Trial design
This study is a multi-centre parallel randomized controlled trial. Participants with BA will be screened based on strict inclusion and exclusion criteria from January 2020 to December 2021. After providing written informed consent, 72 eligible participants will be randomly allocated to one of two groups: an SHP group receiving SHP treatment; a placebo group receiving placebo patch treatments. They will receive treatment for 3 TSs and follow-up assessments for 24 weeks (Fig. 1 and Fig. 2). The trial has been registered with the Chinese Clinical Trial Registry (ChiCTR1900024616, registered on 19 July 2019). The protocol design is based on the guidelines of the Consolidated Standards of Reporting Trials and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). (See Additional file 1 SPIRIT 2013 checklist)
Trial population
The trial will be conducted in 4 centres. These include the First Affiliated Hospital of Guangzhou University of Chinese Medicine, the Fifth Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Second Provincial General Hospital, and Pingshan District Peoples’ Hospital of Shenzhen. The clinical investigators from each centre will be responsible for screening eligible participants.
Randomization and allocation concealment
Random permuted blocks will be generated by Strategic Applications Software (SAS, version 9.2, SAS Institute, Inc., Cary, USA) and performed by the Key Unit of Methodology in Clinical Research in Guangdong Provincial Hospital of Chinese Medicine. The allocation to the SHP group and to the placebo group will be in a 1:1 ratio. An independent researcher will prepare a treatment card with a serial number and one of two names on it. Each name will represent one of the two groups. This researcher will also attach a label on the tube to mark which is the SHP or placebo ointment. Participants are given treatment cards from independent researchers to ensure adequate concealment.
Blinding
Except for the independent researchers, all participants, acupuncturists, operational assistants, nurses, data managers, and statisticians will be blinded to the treatment allocations until the end of the study. Operational assistants will prepare the patches from tubes labelled with the same name on the treatment card. The placebo patch will be identical in appearance to the SHP. In addition, acupuncturists and operational assistants will be instructed not to communicate with participants about the possibility of their allocation.
For the better operation of blinding, participants will be required to wait for 120 minutes in a room and to tear off their treatment patches while facing away from the nurses. In addition, nurses will be instructed not to communicate with participants about the possibility of their allocation.
Participants and recruitment
We intend to enrol a total of 72 participants in 4 centres. Participants are being recruited via local advertising, local newspapers, and physician referrals from respiratory clinics. The recruitment information mainly includes eligibility criteria and contact details. A well-trained investigator in each centre will be responsible for screening all potentially eligible patients based on the eligibility criteria and informed consent.
Inclusion criteria
The inclusion criteria are as follows:
- Aged 18-75 years (either sex)
- Patients with BA of chronic persistence (symptoms appear weekly) or clinical remission (maintaining the absence of symptoms for over 1 year)
- Deficiency of lung and kidney qi syndrome (wheezing, shortness of breath, light and tender tongue with white fur, thin pulse, backache, soft knees, tinnitus, chills and cold limbs, tiredness)[21].
- Mildly to moderately persistent(FEV1≥60%, peak expiratory flow (PEF) variation rate>20%)
- Voluntary participation in the study
Exclusion criteria
The exclusion criteria are as follows:
- BA of acute exacerbation or intermittent state (frequency of symptoms < once a week, FEV1≥80%, and PEF variation rate<20%) and/or severe duration (symptoms appear daily, FEV1<60%, and PEF variation rate>30%)
- Airflow obstruction disorders such as chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary tuberculosis, and so forth
- Serious health conditions such as severe cardiovascular and cerebrovascular diseases, liver or kidney disease, and so forth (routine blood test, routine urine test, heart rate, temperature, breath rate and pulse are examined for safety screening)
- Mental disorders
- Allergy to the test ingredients, or blistering, sputum, or damage to the acupoint skin
- Pregnant women, breastfeeding mothers
Interventions
SHP group
The complete formula for the SHP includes Angelica dahurica 1 gram (g), Asarum 2 g, Pinellia 1.5 g , Corydalis 0.5 g , Euphorbia kansui 1 g, Brassica Alba 2 g , Ephedra 0.6 g , Arisacma Consanguineum 0.8 g, Atractylodes macrocephala 1 g and musk 0.1 g. The herbs are processed into powder and mixed with fresh ginger juice to create the SHP ointment. The SHP and placebo are manufactured by the Pharmaceutical Preparation Department in the First Affiliated Hospital of Guangzhou University of Chinese Medicine to meet the requirements of the regulatory guidance issued by the China Food and Drug Administration.
The selected acupoints are Feishu (BL13), Dingchuan (EX B1), Shenshu (BL23) on both sides, for a total of 6 acupoints. The locations of the acupoints are shown in Fig. 3 according to the World Health Organization Standard Acupuncture Locations.
