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Effectiveness of a home-based and remotely
supervised telerehabilitation program for COVID-19
survivors (TERECO): Study protocol for a
randomized controlled trial
Team leader unit: Jiangsu Provincial People's Hospital
Principal Investigator: Li Jianan
Department: Center for Rehabilitation Medicine
Contact number: +86-13705161766
Participating Units: Jiangsu Provincial People's Hospital,
Hubei Hospital of Integrated Traditional Chinese and Western
Medicine, Huangshi City Hospital of Traditional Chinese Medicine
Research period: April 2020-December 2020
Version number: V1.9
Version date: April 20, 2020
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Note on the translation: This protocol has been developed in simplified Chinese
(Hanyu, mainland China) apart from sample size calculation and statistical procedures
(first developed in English by Jan D, Reinhardt, Sichuan University). This translation
was conducted by Jiayue Wang and Shouguo Liu (both Nanjing Medical University).
English language was edited for wording and grammar by Jan D. Reinhardt (Sichuan
University). This English version was then again cross-checked for accuracy and
consistency with regard to the Chinese version by Jiayi Zhang (Shuangliu People’s
Hospital, Chengdu).
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Summary of protocol
Title of
Research
Effectiveness of a home-based and remotely supervised telerehabilitation
program for COVID-19 survivors (TERECO)
Study
objective
To determine immediate and sustained treatment effects of a
telerehabilitation program as compared to control on cardiorespiratory
endurance, dyspnea, pulmonary function, lower limb muscle strength, and
quality of life in discharged patients with coronavirus disease 2019
(COVID-19).
Study design Design: Assessor-blinded, prospective randomized-controlled, trial with
1:1 allocation ratio based on stratified block randomization.
Sample size
96 patients (48 per group) are needed to detect MID of 50 meters for 6
minute walking distance (sd[control]=99, sd[intervention]=71), with
80% power at 5% alpha error With estimated attrition rate of 20%
recruitment target is 120 (60 per group).
Eligibility
criteria
Inclusion criteria
1.Patients with COVID-19 discharged from hospital; 2. With dyspnea
symptom (mMRC 2~3); 3. 18~75 years of age; 4. Possession and ability to
use smart phone (study subjects or family members); 5. Obtained informed
consent from participant or legal representative and signed informed
consent form.
Exclusion criteria
1. Resting heart rate>100bpm; 2. Taking drugs which affect
cardiopulmonary function or heart rate (such as: trimetazidine, salbutamol,
beta-blocker); 3. Combined uncontrolled chronic disease, such as
uncontrolled hypertension (resting BP≥160/100mmHg), uncontrolled
diabetes (random blood glucose>16.7 mmol/l, HbA1C>7.0%); 4.
Combined severe organic disease, such as unstable hemodynamic heart
disease, heart failure with limited movement (previous diagnosis, or
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having clinical symptoms of heart failure, after consultation by
cardiologist), unstable angina, MI within past 12 months or other cardiac
diseases; 5. Cerebrovascular disease that occurred within the past 6
months; 6. Active stage of digestive ulcer, thyroid dysfunction, or active
tuberculosis; 7. Chronic kidney disease >=stage 3 (eGFR<60ml/min); 8.
Having received intra-articular drug injection or surgical treatment in
lower extremities within past 6 months; 9. Poor compliance, unable to
cooperate with assessment or training; 10. Unable to walk independently
with auxiliary; 11. Diagnosed with mental disease that prevents patients
from living independently or receiving treatment; 12. Alcohol abuse or
illegal drug use history; 13. Pregnancy, nursing or preparing for pregnancy
(including male subjects); 14. Having participated in other clinical trials
within the past 3 months or currently enrolled in other clinical trial. 15
Enrolled in other rehabilitation program.
Interventions
Control group: Receives educational instructions for daily living at
baseline.
Experimental group: Participates in 6-weeks, home-based, remotely
monitored exercise program for cardiopulmonary rehabilitation, delivered
via smartphone (R+ health app software) at 3-4 sessions per week.
Exercises types include breathing control and thoracic expansion, aerobic
exercise, muscle strength exercise. Exercise difficulty, intensity, and
duration is scheduled to increase over time.
Outcome
assessment
Effectiveness evaluation index (primary efficacy index and secondary
efficacy index)
Primary indicator: Cardiopulmonary endurance operationalized as 6
minutes walking distance in meters according to 6 minutes walking test
(6MWT). Secondary indicators: Pulmonary function measured with
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spirometry, dyspnea measured with modified Medical Research council
scale (mMRC), lower limb muscle strength measured with squat test
(squat in seconds), quality of life measured with Medical Outcomes Short
Form-12 (SF-12). Assessment procedures: Assessments will be performed
at home visits at three time points: Baseline (before randomization), 6
weeks, 24 weeks.
