Administrative information
Title {1} | Efficacy and safety of Jia Wei Bushen Yiqi formulas as an adjunct therapy to systemic glucocorticoids on acute exacerbation of COPD: Study protocol for a randomized, double-blinded, multi-centre, placebo-controlled clinical trial TCMWSG: Traditional Chinese Medicine with Systemic Glucocorticoids |
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Trial registration {2a and 2b}. | ID: ChiCTR1900023364, registered on 24 May 2019. |
Protocol version {3} | KY 2019-299,03,03, July, 2019 |
Funding {4} | This project was supported for 3 years to accelerate the development of Chinese medicine in Shanghai, China. [Grant No: ZY (2018-2020)-FWTX-4016], the National Natural Science Foundation of China (Grant No. 81704154), Chinese medicine innovation project of Shanghai Health Committee (No.ZYKC201601023) and National Natural Science Foundation of China (No.81501180) |
Author details {5a} | Qing Kong1#, Shuming Mo2#, Wenqian Wang1, Zihui Tang1, Ying Wei1, Yijie Du1, Baojun Liu1, Lingwen Kong1, Yubao Lv1* Jingcheng Dong1* 1Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China, 2Department of Integrative Medicine, North Hospital of Huashan Hospital, Fudan University, Shanghai, China *Correspondence: Yubao Lv, lvyubao80313@163.com *Correspondence: Jingcheng Dong, jingcheng_dong@yeah.net #These authors have contributed equally to this project. |
Name and contact information for the trial sponsor {5b} | Jingcheng Dong, jingcheng_dong@yeah.net |
Role of sponsor {5c} | Qing Kong and Shuming Mo drafted the manuscript. Wenqian Wang, Zihui Tang, Baojun Liu, Yijie Du and Lingwen Kong participated in the design of the study. Ying Wei, Yubao Lv and Jingcheng Dong conceived the study, participated in its design and coordination, and drafted the manuscript. All authors read and approved the final manuscript. |
Introduction
Background and rationale {6a}
Method {7}
Trial design {8}
Study setting {9}
Code | Participating hospitals | Location |
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01 | Huashan Hospital Affiliated to Fudan University | Eastern China |
02 | The First Affiliated Hospital of Nanjing Medical University | Eastern China |
03 | Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University | Northwestern China |
04 | Xinjiang Production and Construction Corps General Hospital | Northwestern China |
05 | The First People’s Hospital in Kashgar | Western China |
06 | The Second People’s Hospital in Kashgar | Western China |
07 | Puer Hospital of Traditional Chinese Medicine | Southwestern China |
08 | Yancheng Hospital of Traditional Chinese Medicine | Eastern China |
09 | Affiliated Hospital of Nanjing University of Chinese Medicine | Eastern China |
10 | Qingpu Traditional Chinese Medicine Hospital Attached to Institute of Integrative Medicine, Fudan University | Eastern China |
Eligibility criteria {10}
Inclusion criteria | |
1. Age is between 40–90 years old | |
2. Weight is between 45–85 kg | |
3. Acute exacerbation of COPD with clinical grade 1–2 that only requires ordinary hospitalization | |
4. Syndrome differentiation as Fei_Shen_Qi_Yu_Re Zheng in TCM | |
5. Voluntarily signed informed consent | |
Exclusion criteria | |
1. Patients who also have bronchial asthma, bronchiectasis, active tuberculosis, pulmonary fibrosis, pneumothorax, pleural effusion, pulmonary embolism, or neuromuscular disease affecting respiratory function | |
2. Patients who also have leukemia, aplastic anemia, myelodysplastic syndrome, thrombocytopenia, multiple myeloma, or other blood diseases | |
3. Patients who also have malignant tumors | |
3. Patients who also have rheumatic immune diseases and adrenal insufficiency or patients requiring hormones or immunosuppressants | |
4. Pregnant or planning to become pregnant or lactating women | |
5. Severe impairment of heart, liver and kidney function (heart function 3–4 degree, aspartate aminotransferase (ALT) and/or alanine aminotransferase (AST) exceeds 1.5 times of the upper limit of normal, creatinine (Cr) exceeds the upper limit of normal) | |