Participants receive an SHP through the following procedure: (1) Each participant is asked to expose their back. (2) Two grams of ointment is squeezed by operational assistants onto a circular medical proof fabric, 1 centimetre in diameter for one piece of the SHP. (3) One piece of the SHP is attached to each acupoint by an acupuncturist in each centre. (4) Participants are then asked to wait in a room for 120 minutes, and nurses are required to carefully observe them. If a participant feels any unbearable pain or a burning sensation, the SHP is to be removed immediately by nurses. The exact treatment duration of each participant is recorded on the case report form(CRF).
Placebo group
The placebo ointment is similar to the SHP in physical properties such as appearance, colour, dosage form, weight and gas. It is composed of buckwheat flour, caramel and water. Acupoints, dosage of ointment, medical proof fabric and procedures are the same as those in the SHP group.
There are 3 TSs in 2020, and the exact dates for each session are calculated according to the Chinese Lunar Calendar (Table 1).
Concomitant medications
Participants will be allowed to take Budesonide and Formoterol Fumarate Powder for Inhalation (AstraZeneca AB, Sweden), 4.5 μg per dose, twice a day. For participants undergoing an acute attack, Salbutamol Sulphate Inhalation Aerosol (GlaxoSmithKline Australia Pty, Ltd.) will be given at 100 to 200 μg per dose, repeating inhalation every 4 to 8 hours if necessary.
Participants will be requested not to receive any other treatments, such as complementary treatments (moxibustion, herbal medicine, massage, and so on) or other medications, throughout this study. Use of all drugs, if any, will be documented in detail in the CRF.
Trial outcomes
Primary outcome
The primary outcome is the change in the FEV1 from baseline to the end of the 3 TSs. FEV1 will be performed by the Pulmonary Function Test System (MasterScreen, CareFusion Germany 234 GmbH) in the Pulmonary Function Examination Room of the First Affiliated Hospital of Guangzhou University of Chinese Medicine. Clinically, if FEV1 is less than 80% of the expected value, this indicates pulmonary dysfunction[22].
The effect evaluation is as follows:
- Clinically complete controlled: asthma attacks are completely relieved, with FEV1 improved by more than 35%;
- Significantly controlled: asthma attacks are significantly relieved, with FEV1 improved by 25%-35%;
- Partly controlled: FEV1 improved by 15%-24%;
- Uncontrolled: no improvement in asthma attack and FEV1 measurement.
Total treatment efficiency = (clinically complete controlled number + significant controlled number+ partly controlled number) /total number × 100%.
Secondary outcome
Questionnaire test
As secondary outcomes, we will use the Asthma Quality of Life Questionnaire(AQLQ)[23]and the Asthma Control Test (ACT)[24] at the2nd, 3rd TS and at 12th and 24th weeks compared with the baseline.
The AQLQ contains 35 questions with four domains (symptoms, activity limitation, emotional function, and environmental stimuli) as a measure of quality of life for adult patients with asthma. The items are self-assessed by participants using a seven-point scale (1=completely restricted; 2= extremely restricted; 3=severely restricted; 4= moderately restricted; 5=mildly restricted; 6=rarely restricted; 7= unrestricted). The scores for each question are averaged to produce an overall score. The study will compare the mean change scores from baseline at each time point, using the mean scores from each group.
The ACT is a widely used, validated questionnaire for the assessment of asthma control[25]. ACT contains 5 questions, and each allows a response on a 1 to 5 scale, with 5 representing no problems at all. Five points are added to the ACT total score (<20: poorly controlled; 20–24: partly controlled; 25: well controlled asthma).
In addition, participants will be asked to complete an Asthma Long-term Follow-up Scale (ALFS)[26] at the 12th and 24th weeks during follow-up. The frequency and severity of symptoms, occurrence time, FEV1, and the use of medications (name, dose and date) are recorded in detail on the ALFS to assess the safety of each group.
Laboratory indicators
Airway inflammatory factors
The levels of airway inflammatory factors(IL-5, IL-13, IL-23, IL-25, TSLP) will be detected at the baseline and at the end of the 2nd and 3rd TS. Five millilitres of antecubital vein blood taken from participants on an empty stomach will be collected by trained clinical staff in each centre. Sera will be obtained by coagulation and centrifugation of blood samples for 20 min at 1000 g at room temperature and then aliquoted and frozen at −80 °C before analysis. To determine the antibody response, the samples will be tested by a double-antigen sandwich enzyme-linked immunosorbent assay (ELISA)[27, 28]. All samples will be measured in duplicate and averaged.
