Table of Contents
This study is a prospective, parallel-group randomized, controlled, exploratory clinical trial. Participants will be recruited from the Guangdong Provincial Hospital of Chinese Medicine Clinic. They are outpatients attending a clinic or inpatients being discharged home and evaluated by two experienced respiratory physicians. Patients are invited to meet with the research physicians to discuss any remaining questions and sign the informed consent. Thereafter, the participants are randomly assigned to either the trial or control group as a ratio of 1:1. The trial group will receive PR integrated with coached exercise training. The control group will receive a traditional PR program. Owing to the exercise intervention, it is not possible to blind participants or those involved in the provision of care. However, the researchers collecting primary data and performing statistical analyses will be blinded to the allocation. The design is open label with only outcome assessors and data analysts being blinded, so unblinding will not occur. The study design is shown in Fig. 1.
We will include participants aged between 40 and 80 years, diagnosed with COPD (a post-bronchodilator FEV1 < 70% and < 80% of predicted normal values), who are clinically stable, have not experienced an acute exacerbation for at least 4 weeks before the trial, do not participate in systematic exercise training in the past 6 months, and have a 6-min walk test (6MWT) distance between 350 and 550 m.
We will exclude participants with severe comorbidities, including coronary heart disease, arterial aneurysm, severe hepatic and renal dysfunction, and uncontrolled hypertension. Patients with mental diseases, deafness, limb activity disorder, and inability to cooperate are also excluded from the trial.
Patients can leave the study at any time for any reason. Intervention can also be ended by the investigators if the patient is uncooperative and does not attend study visits. This study will be ended in case of any abundance in adverse events or procedure-related complications.
A list of random numbers is generated using IBM SPSS statistical software (version 23.0). Hence, every participant will match a number and the information is blind to other trialists. Opaque envelopes containing a number are used to randomly assign participants to either the trial or control group. Two trialists will generate the allocation sequence and assign participants to interventions together.
Sample size calculation
For the primary outcome, a change of 25 m in the 6-MWT distance is considered to be the minimal important difference (MID) in patients with COPD , based on a two-sample independent t-test with a given MID of 25 m, standard deviation of 44.6 m, power of 80%, and significance level of 0.05 . Accordingly, the calculated sample size of each group is 50. Assuming a dropout rate of 15% resulted in 18 patients being included in the final study population.
After baseline data collection, the patients will be randomly divided into the trial or control group. Participants in both the groups will receive usual care, and PR included health education, nutrition guidance, psychological support, and exercise training [6, 18]. The intervention will be performed three times per week for 12 consecutive weeks. The only difference in intervention between both groups is the exercise training.
In the control group, exercise sessions, which mostly included walking and swimming, lasted for at least 30 min, three times a week, with a weekly follow-up. In contrast, patients in the trial group will receive exercise training guided by a sports coach, which lasts for 60 min, once a week at the hospital, and for 30 min, twice a week at home, conducted through a video. Exercise training for the trial group consists of warm-up exercise, aerobic exercise, resistance exercise, respiratory rhythm adjustment, and respiratory muscle training.
Warm-up exercise is based on Baduanjin combined with lip-constricted breathing and abdominal breathing. Baduanjin is a traditional Chinese physical exercise that involves mild exercise and respiratory regulation .
Considering the tolerance of patients with COPD, sports coaches integrate aerobic exercise into a set of aerobics. Aerobics include eight movements and could be performed in the standing or sitting position according to the patient’s condition. Each movement is performed in 4–6 sets of 8–16 repetitions. Between each set, there is a break of 10 s. If the patient is unable to tolerate the exercise, the break time could be extended.
Resistance training could also be performed while standing or sitting. The sports coach integrates resistance exercises into a set of aerobics, including eight movements with a stretch belt (1.5 m, 22 pounds). Each movement consists of 4–6 sets of 8–16 repetitions. Between each set, there is a break for 10 s. If the patient is unable to keep up, the break time will be extended.
Respiratory muscle training
Patients receive respiratory muscle training through abdominal breathing, wherein the abdomen gently puffed-up during inhalation and sank during exhalation. A sandbag weighing 5 kg will be placed on the abdomen, followed by abdominal breathing for 3 min.
Respiratory rhythm adjustment
Patients breath is through the nose and breath out through the mouth slowly. Respiratory rhythm adjustment runs through the training.
In both groups, each patient has an exercise log, which is completed by a supervisor who instructed the sessions online. The exercise log contains adverse events, completed exercises, and a record of vital signs before and after exercise.
Outcome measures and follow-up
Data on the outcomes will be collected at baseline and after 12 weeks. Patients are followed up weekly in the outpatient department or through online methods, including telephone and WeChat. The primary outcome measure is exercise tolerance using the 6-MWT. Secondary outcomes are the peak oxygen uptake (V̇O2) of cardiopulmonary exercise tests, the COPD Assessment Test (CAT), and the St. Georges Respiratory Questionnaire (SGRQ). Other outcomes include changes in postbronchodilator forced expiratory volume at 1st second (FEV1), forced vital capacity (FVC), body fat and muscle composition, mental status measured using the Hamilton rating scale for depression scores (HAMD-24) and the Hamilton Anxiety rating scale (HAMA).
