Investigator-blinded Randomized Controlled Trial Examining the Safety and Feasibility of Different Exercise Training Programs in Patients Who Have Survived COVID-19
Phase: NA
Conditions: COVID-19
Sponsor: Rigshospitalet, Denmark

 
 
Synopsis and statistical analysis plan 
Official title: Investigator-blinded Randomized Controlled Trial Examining the Safety and Feasibility of 
Different Exercise Training Programs in Patients Who Have Survived COVID-19 
Brief title: Feasibility and Safety of High-intensity Exercise Training in Patients Surviving COVID-19 
 
Study identifier: H-20033733 (amendment number: 75799) 
 
Study group: 
Regitse H Christensen (MD PhD), Principal investigator 
Ronan M G Berg (MD, PhD, DMsc) 
Iben Elmerdahl (Human physiology student) 
Frederik Foged (Human physiology student) 
Mathias Ried-Larsen (MSc, PhD) 
Villads Rasmussen (MSc) 
Rikke Krogh-Madsen (MD, PhD) 
Birgitte Lindegaard (MD, PhD) 
Peter Godsk (MD, PhD) 
Morten Lund (MD) 
Niels Vejlstrup (MD, PhD) 
Lars Køber (MD, DMSc) 
Bente K Pedersen (MD, DMSc) 
 
Place of study execution 
Centre of Inflammation and Metabolism (CIM)/   
Centre for Physical Activity Research (CFAS) 
Rigshospitalet, section M7641  
Tagensvej 20, DK-2200 Copenhagen (study address)  
Blegdamsvej 9, DK-2100 Copenhagen (postal address)  
Telephone: (+45) 3545 7544 
 
 
Date: 22.09.2020 
 
 

 
 
Background 
The novel coronavirus disease 2019 (COVID-19) has caused a global pandemic with millions of cases 
worldwide. Clinically, COVID-19 may cause pneumonia with an intense systemic inflammatory response and 
subsequent organ damage, including cardiac injury and remodeling. Scientifically based guidance for the 
rehabilitation of numerous COVID-19 survivors that are currently emerging is nonetheless sparse.  Of note, it 
is currently unknown if the cardiopulmonary changes and morbidity in patients that initially survive COVID-
19 pneumonia are reversible. Exercise training is a powerful stimulus to improve cardiorespiratory fitness, and 
exercise furthermore elicits a strong anti-inflammatory response, which may potentially either reduce or 
reverse the cardiac changes following COVID-19 pneumonia. Both low- and moderate intensity exercise is 
associated with protection against chronic diseases, and clinical trials have thus generally reported greater 
improvements after high compared to moderate intensity exercise training. Studies already showed that 
cardiopulmonary rehabilitation immediately following acute care admission is both safe, feasible and effective 
as there is seen significant improvements on physical performance and subjective health following COVID-
19.  
 
Aim  
The aim is to clarify the feasibility and safety of three training protocols (10-20-30; 3 x 5 min vs. 6 x 1min vs. 
4 x 4min) in COVID-19 survivors. The investigators hypothesize that patients surviving COVID-19 will be 
able to comply to all training protocols. If feasibility and safety between training protocols are not statistically 
different based on the’ red-amber-green system’, the investigators will choose the protocol based on the 
investigators experience.  
 
Study design 
This study uses a randomized crossover trial testing the feasibility of 3 different training protocols. The study 
consists of 4 visits with 1 baseline session and 3 different training sessions performed on 10 individuals 
following hospital admission for COVID-10 pneumonia. Each training is separated by a 1-week washout.  
 
Sample size considerations 
A sample size of 10 is based on what is feasible in the local context and will allow us to be relatively precise 
in our conclusions regarding feasibility outcomes. Recruitment is terminated when 10 persons have been 
randomly allocated or until November 15th 
 
Randomization, Allocation and Blinding 
Participants are randomly allocated following successful completion of the baseline measurements. A 
researcher, that is not involved in testing or training procedures, generates a computer-generated block 
randomization schedule with balanced permutations stratified by sex (Web site Randomization.com 
⟨http://www.randomization.com⟩. To ascertain allocation concealment, the block sizes will not be disclosed. 
The schedule is forwarded to a research assistant, who is not involved in any study procedures and stored on a 
password protected computer. Following the baseline measurements, the participants are given consecutive 
numbers. These are forwarded to the research assistant, who returns the corresponding allocation sequence to 

 
 
the study coordinator. The participants are blinded for treatment allocation until treatment assignment 
(following the examinations on the training days). However, following the initial two treatments blinding of 
the participants is no longer possible. All study personal involved with data collection will be blinded during 
baseline testing.  
 
 
Figure 1: Study overview and tests 
 
Participants: 
Eligibility of study participants 
 
Inclusion criteria 
Exclusion criteria 
Age ≥ 40 years  
 
A laboratory-confirmed initial positive test 
followed by one negative tests of severe 
acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) ≤ 6 months after hospital 
discharge 
 
≤10 L oxygen requirement during 
hospitalization 
Present atrial fibrillation  
 
Diagnosed with acute myocarditis  
 
Health conditions that prevent 
participating in the exercise intervention 
 
Patients who cannot undergo MR scans 
(e.g. kidney disease or metallic implants) 
 
Treatment with IL-6 receptor antagonists 
(tocilizumab, kevzara) within the last 
month due to drug interference with the 
cardiopulmonary exercise adaptations. 
Table 1: Overview of inclusion and exclusion criteria 
 
VO2max protocol:  
The participants will undergo a graded VO2max test on a bicycle ergometer. The test starts with a 5-minute 
warm-up at 30W for women and at 50W for men. Warm-up is immediately followed by a 20W increase every 

 
 
1 min until exhaustion. VO2max is reached when two of the following criteria are reached: RER > 1.10, plateau 
in oxygen consumption (≤150 ml ∙ min-1) or Borg scale < 17.  
 