Tracheal smooth muscle cell regulatory proteins
Five millilitres of serum and urine of participants will be obtained from participants at the baseline and at the end of the 2nd and 3rd TSs. ELISA will be used to measure the levels of tracheal smooth muscle cell regulatory proteins (Metallothionein-2, Transgelin-2) in serum and urine. Urine samples will be obtained by centrifugation of urine at 1000 g for 20 minutes, particulates will be removed immediately, and stored at -80 °C.
ELISA will be performed according to the kit instructions (Wuhan Youersheng Trading Co., Ltd, China), at Lingnan Medical Research Centre in the First Affiliated Hospital of Guangzhou University of Chinese Medicine.
Safety aspects
Adverse events
Any adverse events (AEs) occurring to participants during the treatment period and follow-up, whether associated with the intervention or not, will be assessed and recorded at any time. Some AEs, such as local itching, redness, and blisters, might be related to the SHP[29]. If slight burning or redness in the local skin or a slight tingling feeling occur, THE SHP will be removed by the nurses in advance. If small blisters occur, the nurses will carefully prick the blisters with a disinfection needle, and then cover them with sterile gauze in case of infection. All details of AEs will be recorded on CRFs.
Severe adverse events (SAEs) or adverse drug reactions (ADRs) include repeated episodes of BA, admissions for treatment, prolonged hospital stays, life-threatening conditions and death. SAEs must be reported to the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine within 24 hours. In the event of an emergency medical situation, the individual’s randomization code and group allocation can be identified via a standard operational procedure.
Statistical methods
Sample size
The sample size was calculated based on the primary outcome measure by PASS11.0(Power Analysis and Sample Size, NCSS, LLC. Kaysville, Utah, USA). The power was set at 90% and calculated based on two-sided 95% confidence intervals. Based on a mean score of 79.41 with a standard deviation (SD) of 13.87in the SHP group and a mean score of 59.61 (SD: 11.52) in the placebo group after treatments[30], the sample size was determined to be 30 for each group. Considering a 15% drop-out rate, 36 patients will be included in each group. Finally, we will require a sample size of 72 patients with BA in this study.
Data analysis
The final data will be double entered by two statisticians and analysed by PASW Statistic 24.0 (IBM SPSS, Inc., Armonk, New York, USA). (1) All analyses will be based on the intention-to-treat principle. Thus, multiple imputations will be used to address the missing data. Two-tailed 𝑝 values < 0.05 will be considered statistically significant. (2) For continuous variables, all data will be firstly to be tested for normality. The t-test will be used for the fitted data, while the rank sum test will be used for the non-fitted data. Continuous variables will be described as the mean ± standard deviation (¯x ± SD), maximum, and minimum. (3) Repeated measures will be used to compare the value differences of several continuous observations. (4) For categorical variables, the Achi-square test or Fisher’s exact test will be used to examine the between-group differences, and percentages and frequencies will be presented to describe the effect size.
Quality supervision and management
Before recruitment, the whole research team in 4 centres, including acupuncturists, operational assistants and data statisticians, will be required to attend a training workshop to ensure strict adherence to the study protocol. They will be provided with a written protocol and standard operation procedure documents. During the study period, clinical trial collaboration meetings will be held regularly to check the progress of the research.
All data collected from participants and modifications will be documented clearly on CRFs. The last-visit-carried-forward method will be used to handle the missing data. Data will be entered using the double-entry method and reported to the clinical trial centre. Data managers will recheck the data before logging them and will promptly notify the research team if any discrepancy is found.
The clinical trial will be suspended or discontinued if the safety of any participant is compromised or if any SAEs are not reported within the prescribed time. If the trial is suspended or discontinued, the participants, the project funder, and the ethics committee will be informed of the reason.
Ethics and dissemination
Patient consent and dissemination policy
This protocol has been registered with the Chinese Clinical Trial Registry. In the first visit, each participant will be informed in detail about the study procedures and provided with enough time to decide whether to sign the written consent before randomization. All blood and urine samples taken from participants will be destroyed after the trial. Participants can withdraw their informed consent at any time during the study. Participants who experience severe adverse reactions or irreversible injuries as a result of the trial will be reasonably compensated, according to the circumstances.
Access to data and confidentiality
Every precaution will be taken to respect the privacy of participants in the conduct of the study. Only research team members will have access to the research data. All data will be kept strictly confidential during the study. Information will be stored in password-protected files and held independently by the staff of the Key Unit of Methodology in Clinical Research in Guangdong Provincial Hospital of Chinese Medicine. In the course of monitoring data quality and adherence to the study protocol, the monitors will refer to medical records at 4 centres. On completion of the study, participants will receive a personal summary of the data collected in the study.