Additional assessments: Adverse events and serious events (both groups),
safety evaluation index (exercise group).
Statistical
methods
Primary outcome will be evaluated on intention to treat basis with
constrained longitudinal data analysis (linear mixed effects regression with
random intercept). Secondary outcomes pulmonary function parameters,
squat time in seconds, and SF-12 are evaluated as primary outcome.
Dyspnea mMRC score (favorable outcome) will be analyzed with
longitudinal data analysis for binary outcomes (logistic mixed effects
regression with random intercept). Main analysis will be performed
adjusted for center (fixed part) and on unimputed data. Sensitivity analyses
will be performed on multiply imputed data. In addition, analysis of the
per protocol sample will also be performed. Proportions for occurrence of
adverse events in both groups will be provided: overall, during
intervention, and during follow up period.
Research
duration 8 months
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1. Background
As of the time of writing this protocol, the number of confirmed COVID-19 cases in
China is 81,118, the death toll is 3,231, and the mortality rate is 3.9%. COVID-19 has
been identified as a global pandemic by the WHO. Main clinical manifestations of
patients with COVID-19 include respiratory complications and impaired
cardiopulmonary function. Patients often present with fever, cough, sputum
expectoration, dyspnea, shortness of breath after physical exertion, which may be
accompanied by respiratory muscle weakness and impaired lung function1-3
. At
present, clinical interventions are mainly targeted at maintaining vital signs, treatment
of pneumonia, and improving symptoms .
Assessment of cardiopulmonary function of patients with Covid-19 is not
included in current clinical discharge standards. However, due to functional damage
to the lungs caused by severe acute respiratory syndrome coronavirus 2 (SARS Cov-2)
as well as decrease in muscle strength and decrease in cardiopulmonary function
caused by long-term bed rest, patients may not be able to recover fully until discharge
from hospital. After discharge, many patients with COVID-19 will thus likely still
experience health problems and disability such as respiratory dysfunction, insufficient
cardiorespiratory endurance, limitations in activities of daily living, and participation
restrictions. With its effectiveness having been demonstrated in chronic respiratory
disease4-6
as well as SARS7, cardiopulmonary rehabilitation could be an effective
means to address those problems8.
Given the current pandemic situation and corresponding risk of disease
transmission, institution-based in- and outpatient rehabilitation is however a limited
option. Home-based exercise has gradually become a more and more accepted
alternative in physical therapy and sports rehabilitation9-11
. Compared with traditional
outpatient rehabilitation, home rehabilitation allows more flexible timing, requires
less space, and entails lower overall medical costs. However, three core issues need to
be considered when implementing home-based exercise programs: 1) Individual
prescription of appropriate exercise type and intensity based on professional
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assessment, 2) guidance through the exercise rehabilitation program including
measures to improve adherence, and 3) monitoring of patient safety during exercise.
Addressing these issues involves the integration of clinical resources including health
care professionals and clinical practice guidelines with innovative software solutions12
.
Based on these principles, we developed a telerehabilitation program for COVID-19
survivors (TERECO) comprising a smart-phone application, remote monitoring
techniques, and tele-consultations with clinicians in order to provide a low-cost, safe,
effective, and easy-to-operate means for patients to recover at home.
2. Study objective
2.1 Main purpose: To evaluate the immediate (post-intervention) and sustained
(longer-term) effectiveness of TERECO with regard to improvements in exercise
capacity, pulmonary function, dyspnea, lower limb muscle strength, and quality of life
in discharged patients with coronavirus disease 2019 (COVID-19).
2.2. Additional purposes: 1)To monitor occurrence of adverse events in both groups.
2) To evaluate the feasibility of TERECO in terms of design (e.g. appropriateness of
exercise specifications), safety (unintended side effects) of and compliance.
3. Research design types, principles and trial procedures
3.1 Research Design
This is an assessor-blind, randomized-controlled, prospective trial. Allocation ratio to
parallel groups will be 1:1. The random sequence will be computer generated.
Block-randomization stratified by study center will be used. Allocation sequence as
well as block size will be permutated (the latter within the range of 10 to 14).
Allocation will be concealed by central randomization. To ensure assessor blinding
allocation will only be revealed after baseline assessment and after assessors have left
the study site. In practice, each baseline visit will involve two research assistants: an
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assessor and an allocator. Assessors will be rehabilitation doctors who are not
otherwise involved in intervention delivery and monitoring in this trial. Allocators are
therapists who are responsible for intervention delivery including installation and
explanation of the software for patients allocated to the intervention group. To ensure
trust of the patients in the allocation procedure allocators will carry an envelope with
the random number according to the block sequence. Once the assessor has left this
envelop will be opened together with the patient and a call to the allocation center will
be made to reveal group allocation. Patients and those responsible for intervention
delivery and monitoring are requested to not communicate group allocation to
assessors.
