Clinical efficacy of acupoint application of Chinese herbal medicine to prevent acute exacerbation of stable chronic obstructive pulmonary disease: A study protocol for a randomized placebo-controlled trial

Background: Chronic obstructive pulmonary disease (COPD) is a major public health problem that severely affects the quality of life of patients and may even endanger their lives. The key to prevent the progression of COPD is active treatment during the stable phase that prevents and reduces acute exacerbation of COPD. Although modern medicine has achieved significant results in relieving the clinical manifestations of COPD, it is difficult to prevent its progression and acute exacerbation entirely. As one of the classic aspects of acupuncture and moxibustion therapy, acupoint application of Chinese herbal medicine (CHM) can improve the clinical efficacy of Western medicine in treating COPD. To date, however,there is no high-quality clinical trial to assess the effectiveness of CHM acupoint application directly in preventing acute exacerbation of stable COPD.Thus, we designed this randomized placebo-controlled clinical trial to evaluate the long-term efficacy and safety of CHM acupoint application in preventing the acute exacerbation of stable COPD. Methods: The study is a randomized, double-blind, placebo-controlled trial, in which 200 stable COPD patients will be randomly and equally divided into the experimental group or control group. Both groups will undergo standard Western medicine treatment; however, the patients in the experimental group will be also treated with CHM acupoint application, while the control group will be given placebo acupoint application. The duration of the treatment will be 1 month and a follow-up for 11 months. The primary outcome will be the number of acute exacerbation episodes of COPD, and the secondary outcomes will include the lung function, St George's Respiratory Questionnaire, COPD Assessment Test, and 6-Minute Walk

4 Test. A safety assessment will also be performed during the trial.

Discussion:
The aim of this study is to evaluate the efficacy and safety of CHM acupoint application in preventing acute exacerbation of stable COPD. Our study will provide sound evidence to support the evidence-based medicine of CHM acupoint application as an additional measure in the prevention of acute exacerbation of stable COPD.

Background
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in the world 1 . It is estimated that 384 million people worldwide suffer from COPD 2 , of which China accounts for 100 million 3 . In 2017, 3.2 million people died of COPD, a toll that is expected to reach 4.4 million per year by 2040 1 . Acute exacerbation episodes of COPD occur 0.5-3.5 times a year, which lead to further deterioration of airway injury, promotes the progression of the disease, and causes a huge economic burden on pateints 2,4 . Therefore, the key to COPD treatment is to treat it effectively during its stable period to prevent the occurrence of acute exacerbation.
Inhaled bronchodilators in stable COPD are central to symptom management. If necessary, triple therapy (inhaled glucocorticoids + long-acting β2-agonist + longacting muscarinic receptor antagonist) may be considered to reduce the deterioration frequency and increase labor tolerance. However, it cannot be confirmed if these drugs completely prevent disease progression and control COPD at different stages 5 . Moreover, these drugs have certain adverse reactions, such as palpitations, arrhythmia, and tremor, which limit the application of the drugs to a 5 certain extent. Acupuncture has been confirmed by some meta-analyses and clinical studies to safely and effectively treat patients with COPD and improve the exercise capacity as per the 6-Minute Walk Test and the quality of life of COPD patients as per the St George's respiratory questionnaire (SGRQ) 6− 7 . Acupoint application therapy is a compound treatment method that integrates meridians, acupuncture points, and herbs. First, the processed herbal ointment is placed on the medical adhesive medicine plaster. Then, some points are affixed with medicinal paste that has the characteristics of being non-traumatic, needing only small dose of medication, and having a direct effect on the acupuncture points. According to the basic Traditional Chinese Medicine (TCM) theory, acupuncture points application is similar to acupuncture in regulating meridians, yin and yang, and qi as well as the blood of the human body. Chinese medicines commonly used in acupoint application include Acupoint application has been recorded in the Compendium of Materia Medica in detail. It is a common therapy for chronic pulmonary diseases, such as COPD, and it 6 has been used by Chinese doctors for about 1300 years. Since the 1950s, acupoint application therapy has been widely carried out in 30 provinces, municipalities, and autonomous regions in China. A meta-analysis based on Chinese clinical trials (3,481 out of 32 randomized control trials [RCTs]) has shown that different combinations of Chinese herbal medicine (CHM) and acupoint application can improve the clinical efficacy of Western medicine in treating COPD 10 . To date, however, there is no high-quality clinical trial to assess the effectiveness of Chinese medicine acupoint application directly in preventing acute exacerbation of stable COPD. Therefore, we designed this clinical trial. To the best of our knowledge, this study is a rare, randomized, placebo-controlled design of RCT to evaluate the efficacy and safety of acupoint application of Chinese medicine in preventing the acute exacerbation of stable COPD.

