-effects model is used for meta-analysis; on the other hand, if there is large statistical heterogeneity detected between the results of the studies (I²≥50%, P<0.1), we will try to explain the potential reasons for the differences in heterogeneity by subgroup analysis or sensitivity analysis. After excluding the influence of obvious etiologies of clinical heterogeneity, the random-effects model was used for meta-analysis.
Sensitivity analysis will be performed based on risk of bias and analysis method (random-effects model and fixed-effects model) to assess the robustness of our results.
Subgroup group analysis will be used to explore possible sources of heterogeneity. If necessary, we will try to conduct subgroup analysis based on the different age, severity, course of disease, duration of treatment, drug dose and frequency, dosage form, follow-up period, trial size, risk of bias.
Grading the quality of evidence
We will use Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the certainty of evidence for each outcome and entire body of evidence. The quality of evidence will be assessed according to risk of bias, consistency, directness, precision and publication bias. Quality will be adjudicated into four levels: high, moderate, low, or very low. Two reviewers (F Sun, ZC Wu) will independently conduct this assessments. For all phases of the project, reviewers can resolve disagreements by discussion or in consultation with a third reviewer (LS Zhang).
Reporting bias and outcome reporting bias
Funnel plot or Egger’s test to assess the risk of publication bias. Also, we will screen the clinical trial register to evaluate whether selective reporting of outcomes is present.
Ethics and dissemination
This research is a systematic review and meta-analysis, patients will not be treated directly in the course of the study, and the personal information of patients will not be disclosed. Therefore, informed consent and ethical permission are not required for our research. We intend to update the public registry with this review in all phases of its execution and publish the results in a widely accessible journal after the completion of the research.