We will conduct a A randomized, double-blind, placebo-controlled trial. A flowchart of the study protocol is shown in Figure 1.
Ethics and recruitment
All patients will sign the informed consent before inclusion. The study has been approved by the Ethical Research Committees of the China-Japanese Friendship Hospital with identifier 2018-57-K41-1. Any revisions of the study protocol will be submitted to the ethics committee.
COPD patients will be recruited from either the out-patient department or open recruitment. Recruitment began from November 2018 until a sample of 100 patients are enrolled.
The inclusion criteria are outlined below:
- The diagnostic criteria of COPD reference to Guidelines for the Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease（2013 Revision）[[i]]will be adopted as inclusion criteria for this trial;
- Patients with stable symptoms such as cough, sputum production or breathlessness for
- 4 weeks with no AE;
- The risk assessment of AECOPD is high risk（in the past 1 year, the number of AE is ≥ 2 times or being hospitalized is ≥ 1 time due to AE);
- the TCM syndrome pattern of lung qi and spleen qi deficiency, reference to Guidelines for TCM Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease（2011 edition）[[ii]];
- aged between 40 and 80 years;
- with informed signed consent and participate voluntarily in the study.
Exclusion criteria include the following:
- confirmed diagnosis of Pneumonia and/or moderate to severe AECOPD in the past 4 weeks;
- Accepted Pneumonectomy in the past or Lung volume reduction surgery in 12 months before screening;
- Accepted long-term oxygen therapy（time > 15h / d）or mechanical aerator;
- Patients with a history of asthma, active tuberculosis, lung cancer, bronchiectasis, pulmonary embolism, pulmonary heart disease, interstitial lung disease or other active diseases;
- Patients with lower extremity activity limitation are unable to complete the six-minute walk test;
- Patients were diagnosed with serious hypertension, diabetes, tumors, primary heart, liver, kidney or blood system disease;
- Scr exceeds the upper limit of the reference value by 1.5 times, or AST, ALT ≥ 2 times the upper limit of the reference value;
- Patients with congenital or acquired immunodeficiency disease;
- Patients who are known or suspected of a history of alcohol or drug abuse;
- Patients with confusion, dementia or any kind of mental illness;
- Pregnant or breast-feeding women;
- Allergic to the used medicine;
- Frequent use of glucocorticosteroids orally;
- Patients were enrolled in other clinical trials during the previous three months;
- Researchers believe that who is not appropriate to participate in clinical trials.
Withdrawal, dropout and discontinuation
Participants are free to withdraw at any time during the trial. Participants who wish to withdraw will be offered the option to cease trial medication but continue attending scheduled visits for outcome measurement. Participants who withdraw will be followed to investigate the reason for withdrawal. Participants may be advised to discontinue the treatment if there is a product-related adverse event of a serious nature or if the participant was not compliant with the study requirements. Discontinuers will not be replaced by new participants. Intention-to-treat analysis will be performed on missing data from discontinuers with the last observation carried forward method.
A total of 100 patients will be enrolled into this study with 50 in each group, respectively. The frequency of acute exacerbation of COPD is considered as the primary outcome. According to a previous study[[iii]][[iv]], the number of the exacerbation frequency was 1.17 times every year by treatment of conventional medicine, and that was 0.97 times every year by treatment of TCM, and that was 0.68 times every year by treatment of both conventional medicine and TCM. Assume that there would be promotional value only when the exacerbation frequency decreased at least once for one patient every six months. The standard deviation（SD）value is 1 .25 times per year，the two-sided α is 0. 05，and β is 0. 10. Based on the formula (Due to technical limitations, the formula has been placed in the supplementary files section) of the comparison between the means of the two samples, the sample size in each group is 40. Considering a 20% dropout rate over the course of the study, 50 patients will be enrolled in each group and the total sample size will be 100.
Randomization and masking
Randomization The block randomization method was used. Select the appropriate length of the segment, and use the SAS9.4（SAS Institute Inc., Cary, NC, USA）to generate a randomization sequence for 100 subjects（test group, control group) according to a 1:1 ratio, and list the treatment allocation corresponding to the serial number 001-100（That is a random coding table). The placebo is made of SHGBZK Chinese medicine（5%） and dextrin（95%）to insure the mimic appearance, smell, and taste. Both researchers and participants will not know the assignment. The randomization sequence table will be kept in a file. The method, process, group setting, and grouping result of the randomization sequence will be recorded either, so as to be checked when necessary. The information on intervention assignments will be kept in the third consulting center of biomedical statistics.
Blind Blind Design: In this study, the two stage blind was used. The first stage blind was represented by groups A and B. The second stage blind was respectively designated with the corresponding test drugs and placebo; The blind management and preservation: The blinding is carried out by the statistical unit. The clinical trial unit and the statistical analysis unit are respectively deposited in accordance with the relevant regulations after the blind sealed. The process of drug coding will be written by the blinder and saved; Emergency unblinding: if adverse event occurs during the study, the main investigator can decide whether to unblind according to the subject. The investigator needs to record the time, location and cause of the unblinding, and record in the medical record and CRF（the group information after unblinding should not be recorded in the CRF).