Sample size calculation: Sample size is calculated for the primary outcome 6
minute walking distance (6MWD) measured with 6 minutes walking test (6MWT). A
systematic review on measurement properties of field walking tests conducted by the
European Respiratory Society and American Thoracic Society13
found a median
minimal important difference (MID) of 30 meters for the 6MWT (range 22-57 meters)
across studies using anchor- or distribution-based approaches in different lung disease
including COPD, pulmonary arterial hypertension, and interstitial lung disease. Since
an MID for 6MWT in COVID-19 has not been established at the time of the
development of this protocol and learning effects may also occur - particularly in the
exercise group, a larger and thus more conservative MID of 50 meters is assumed
here. We further assume a standard deviation of change in 6MWD over six weeks of
99 meters in controls and 71 in the intervention group as reported in a previous trial
on the effectiveness of an exercise program in SARS survivors7. The assumption of a
greater standard deviation in controls makes sense in so far as a greater variety of
outcomes can be expected in this group due to greater variations in disease course and
environmental influences as these are not influenced by a targeted intervention. With a
power of 80% and an alpha error of 5% this yields a sample size of 96 participants
respectively 48 per group to detect a statistically significant signal for a difference in
change in 6MWD between groups with an independent samples t-test. This
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corresponds to power analysis for ANCOVA or constrained longitudinal data analysis
for high correlations (r>=0.8) between repeated measurements 14 15
. An assumption of
such high correlation is conservative and justified given that we have no previous
knowledge about the effectiveness of similar interventions in the target population.
Assuming an attrition rate of 20% our recruitment target is 120 participants or about
60 per group.
3.2 Research Steps
1) The experimental group uses exercise rehabilitation software (R+ health app)
installed on smartphone and a remote monitoring device with remote monitoring
during exercise performance for 6 weeks of cardiopulmonary rehabilitation; the
control group is given one time educational instructions;
2) A total of three evaluations is planned: baseline evaluation, post-treatment
evaluation after 6 weeks, and follow-up evaluation after 24 weeks;
3) Both exercise and control group are followed up every two weeks during the
intervention period to record dyspnea symptoms and prompt for adverse events that
may have occurred.
4) The exercise group is followed up every week to record problems and discomfort
related to the exercise program, evaluate progress, and modify the exercise program
for individual patients if necessary.
5) Outcome data will be analyzed after conclusion of the final follow up assessment
and no interim analyses will be performed apart from those relating to monitoring of
adverse events.
4.Eligibility criteria
4.1 Inclusion criteria are as follows: 1.Patients with COVID-19 (confirmed SARS
CoV-2 infection) discharged from hospital; 2. With dyspnea symptom (mMRC 2~3);
3. 18~75 years of age; 4. Possession and ability to use smart phone (study subjects or
family members); 5. Obtained informed consent from study participant or legal
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representative and signed informed consent form.
4.2 Patients will be excluded under the following conditions: 1. Resting heart
rate>100bpm; 2. Taking drugs which affect cardiopulmonary function or heart rate
(such as: trimetazidine, salbutamol, beta-blocker); 3. Combined uncontrolled chronic
disease, such as uncontrolled hypertension (resting BP≥160/100mmHg), uncontrolled
diabetes (random blood glucose>16.7 mmol/l, HbA1C>7.0%); 4. Combined severe
organic disease, such as unstable hemodynamic heart disease, heart failure with
limited movement (previous diagnosis, or having clinical symptoms of heart failure,
after consultation by cardiologist), unstable angina, MI within past 12 months or other
cardiac diseases; 5. Cerebrovascular disease that occurred within the past 6 months; 6.
Active stage of digestive ulcer, thyroid dysfunction, or active tuberculosis; 7. Chronic
kidney disease >=stage 3 (eGFR<60ml/min); 8. Having received intra-articular drug
injection or surgical treatment in lower extremities within past 6 months; 9. Poor
compliance, unable to cooperate with assessment or training; 10. Unable to walk
independently with auxiliary; 11. Combined mental disease that prevents patients
from living independently or receiving treatment; 12. Alcohol abuse or illegal drug
use history; 13. Pregnancy, nursing or preparing for pregnancy (including male
subjects); 14. Having participated in other clinical trials within the past 3 months or
currently enrolled in other clinical trial. 15 Enrolled in other rehabilitation program..