Study design and setting
This study is a prospective, double-blind, randomized, placebo-controlled clinical trial. To prevent design bias, we will follow the Consolidated Standards of Reporting Trials statement 11  participants, and the participants will be informed of the benefits and risks of the study in detail. The written informed consent form will be included before the study, 7 and the participants will be protected throughout the study. After obtaining written informed consent, eligible participants will be randomly assigned to the experimental group and control group in a ratio of 1:1. The entire study includes a screening assessment period, a 2-week run-in period, a 1-month treatment period, and an 11-month follow-up period. The schedule of enrollments, interventions, and assessments is shown in Figure 1 (the SPIRIT figure). The illustration of the design for clinical studies is presented below in Figure 2. The SPIRIT 2013 checklist is presented in Additional File 1.

Participants
This study will be conducted in the Hospital of Chengdu University of TCM.
Participants will be recruited through a recommendation by the respiratory clinician and social media. All participants must meet the diagnostic criteria of Western medicine for COPD (Table 1) 13 and the diagnostic criteria of TCM for lung-spleen qi deficiency syndrome (Table 2) 14 . The syndrome differentiation shall be determined independently by two designated deputy physicians of TCM.

Randomization, allocation concealment
A statistician, the member of the Sichuan TCM evidence-based Medicine Center will generate 200 random serial numbers using the SAS 9.2 Software (SAS. Cary, USA), and stratified randomization will be based on the GOLD classification of COPD.
Eligible patients will be randomized into the experimental or control groups in a 1:1 ratio. The group numbers will be provided in a continuous manner in sealed envelopes made from carbonless paper. The envelopes will be kept by a study administrator who will not directly participate in the recruitment or follow-up of any participant. The administrator will open one envelope and provide the participant 9 with their group number on the day of inclusion. Until the completion of the trial, the researchers will not know the grouping of the participants.

Blinding
The placebo paste used in this study is similar to the CHM paste of the trial group in shape, smell, and color. Acupoint application therapists and patients will be blinded to the treatment allocation throughout the course of the study. Only in emergencies, such as serious adverse events (AE), or if the patient needs emergency treatment, can the researchers report to the principal researcher to decide whether to expose the blind. Once the participant is exposed, the case will be treated as an exfoliated case and will not be included in the efficacy analysis.
However, if there are adverse reactions, these should be included in the AEs analysis and detailed information about exposure will be recorded in the "early exit page of participants" of the case report form (CRF), including the time, cause, treatment, and treatment status of blind-exposed participants.

Interventions
Both groups will be treated with standard Western medicine. The treatment plan is based on the GOLD 13 and the Guidelines for the Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease (Revised 2013) 15 . All participants will be taught to use inhaled agents correctly, and they would have to quit smoking and prevent catching colds. Drug selection (based on the patient's pulmonary function) and symptoms and risk of acute exacerbation will be stratified, including that of GOLD [Sweden], 160 µg/4.5 µg/inhalation, 60 inhalations), 164.5 µg per inhalation, twice a day. The experimental group will be treated with acupoint application of CHM at the same time, while the control group will be treated with acupoint application of placebo. The course of treatment is 1 month, and the course of follow-up will be once every 3 months for 11 months. The TCM and acupoint selection program is based on academic literature data [16][17]  will be performed twice a week for 4 weeks, total 8 times.
In this study, we will take the following measures to control the quality of acupoint application: (1)

Outcome measurement
The primary outcome includes the number of acute exacerbation episodes of COPD.
COPD exacerbation is defined as an acute worsening of respiratory symptoms resulting in additional therapy 19 .

Criteria for stopping treatment
Participants will be informed that they have the right to discontinue treatment and withdraw from the research project for any reason at any time, and the reason for withdrawal will be recorded in the CRF. If they quit, they will receive standardized treatment. The criteria for stopping treatment and withdrawal from research projects are as follows: (1)

Compliance
In this study, certain measures will be taken to ensure the compliance of the participants. Before entering the group, the participants will be carefully screened to understand their history of previous drug use, detailed information on the test content, course of treatment, adverse reactions of the treatment, and some possible burdens on the participants. Furthermore, written informed consent of the participants will be obtained. During the experiment, the professional and service quality of medical personnel should be maintained at optimum to create a good doctor-patient relationship. It is also important to establish healthy communication channels in time. For example, a contact card can be created to contact the participant, or record the telephone number in the record book. Two to three days before each follow-up visit, the researcher can call the participant to remind them of the last time they were interviewed. If the participants have difficulty getting to the hospital, a shuttle bus can be arranged.