6. Received systemic glucocorticoids within 2 weeks or participation in other drug clinical trials within 3 months prior to the trial | |
7. Other conditions that the investigators consider to be improper |
Primary symptoms | |
(1) Wheezing, shortness of breath, and deterioration with movement | |
(2) Fatigue, or spontaneous sweating, and aggravation when in movement | |
(3) Easy to catch cold, fear of wind | |
(4) Quantity of sputum is yellow or sticky | |
(5) The face or lips look purple and blue | |
Secondary symptoms | |
(1) Fever or thirst, like cold drink | |
(2) The waist and knees are sore and weak | |
(3) Tinnitus, dizziness | |
(4) Incontinence or heavy urine volume | |
(5) Pale or spotted tongue with yellow fur, slipping quick pulse |
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
During hospitalization | |
Oxygen therapy | Continuous low-flow oxygen absorption (oxygen concentration is 2 L/min). |
Short-acting inhaled bronchodilator | Albuterol atomization solution 5 mg, ipratropium bromide atomization solution 500μg, nebulization, Bid. |
Theophylline | Aminophylline 0.5 g for injection, intravenous drip, Qd; Peony ambroxol 60 mg, intravenous drip, Bid. |
Antibiotics | Penicillins: piperacillin tazobactam 4.5 g, intravenous infusion, Q8h; quinolines: levofloxacin injection 0.5 g, intravenous infusion, Qd. Antibiotics for 7–10 days. |
After discharge | |
Group A use a bronchodilator | |
Group B use LAMA or LABA | |
Group C use LAMA | |
Group D use LAMA and/or LABA+ICS |
TCM treatment
Criteria for discontinuing or modifying allocated interventions {11b}
Strategies to improve compliance to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Primary outcomes measurements
Secondary outcomes measurements
Safety outcomes
Exploratory outcomes
Participant timeline {13}
Sample size {14}
Variable | TCM treatment | Systemic glucocorticoid treatment |
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Primary outcome | CAT score | Time to next exacerbation |
Way | 2-group,1-sided | 2-group non-inferiority |
Group A mean | 10.30 | 29 |
Group B mean | 12.95 | 43.5 |
Group A standard deviation | 6.31 | 12 |
Group B standard deviation | 5.99 | 12 |
Non-inferiority margin | 10 | |
Sampling ratio | 1 | 1 |
Type 1 error | 0.05 | 0.05 |
Power | 0.8 | 0.8 |
Sample size | 67 | 88 |
Recruitment {15}
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
Plans to promote participant retention and to complete follow-up {18b}
Data management {19}
The writing and transfer of case report
The design and establishment of database
Data coding
Data entry
The audit of data
Data locking
Data storage
Confidentiality {27}
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
The process and collection of blood samples
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Outcomes | Hypothesis | Outcome measurement | Analysis method |
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Primary | TCM improved outcomes from baseline to 10 days | ||
Interval time to next exacerbation | Telephone visit (continuous) | GLM | |
CAT | Questionnaire score (continuous) | MENM | |
Secondary | Improved occurred | ||
Duration of COPD exacerbation | Calculating days in dairy (continuous) | GLM | |
TCM syndrome assessment | Questionnaire score (continuous) | GLM | |
Lung function | FEV1, FVC, PEF (continuous) | GLM | |
Blood gas analysis | Pa (CO2), Pa(O2) (continuous) | GLM | |
Infection index | EOS count, CRP, proclamation (continuous) | GLM | |
Inflammation cytokine | IL-6, IL-8, IL-10(continuous) | GLM | |
HPA axis | ACTH, CRH, CORT (continuous) | GLM | |
Subgroup analysis | Effects adherence | Groups | |
Age (in years) | < 64, ≥ 64 | ||
Gender | Male, female | ||
Body mass index (kg/m2) | < 18.5, ≥ 18.5 to < 24, ≥ 24 | ||
Smoking history | Ex-smoker, current smoker | ||
GOLD stage | I-II, III, IV | ||
Infectious | Infectious, un-infectious | ||
EOS count | < 300/μl, ≥ 300/μl |