4.3 Termination criteria
If conditions occur for a study participant that make it unsuitable to continue the study,
including: exacerbation of disease, serious adverse events, safety concerns regarding
performance of exercise, new development of a health condition or symptoms listed
under exclusion criteria, withdrawal of consent, poor compliance with assessments,
etc., the study will be terminated for this patient.
If serious adverse events (death; or re-hospitalization related to the intervention or
the studied disease) or uncontrolled disease progression occur in 10 percent or more
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of the study participants, the study will be terminated.
5. Research methods and technical routes
5.1 Intervention plan
Both groups will be given advice on lifestyle and measures to reduce the risk of
disease transmission, in personal consultation with the responsible doctor and in the
form of a respective patient instruction sheet. The experimental group will receive
remote monitoring and rehabilitation software installed on their smartphone as well as
hardware equipment (heart rate monitoring device) for the duration of the home
exercise intervention (6 weeks). Online follow-up (online survey and telephone
follow-up) will take place every 2 weeks during the intervention period,
post-treatment evaluation of outcome indicators will take place after 6 weeks, and
follow-up evaluation after 24 weeks.
5.2 Exercise prescription for test group
The experimental group (6 weeks remote exercise group) will be provided with
remote monitoring and rehabilitation software (R+ health app), and formulated
cardiopulmonary rehabilitation prescriptions based on the ACSM guideline for
exercise prescriptions16
and the 2019 new coronavirus pneumonia respiratory
rehabilitation guidelines (second edition) of the national health commission of China8.
The rehabilitation program of the experimental group includes respiratory function
training, cardiopulmonary endurance training, and lower limb muscle strength
training, for a total of 6 weeks, training 3-4 days a week. Apart from the schedule,
decisions upon suitability for patients to progress to a higher level of exercise are
based on patient feedback, data from remote monitoring of exercise performance, and
weekly consultations of patients in the exercise group with therapists. Exercise plans
may also be adapted and specific exercises could be replaced for individual patients
should difficulties arise. The overall schedule is given in Table 1.
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Table 1: Overview of exercise prescription for patients
Week Exercise type Exercise names Target
duration Sessions/week
Week 1&2
Breathing control
and thoracic
expansion
1.1 Reclined seated
diaphragmatic breathing
1.2 Open chest, thoracic spine
extension (seated)
6 mins
3-4 sessions/week Aerobic 2. Brisk walking or running 20 mins
Lower limb
strengthening
3.1 Seated unilateral hip
abduction and adduction
3.2 Seated leg lifting
3.3 Seated forward toe tap
6 mins
Week 3&4
Breathing control
and thoracic
expansion
1.1 Reclined seated
diaphragmatic breathing
1.2 Open chest, thoracic spine
extension (seated)
6 mins
3-4 sessions/week Aerobic 2.Brisk walking or running 25 mins
Lower limb
strengthening
3.4 Knee to chest walk
3.5 Toe stand and hold
3.6 Mini squat (with chair)
6 mins
Week 5&6
Breathing control
and thoracic
expansion
1.1 Reclined seated
diaphragmatic breathing
1.3 Open chest, thoracic spine
extension (standing position)
1.4 Bend over rowing and arm
extension (dumbbells)
9 mins
3-4 sessions/week
Aerobic 2.Brisk walking or running 30 mins
Lower limb
strengthening
3.7 Squat
3.8 Alternating lunge and
shoulder flexion
3.9 Sideward lunge
9 mins
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Figure 1: Pictures of typical exercise positions and aerobic exercise monitoring
1.1 1.2 1.3
1.1 Reclined seated diaphragmatic breathing; 1.2 Open chest, thoracic spine extension (seated); 1.3
Open chest, thoracic spine extension (standing position);
1.4 2. 3.1
1.4 Bend over rowing and arm extension (dumbbells); 2. Monitoring of risk walking or running; 3.1
Seated unilateral hip abduction and adduction;
3.2 3.3 3.4
3.2 Seated leg lifting; 3.3 Seated forward toe tap; 3.4 Knee to chest walk
3.5 3.6 3.7
3.5 Toe stand and hold; 3.6 Mini squat (with chair); 3.7 Squat
3.8 3.9
3.8 Alternating lunge and shoulder flexion; 3.9 Sideward lunge
1) Principles of respiratory function training
The main measures of respiratory rehabilitation include breathing control and thoracic
expansion training. In the first two weeks of exercise, the main body position is sitting,
which gradually transitions to standing position from the third week on. According to
the 2019 Novel Coronavirus Pneumonia Respiratory Rehabilitation Guidance (second
edition)8, and with reference to the traditional Chinese medicine technique Baduanjin,
14
a relevant breathing training action plan was developed. [Baduanjin is a traditional
Chinese Qigong exercise. This ancient exercise dates back to the Chinese Song
dynasty and involves breathing control, muscular relaxation and stretching, and
mental focus17
. Recently, a meta-analysis of 20 clinical trials, involving 1975 COPD
patients reported that Baduanjin has the potential to improve pulmonary function,
exercise capacity, and quality of life in COPD patients18
; added to English version for
clarification ]. See Table 1 and Figure 1 for detailed action plans.