The investigator will inquire about the occurrence of adverse events. The details of every adverse event will be reported in the case report form (CRF). The same investigator will record all outcome measures to maintain standardization in the procedure.
6-min walking test
This test measures the distance a participant can walk in 6 min. The patients will be instructed to walk as far as possible in 6 min and receive recommended standardized encouragement. Two tests will be performed on each occasion, and the best distance is recorded. A 30-min rest will be mandatory between the first and second 6-MWT [20, 21].
Peak oxygen uptake of cardiopulmonary exercise tests
Cardiopulmonary exercise testing (CPET) will start with an initial rest of 3 min, followed by unloaded cycling for 3 min and a subsequent increment of 5–15 W after each minute. The aim is achieving a total exercise performance time of 8 to 12 min. Patients are asked to maintain a pedaling frequency of 50–60 rpm on a cycle ergometer (SCHILLER CS-200 Ergo- Spiro, Switzerland). If the patients display symptoms such as unsustainable dyspnea or leg fatigue, chest pain, ECG-significant ST-segment depression, and a drop in systolic blood pressure or oxygen saturation (SpO2) ≤ 84%, the test will be stopped. V̇O2 will be recorded as the mean value of VO2 during the last 20 s of the test. VO2 will be expressed both as an absolute value (l/min) and in terms of mL/kg/min [22, 23].
COPD Assessment Test (CAT)
CAT is a patient completes an 8-item questionnaire that assesses the impact of COPD on self-reported health status and symptoms . Each item is scored from 0 to 5 points (0 indicating no impact or symptoms and 5 indicating the worst possible impact or symptoms) summing up to a total CAT score in the range of 0–40 points.
St. Georges Respiratory Questionnaire
The SGRQ is a self-administered questionnaire designed to measure self-perceived impairments in health and quality of life in individuals with airway diseases . The three component scores of the questionnaire, including symptoms, activity, and impact (on daily life) were calculated, giving a total score between 0 and 100, wherein 0 indicates good health and 100 indicates very poor health.
Pulmonary function testing
Pulmonary function tests are performed by spirometry using the same machine and the same technician for all patients according to international recommendations [26, 27]. A flow-sensing spirometer and a body plethysmograph connected to a computer (Master Screen Diffusion Combined Pulmonary Function Tester, Jaeger, Germany) will be used for the measurements.
Body fat and muscle composition
Body fat and muscle composition will be measured using multifrequency bioelectrical impedance analysis (BIA) via a body composition analyzer (InBody 770, Biospace Co Ltd, Seoul, South Korea). The participant stands barefoot on the platform of the device with the soles of their feet on the electrodes. The participants then grasp the handles of the unit with their thumb and fingers to maintain direct contact with the electrodes and stood still for 1 min while maintaining their elbows at full extension and shoulder joints abducted to approximately 30° angle. During the assessment, BIA analyzers introduce a small electrical current into the body and measure the resistance or impedance to the current flow to calculate skeletal muscle, fat content, and other components of the body. Data on total body composition, body fat percentage, muscle mass, and bone mass will also be collected.
Hamilton Rating Scale for Depression (HAMD-24) and Hamilton Anxiety rating (HAMA) scales
HAMD-24 and HAMA are used to evaluate depression and anxiety levels of participants . The HAMD scale includes 24 problem items, which can be classified into seven-factor structures: anxiety/somatization, body mass, cognitive impairment, day-night change, block, sleep disturbance, and sense of hopelessness. A total score of ≥ 8 indicates that the patient has positive depressive symptoms. The HAMA scale contains 14 items, most of which can be scored on a 0–4 scale.
The study will last for 3 years. Recruitment of patients started in March 2021. Baseline information including sex, age, body mass index, and history of smoking will be collected at the beginning. Vital signs including blood pressure, heart rate, oxygen saturation, and respiratory rate are collected every week during the period of intervention to evaluate safety. Outcome data are collected before intervention and at 12 weeks. The protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 . And A brief SPIRIT flow diagram is shown in Table 1. A populated SPIRIT checklist is provided in Additional file.
Adverse event reporting
Adverse events will be recorded in CRF (Case Report Form). Serious adverse events will be reported within 24 h to the principal investigation and Institutional Review Board. The steering committee consists of a pulmonologist and a respiratory nurse who will survey the study procedure and evaluate serious adverse events. The steering group is the trialists of this study. If there is any damage related to the study, the research group will pay the medical expenses and make corresponding financial compensation according to laws and regulations.
Data management and statistical analysis
Researchers will make appointments for the next follow-up to promote participant retention. Data will be collected in the CRF on paper by the same investigator. All the CRF on paper will be stored in a locked cabinet. Access to the data sets is only available to the investigators in this study. Incomplete data of patients who are lost to follow-up for various reasons will be eliminated. Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine makes a visit per year and checks the presence and completeness of the investigation file. All substantial amendments will be notified to the Committee, and non-substantial amendments will be recorded.
Outcome measures will be analyzed using a t-test at the end of the trial. IBM SPSS statistical software for Windows (Version 23.0) is used to analyze the data for the outcome measures. Data is presented as the mean and standard deviation.
Results of this research will be disclosed completely in international peer-reviewed journals. Both positive and negative results will be reported.