The two groups will receive basic treatment for COPD according to the 2017 GOLD Guidelines for Chronic Obstructive Pulmonary Disease. Patients will stick to the treatment they used to take as much as possible, and will be given present general treatment when AECOPD occurs during the study. Patients in the experimental group will take SHGBZK, while the control group will take SHGBZK placebo. The TCM granules are compound preparations of Chinese herbs and its main components are shown in Table 1. Each bag of SHGBZK granule（batch number: 180606）contains 3 g. The components of the TCM granules are produced and packed by An Hui Ji Ren Pharmaceutical Co. Ltd. with the authentication quality of Goods Manufacturing Practice（Approval Number: AH20160363), Anhui, PR China. The test results of drug quality were consistent with the required quality standards. Each type of granule will be given orally, four bags each time, three times a day for 24 weeks.
Patients need to take medication as directed by the doctor from us. The use of glucocorticoids, antibiotics, mucolytic agents and antitussive agents was prohibited during the study except there is AECOPD, and oral or external Chinese medicine preparations with the effect of tonifying spleen and lung were prohibited during the trial period.
Primary outcome measure
The frequency of AECOPD is the primary outcome measure. AECOPD is characterized by increased respiratory symptoms, which is beyond daily routine variation, and requires a change in regular medication. Its reductions are a major goal of COPD management and an important indicator for evalu-ating the treatments. If at least 2 major symptoms or 1 major symptom plus more than 1 minor symptoms occur: ① Major symptoms: increased difficulty in breathing, increased sputum volume, purulent sputum; ② Minor symptoms: upper respiratory tract infection, unexplained fever, and wheezing. If the interval between two onsets of acute exacer-bation is within 1 week, and the acute exacer-bationand last for at least 2 days, it is counted as one number acute exacerbation. The number of frequency and duration of AECOPD occurred each time during the 24-week treatment period and 7-month follow-up, and then count the total number and average number of frequency and duration.
The secondary outcome measures
AECOPD situation Time of first AECOPD occurs, the interval between two onsets of acute exacer-bation, the duration of AECOPD and the severity of AECOPD after the treatment.
TCM symptom score TCM symptom of COPD patients at stable stage that diagnosed with syndrome of deficiency of lung qi and spleen qi will be adopted. The TCM symptom score scale is scored from 0（normal）to 22（severe. TCM symptom score is shown in Table 2.
Lung function The indicators of forced vital capacity（FVC), forced expiratory volume in 1 s （FEV1）, forced expiratory volume in 1 second（FEV1% pred） and（FEV1/FVC); maximum expiratory mid-flow（MMEF）and peak expiratory flow（FEF）will be tested. A positive change from baseline in them will indicate the improvement in lung function.
Dyspnea The Modified Medical Research Council（MMRC） by the American Thoracic Society  will be assessed to evaluate the level of dyspnea. The MMRC scale is a simple grading system that scored from 0（less severe）to 4（severe).
Quality of life The COPD Assessment Test（CAT）will be adopted. The CAT is the self-complete questionnaires with eight items, each formatted as a semantic six-point ranging from 0 to 5. Range of CAT scores from 0 to 40. Higher scores denote a more severe impact of patient’s quality of life. The patients will be invited to complete the questionnaires through face-to-face survey. The patients can answer each question and check the most appropriate opinion（a specific score） in their standards, hopes, pleasures, and concerns. Meanwhile, an investigator in each center will be assigned in the office to help the patients, and to check through each completed questionnaire to ensure that the patients answer all the questions.
The 6-minute walking distance（6MWD）This is to evaluate the distance a person can walk on a flat surface in 6 min to assess the exercise capacity.
BODE index will be adopted. BODE stands for Body mass index, airflow Obstruction, Dyspnea and Exercise capacity. Range of BODE scores from 0 to 40. The BODE score was further quartilized as follows: quartile 1（a score of 0 to 2 points）, quartile 2（a score of 3 to 4 points, quartile 3（a score of 5 to 6 points, and quartile 4（a score of 7 to 10 points. The higher the level, the worse the patient's condition.
Concomitant medication status. Drug therapy that used to treat COPD during the study will be recorded.
Mortality All-cause mortality and COPD mortality will be calculated for the subjects during the study.
Safety The routine blood, urine, and stool tests, liver and kidney function tests, and an electrocardiogram are performed. Adverse events will be recorded at any time during the treatment period and follow-up period.
Screening and run-in, baseline, treatment periods and endpoint
The Adverse event, Physical examination, AECOPD situation, MMRC, CAT and TCM symptom score will be recorded at baseline（week 0, in the every 4weeks during the study period. The 6MWD and BODE will be recorded at weeks 0, 4, 12, 24, 32 and 52. The lung function will be observed at weeks 0, 24, and 52. Safety will be measured at weeks 0 ,12and 24, except Adverse event and Physical examination. The schedule of the assessment and interventions is depicted in Figure 2.
All data will be analyzed by an independent statistician using SAS 9.4. For all analyses, P < 0.05 is considered statistically significant. Measurement data will be presented as number of cases, mean, standard deviation, minimum, median, maximum, upper quartile（Ql）, lower quartile（Q3）, 95% confidence interval（95% Cl）data. The paired-sample t test or signed rank sum test will be used to compare the difference between the two groups or pretreatment and posttreatment within one group. The analysis of covariance will be used to compare the differences of center effector other confounding factors.