2) Principles of aerobic exercise
The intensity of initial cardiopulmonary training will be determined according to the
Karvonen formula19
, Borg rate of perceived exertion and dyspnea rating scale (0-10)20
The target heart rate intensity of aerobic training falls within 30-60% heart rate
reserve (HRR). Starting from HRR at 30-40%, intensity and exercise duration are
gradually increased to 40-60%10
. See Table 2 for details. Appropriate resting periods
in between, and warm-up and cool-down exercises before and after training will be
scheduled.
Table 2 Aerobic exercise prescription:
Week %HRR RPE
（6~20分）
Effective exercise
time
(Minutes/day)
Total exercise
time
(Minutes/day)
Sessions/week
Week
1
30%≤ X＜
40% 11~13 14 20 3-4
Week
2
30%≤ X＜
40% 11~13 14 20 3-4
Week
3
40%≤ X＜
50% 11~13 19 25 3-4
Week
4
40%≤ X＜
50% 11~13 19 25 3-4
Week
5
40%≤ X＜
60% 11~13 24 30 3-4
Week
6
40%≤
X≤60% 11~13 24 30 3-4
15
3) Principles of lower limb muscle strength training
Lower-extremity muscle strength training includes multi-joints and weight-bearing
training, such as squat, sit to stand transferring, multi-direction lunges. These
exercises aim at improving muscle strength and endurance in lower limbs. As
respiratory function training, lower limb strength training is scheduled to move
gradually from exercises performed in sitting position to exercises performed standing
position (see Table 1 and Figure 1 for details).
6. Detection time points and observation items
6.1 Detection time points and location of main assessments: A total of three
assessments, initial assessment, re-assessment after 6 weeks and follow-up after 24
weeks will be conducted. All assessments will take place at the patients’ home or near
the patients’ home (main indicator).
6.2 Main indicator: 6-minute walking test
6.3 Secondary indicators: lung function, dyspnea degree mMRC, lower limb muscle
strength, quality of life evaluation form SF-12.
6.4 Compliance with exercise protocol: Total exercise time for a given day will be
determined as the time from opening to closing the smartphone rehabilitation
application as recorded by RehabApp. The time during aerobic exercise within which
the monitored heart rate reaches the target heart rate or above will be counted as
effective exercise time. Having reached at least two thirds (66.66%) of the scheduled
total AND effective target time in any given week for at least five of the six weeks
according to RehabApp records will be considered compliant with the protocol.
6.5 Adverse effects: As reported by patients during study period. Prompts for
occurrence of adverse effects will be included in the case record form for each major
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assessment point and 2 weeks and 4 weeks consultations during the first 6 weeks.
Spontaneous reporting by patient through phone or online is possible at any time.
7. Efficacy evaluation criteria
7.1 Main indicator: Total distance walked in meters according to 6 minutes walking
test
The primary outcome of this trial is change in distance walked in meters within six
minutes (6MWD) from baseline to 6 weeks (end of intervention program) assessed
with the 6-minutes walking test (6MWT). The 6MWT demonstrated good reliability
across different diagnostic groups with pulmonary conditions and good concurrent
validity with respect to peak exercise capacity and physical activity13 21
. Chinese
population norms for 6MWT are available22
.
Set up for the 6MWT will be as follows: The test will be performed in accordance
with guidelines from the European Respiratory Society/American Thoracic Society23
.
A parcours will be arranged in the patient’s residential district. The walking course
will be 30 meters straight, flat territory with every three meters marked by colored
tape. Two small cones will be placed at the turnaround point. Patients will be
instructed to walk as far as possible in 6 minutes. HR, arterial oxygen saturation
measured by pulse oximetry (SpO2), and perceived dyspnea (according to Borg’s
category ratio-10 scale20
) will be assessed before and after each 6MWT trial. If a
patient uses a walking aid in daily life (e.g., a rollator or a crutch), he/she will be
allowed to use that aid during the 6MWT. Patients will receive standardized
encouragement during the test as described in the guidelines for 6WMT from the
American Thoracic Association21
. The results will be recorded as six minute walking
distance (6MWD) in meters. If a patient can not complete the test, distance walked
until interruption will be recorded. If a patient cannot perform the test at all due to a
medical condition zero meters will be recorded.