Observation and treatment of adverse events
The dosage of CHM used in this study is within the recommended range of the Pharmacopoeia of the People's Republic of China (2015 edition), and all operating procedures will strictly follow the standard operating guidelines. In this study, patients could be allergic to research drugs or dressings during the application period, such as rash, skin itching, skin redness and swelling, or skin burning. We will strictly adhere to the criteria and avoid including those who are allergic to TCM or the accessories/dressings used in this study. In the course of the trial, it is necessary to determine whether the patients have related AEs due to the application. Moreover, laboratory tests will be performed to analyze blood, urine, feces, electrocardiogram, and kidneys and liver function, before and after treatment. Individuals reporting mild and moderate AEs will be treated for symptoms and closely observed. If serious AEs occur, the patients will be admitted to the hospital immediately for systematic treatment and reported to the principal researcher and ethics committee within 24 hours. All details of relevant and unexpected AEs, such as the time, severity, and suspicious causes of the AEs, will be recorded in detail in the CRF.

Sample size estimation
This is a parallel, randomized controlled study. The experimental group will be treated with acupoint application of CHM, and the control group with placebo acupoint application. The number of acute attacks of COPD will be observed as the (bilateral) and β = 0.10. The sample size was 76 each in the experimental group and the control group and was calculated using the PASS 11 software. With an estimated dropout rate of 20%, a total of 190 patients is enrolled. In the actual study, 100 cases will be included in each group.

Data management and quality control
The researchers in the trial team will be required to attend a training workshop before the trial begins. Each one will receive a copy of the trial protocol, and they will be asked to adhere to the protocol throughout the study. Researchers should fill in clinical trial records in a timely, accurate, complete, standardized, and true manner to ensure that all CRFs are accurate and consistent with the original data.
Data management should be carried out according to the SOP of data management, and data entry and sorting will be done using EpiData 3.1 software. In order to ensure the reliability and accuracy of the data, two database operators will independently enter the same data, then conduct data consistency test, and proofread it multiple times. Files are stored in a secure and accessible manner.
Security measures will be managed by user identification codes and passwords, and monthly backups are stored on CD media. Finally, the database is locked and analyzed according to the protocol, and confirmed and reviewed by the main researchers.

Statistical analysis
We will use the Statistical Package for the Social Sciences (SPSS version 21.0) statistical software for analysis, and use subgroup analysis methods to explain the efficacy and safety of acupoint sticking in different grades of GOLD patients to obtain comprehensive information. The measurement data will be expressed as mean ± standard deviation, which is consistent with the normal distribution. The pairing t-test will be used before and after treatment. The t-test will be used for comparison between groups (homogeneity test of variance was performed, 0.05 is used as the test standard). For those which do not conform to the normal distribution or whose variance is not uniform, the rank sum test will be applied instead. The count data will be analyzed by chi-square test, and the grade data will be tested by rank sum test. All tests will be performed on both sides, and P < 0.05 will be statistically significant. Compared with previous studies, we focus on assessing the effects of acupoint application on the long-term efficacy of stable COPD (future acute exacerbation) and patient activity tolerance. However, it cannot be ignored that this study also has certain limitations. First, in clinical practice, pure COPD patients are rare, and most patients present with other diseases such as cor pulmonale, hypertension, diabetes, and coronary heart disease. Therefore, the practicability (extrapolation) of the results in this study is not clear and needs to be further evaluated. Second, the study is being performed in Sichuan, China, and it is uncertain whether the relative effects of the trial drugs would be similar in other ethnic groups. Despite the limitations, we believe that this study will be helpful in finding the long-term benefits of CHM acupoint application in the prevention of acute exacerbation of stable COPD. In the future, multi-center RCTs should be conducted and multidimensional comparison should be conducted.

Ethical approval
The research program has been approved by the China Ethics Review Committee for Registered Clinical Trials (Approval No. ChiECRCT20190221), and the members of the ethics committee tracked the design and implementation of the research. Prior to randomization, all individuals will be explicitly explained that the trial involves two types of interventions, and that only those who agree to sign the informed consent and voluntary participation in the trial will be included in the study.

Trial status
This paper is based on protocol version 2.0 dated 3 November 2019. Recruitment began in December 2019, and approximate date of completion is December 2020.
Any major protocol changes will be notified to the ethics committee and updated on the Chinese Clinical Trial Registry.

Ethics approval and consent to participate
The study is in compliance with the Declaration of Helsinki (Edinburgh 2000   version    Additional file 1.doc