17
7.2 Secondary indicators:
1) Change in 6MWD in meters from baseline to 24 weeks.
2) Pulmonary function will be evaluated by forced vital capacity (FVC), forced
expiratory volume in the first second (FEV1), the ratio of FEV1 and FVC
(FEV1/FVC), Peak Exploratory Flow (PEF), and Maximum Voluntary Ventilation
(MVV)24
assessed with a portable pulmonary function device according to the
guidelines of the American Thoracic Society25 26
After 15 minutes in resting state,
patients are instructed to inhale as deeply as possible and then to forcibly exhale into
the mouth piece of the device. No nose clip will be used during this procedure. Two
tests will be taken and the highest value recorded. Percent of predicted value for
FEV1, FVC, and FEV1/FVC will be calculated based on Global Lung Initiative
(GLI-2012) equations for South-East Asia27
. Percent of predicted PEF and MVV will
be calculated based on equations for mainland China provided by Mu and Liu28
.
3) Perceived dyspnea will be assessed with the modified Medical Research Council
scale (mMRC)29
. The mMRC is a patient-reported ordinal scale which distinguishes
five grades of dyspnea with 0 indicating no dyspnea and 5 indicating extreme
problems with breathlessness making it impossible to leave the house or occurring
while dressing or undressing. Given that patients will be included in this trial only if
they have baseline mMRC scores of 2-3, an mMRC score of zero is defined as a
favorable outcome.
4) Lower limb muscle strength and endurance will be measured with the static squat
test30
. Participants are asked to perform a squat with their back against the wall
starting from a standing position, feet flat on the ground, and approximating a 90°
angle at the hip and knees. The time in seconds participants can remain in this
squatting positions is recorded. Participants will be allowed to hold the hands of a
research assistant standing in front of them, for balance control and as a precaution to
avoid falls. When participants shift their weight so that the evaluator has to bear at
least some of the weight (pulling on the evaluators arms), the test will be terminated
and time taking stopped by the evaluator.
18
5) Quality of life will be evaluated with Short Form Health Survey-12 (SF-12)
Version 2 31 32
. Results of the SF-12 are commonly reported as two composite scores:
Physical Health and Mental Health Composite score, with higher score indicating
better health. SF-12 has been translated and validated for the use in China33
. Scores
will be standardized according to US norms32 34
for reasons of international
comparability and due to lack of general population reference data for mainland
China.
6) Occurrence of any adverse events during the intervention or follow up period will
be recorded as described below (point 8).
8. Clinical safety
The intervention measures in this study do not involve invasive operations and drug
treatments. All research subjects’ diagnostic criteria, treatment methods and drug
usage follow clinical guidelines to ensure that patients get the most benefit from
clinical treatment. If there is a conflict between the best clinical interest and the trial
process, the patient's interest shall be guaranteed first, and the trial shall be terminated
if necessary. Patients in the study group can actively report adverse events to the
responsible doctor at any time through the smart phone app or contact the responsible
doctor, clinical department, or researcher by phone or WeChat. Patients in the control
group can actively report adverse events by contacting the responsible doctor, the
clinical department, or the researcher by phone or WeChat. In addition, all patients
will be asked at 2 and 4 weeks telephone consultations, at the 6 weeks post-treatment
assessment and at 24 weeks follow-up assessment if any adverse events occurred
during the previous period. Researchers will make a detailed record of all adverse
events during the trial, including time of occurrence, symptoms, treatment methods,
and analysis of cause, and report them to the supervisory board, ethics committee,
clinical partners, and sponsors.
19
Measures to ensure the safety of subjects include:
8.1 The subjects in the intervention group will be remotely monitored while
performing exercise at home using heart rate telemetry. The intelligent software
system records and feeds back the patient's heart rate in real time. Once the heart rate
exceeds the upper limit of the target heart rate, the software will promptly remind the
patient to reduce the exercise intensity or stop movement;
8.2 The software will record the patient's effective exercise time, the rate of perceived
exertion after exercise, whether there is discomfort after the exercise and other related
data, and the patient's exercise data will be reviewed remotely online on a weekly
basis to fine-tune the program and replace inappropriate exercise activities; exercise
data will be reviewed immediately if any problems are reported by the patient.
8.3 The subject is equipped with a finger pulse oxygen saturation tester, and the
patient is required to record the finger pulse oxygen saturation before and after
exercise. In the case of blood oxygen saturation <90% or a decrease of > 4% from the
baseline value before or after exercise the software issues a warning and the patients
are advised to terminate training11
;
8.4 It is recommended that patients exercise with their family members being present.
Patients and family members are advised that if breathing difficulties increase
significantly or chest tightness, dizziness, pain, or other discomforts occur during
exercise, the exercise should be stopped immediately, help from family members and
medical attention should be sought, and the responsible doctor or researcher should be
contacted if symptoms persist.
8.5 All subjects (test group + control group) will be given written exercise precautions
and patient education materials.
20
9. Prevention, observation, and control of adverse events
Adverse events refer to untoward medical occurrences that arise after the subject
receives the intervention, but are not necessarily related to the intervention. If the
study participant has a pre-existing comorbid condition according to medical history
and physical examination, this condition should not be regarded as an adverse event
unless it changes in nature, severity, and relevance.
The intervention of this study includes a remote monitoring device (chest worn
heart rate recording device + smart phone application). The intervention measures do
not involve invasive operations and drug treatment. The diagnostic criteria and
treatment methods for all research subjects comply with clinical guidelines. Possible
adverse events may be related to the underlying disease itself or the intervention. In
the course of the trial, once a serious adverse event occurs, relevant treatments should
be carried out immediately to minimize the impact of the adverse event on patients
and their families; referral and treatment seeking will be facilitated by the study
personnel and responsible health professionals. The researchers responsible for data
collection need to record any adverse event in detail in the case record form, including
the time of occurrence, the detailed course of the event (symptoms, signs, inspection
reports, etc.), treatment methods, and treatment results. All adverse events must be
tracked until they are resolved. The researcher is required to issue an analysis report
on the cause of the adverse event.
10. Research quality control and quality assurance
All assessors will receive online training (video conference) with regard to the study
protocol including ethics and detailed instructions for procedures for assessments.
Problems occurring during assessments will be referred to the study coordinator for
each center who refers them to the PI where appropriate. The PI and chief-statistician
have access to all study data at any time. Case record forms will be scanned upon
completion and made available to the study center at Nanjing Medical University.
21
Data entered electronically will be checked against case record forms by two
independent assistants. All data will be checked for outliers and implausible as well as
artificial patterns.
11. Data security audit
This clinical research will comply with the following regulations [of the PRC]35
:
Clinical research projects will develop a corresponding data security monitoring plan
based on the level of risk. All adverse events will be recorded in detail, properly
handled and tracked until they are properly resolved or the condition is stable. Serious
adverse events and unexpected events will be reported to the ethics committee,
competent authorities, sponsors and drug regulatory authorities in a timely manner in
accordance with regulations; the main investigator will regularly checks that all
adverse events are reviewed cumulatively, and investigator meetings are held when
necessary to evaluate the risks and benefits of the research; double-blind trials can be
urgently unblinded when necessary to ensure the safety and rights of the subjects; an
independent data monitor will monitor research data if risk of study is classified as
low risk [applies to this study]. For high-risk research, an independent data security
monitoring committee will be established to monitor the accumulated safety data and
effectiveness data to make recommendations on whether the research should continue.
12. Statistical processing
12.1 Descriptive analysis: Demographic and relevant clinical baseline data is
expressed by descriptive statistics (proportion or mean ± standard deviation, in total
and by intervention group)
12.2 Outcome evaluation (main analysis of primary and secondary outcomes):
Crude change in outcomes for both groups from baseline to post-treatment and follow
up will be provided as mean change scores with standard deviations or proportions.
22
Main analysis of treatment effects will be performed on an intention to treat basis and
adjusted for study center (as fixed effect). No corrections for multiple testing will be
applied. As mixed effects models are used for analysis of treatment effects and
listwise deletion of cases with missing data is thus avoided, main analysis will be
performed on available (unimputed) data, assuming that data are missing at random
(MAR) and missing values depend on observed variables in the model (center, time
point, and the interaction of group and time point)36 37
. This assumption will be tested
in sensitivity analysis (see below). The primary outcome will be analyzed with
constrained longitudinal data analysis (cLDA), i.e. a linear mixed effects model with a
random intercept for subject will be fitted to regress 6MWD at baseline and 6 weeks
on study center, time point of assessment and an interaction of time point and
intervention group14 38
(not including a mere group effect as in regular LDA such as
repeated measures ANOVA). This type of model adjusts for baseline mean differences
in the outcome between intervention groups similar to analysis of covariance
(ANCOVA). In fact, it is equivalent to ANCOVA in the absence of missing outcome
data. In the presence of missing data cLDA in contrast to ANCOVA considers all
available data in the estimation of the overall baseline mean and avoids listwise
deletion of cases lost to follow up. For analysis of the overall trajectory of 6MWD
until final follow at 24 weeks data from all time points will be considered and terms
for the 24 week time point and its interaction with intervention group will be added to
the above model. Secondary continuous outcomes (pulmonary function parameters,
lower limb muscle strength as time in seconds remaining in squatting positions, and
SF-12 composite scores) will be analyzed analogously, estimating treatment effects at
6 weeks and 24 weeks simultaneously. Occurrence of a favorable outcome with
regard to dyspnea (mMRC) will be analyzed with longitudinal logistic regression39
.
Estimates of treatment effects and changes in mean scores (continuous outcomes) or
percentages (discrete outcomes) from baseline to 6 weeks and 24 weeks follow up by
intervention group will be provided with 95% confidence intervals. Residuals of all
linear models will be checked for normal distribution using qq-plots; if this
23
assumption is violated robust standard errors (Huber-White sandwich estimator) will
be calculated.
12.3 Sensitivity analysis, per protocol analysis, and sub-group analysis: Two types
of sensitivity analysis will be performed. First, above analyses will be repeated on 50
multiply imputed datasets40
whereas imputation is based on available outcome data as
well as available baseline information including variables not included in the analysis
models. This compares the simple MAR assumption outlined under 12.2 with an
extended MAR assumption, i.e. that missing values are also dependent on observed
(auxiliary) variables not included in the models used for analysis. Apart from center,
these auxiliary variables comprise gender, age, disease severity, time from first
hospital admission for Covid-19 to baseline assessment, presence of comorbidities,
smoking history, and body mass index. Imputation is preferred over adjustment within
the mixed models (adding covariates) as conditioning on covariates is not intended
given this is a pragmatic trial and to avoid overfitting of the models. Chained
equations will be used for simultaneous imputation of all missing outcome data.
Second, reference-based multiple imputation will be used for simulating a
non-missing at random (NMAR) scenario where patients with missing assessments in
the intervention group are supposed to experience change in the outcome that is
similar to that observed in the control group after the last available data point before
dropout. This is called copy increments in reference (CIR) approach. Imputation is
based on a joint multivariate normal distribution of the outcome for each treatment
arm. In the case of CIR those in the intervention group are supposed to switch to the
distribution of the control group after dropout41
. CIR imputation is done separately for
each outcome and considering center and auxiliary covariates specified for extended
MAR imputation. Per protocol analysis will also be performed estimating the
previously specified models specified under (12.2) on data including only those
participants from the intervention group who had adhered to the TERECO protocol as
defined in (6.4). Due to lack of power for this type of analysis, no pre-specified
24
sub-group analysis will be performed.
12.4 Additional analysis: We will provide proportions of patients reporting any
adverse events and serious adverse events during the whole study period, during the
intervention period, and during the follow up period stratified by intervention group
as randomized and the difference in these proportions with logistic 95% confidence
intervals. Number of adverse events per patient reporting any such events will also be
given as well as types of events and supposed relationship with interventions and/or
Covid-19.
13. Ethics of clinical research
This research will follow relevant regulations such as the Declaration of Helsinki of
the World Medical Congress. Before the start of the study, this trial will be registered
at the Chinese Clinical Trials Registry [registered on April 11, 2020] and this study’s
implementation will commence only after the relevant ethics committees have
approved the trial protocol [approved by relevant IRBs on April 9, April 14, and April
20, 2020]. Before recruiting each subject into this this study, the investigators are
responsible for fully and comprehensively introducing the purpose, procedures and
possible risks of the study to the subject or his agent, and provide a written informed
consent form for signature. Participants will be informed that they have the right to
withdraw from this study at any time, and the signed informed consent form will be
kept as a clinical study document for future reference. The personal privacy and data
confidentiality of the subjects will be protected during the research process.
25
14. Research schedule
April 2020-June 2020: Complete the recruitment of subjects and baseline evaluation
June 2020-August 2020: Complete intervention delivery and post-treatment
evaluation
October 2020-December 2020: Complete subject follow-up
December 2020-January 2021: Statistical analysis, summary report
15. Participants
Name Title/Professional Task GCP Training
(date)
Li Jianan Chief
Physician/Rehabilitation
Medicine
PI，Project Design
January 28, 2010
Liu Shouguo
Deputy Chief
Technician/Rehabilitation
Patient recruitment,
project
implementation
April 27, 2019
Li
Yongqiang
Chief
Technician/Rehabilitation
Therapy
Project
implementation
April 27, 2017
Liu
Yuanbiao
Chief
Physician/Rehabilitation
Medicine
Project
implementation
Yin Zhifei Deputy Chief
Technician/Rehabilitation
Project
implementation
February 5, 2018
Jan D.
Reinhardt
Professor for Public
Health, Epidemiology
and Biostatistics
Chief-Statistician
n.a.
GCP = Good Clinical Practice
26
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