Training protocols 
The 10 participants will test the feasibility of the 3 different training protocols. The exercise workload is set 
according to the patients HRmax or wattmax from the VO2max test. All training protocols start with a 10-minute 
warm up and a 5-minute cool-down period. The intervals in the training protocols are interspersed with a 3-
minute active rest. The accumulated time spend with a heart rate >85% of HR max will be evaluated to 
determine the intensity. 
 
  
4x4 min 
6x1 min 
10-20-30 3x5 min 
Total time 
38 min 
38 min 
38 min 
Warm-up 
  
  
  
10 minutes warm up with a 
heart rate of 60-70% of 
HRmax 
10 minutes warm up on 30% 
of watt-max 
10 minutes warm up at 60-
70% of HRmax 
Intervals 
4 intervals of 4 minutes at 
an intensity that will induce 
at least 85% of HRmax (we 
will start with 75% of watt 
max). 
Each interval is separated 
by 3-minute active pauses, 
biking at 50-70% of HRmax. 
6 intervals of 1 minute at 
100% of the watt-max. 
Each interval is interspersed 
by 3-minute active pauses at 
30% of watt-max. 
3 intervals of 5 minutes 
interspersed by 3 minutes on 
50-70% of HRmax. 
Each interval consists of 5 
minutes of 5 repeated 30-20-
10 intervals, consisting of 30 
seconds at easy pace, 20 
seconds at medium pace and 
10 seconds at all-out. 
Cooldown  
3-minutes cooldown at ~ 
warm up intensity 
7-minutes cooldown at ~ 
warm up intensity 
7-minutes cooldown at ~ 
warm up intensity 
Succes 
criteria 
The participant needs spend 
at least 25% of the training 
time above 85% of HRmax  
 
The participant needs to 
reach 85% of HRmax during 
the first 3 min of each 4-
minute interval. If the 
participant does not reach 
85% of HRmax the last 
minute of the 4-minute 
interval, the watt will be 
upgraded based on how far 
The participant needs to hold 
RPM above 60 in each 
interval. If the patient is not 
capable of keeping the right 
pace, the watt will be 
downgraded by 10% from 
the next interval. 
 
The participant needs spend 
at least 25% of the training 
time above 85% of HRmax 

 
 
the heart rate is from the 
desired zone. 
Likewise, the watt will be 
downgraded if the RPM 
falls below 60 or in the next 
interval if the HR spikes 
above 90 % of HRmax 
Table 2: The three different high intensity interval training protocols  
 
Outcomes 
Feasibility and fidelity evaluation 
The primary endpoint is a composite of i) participant adherence to the training dose (duration and intensity), 
ii) adverse events and iii) a 10-point Likert scale (see the yellow-amber-green section for details).  
 
Key secondary outcome is the 10-point Likert scale, which evaluates enjoyment and perceived tolerance of 
each training protocol at the end of each training session using a 10-point Likert scale, which is one of the 
most fundamental and frequently used psychometric tools in social science research. Patients have to indicate 
the degree to which they agreed with the following statement before training: “How motivated are you for 
today's training?” following two statements after the training: “How enjoyable have today´s training session 
been?” and “How tolerant has today´s training been?” 
 
Other outcomes to further evaluate feasibility and fidelity include success criteria for each protocol. The 
success criteria are defined based on prior work. Verification of training intensity is evaluated by rate of 
perceived exertion after each interval (6-20 Borg scale) and after completed training (1-10 Borg scale), and 
from accumulated minutes in the predefined heart rate zones.  
 
Functional capacity of the patients is another outcome which is assessed with the Post COVID-19 Functional 
scale, which is a scale to measure the consequence of the disease beyond binary outcomes.  
 
The primary composite outcome will be based on the ‘red-amber-green system’, that is designed to evaluate 
the specific training session/intervention. After a participant has completed a training session, the session will 
be ranked as red, amber or green based on 3 parameters: 1) Likert scale 2) Adverse events 3) Dosage 
reduction/adherence. Whichever category the specific training session scores the lowest in will the rating of 
the training.  
 
 
Red 
Amber 
Green 
Likert scale 
(Tolerance) 
1-2 
3-4 
5+ 
Adverse 
events 
If the patient experiences 
angina, must stop the 
training due to any adverse 
event or has ST depression 
on the post training ECG 
If ≥ 3 adverse events are 
registered 
during 
the 
training session 
If ≤ 2 adverse events are 
registered during the training 
session   

 
 
Dosage 
reduction 
If ≤ 50% of the total 
training is completed  
If 50-85% of the training is 
completed  
If ≥ 85% of the training is 
completed 
Specific 
dosage 
reduction  
for 4x4min 
If HR has been over 85% 
of max < 15% of the time 
during the intervals (< 
2:20) 
If HR has been over 85% of 
max 15-24% of the time 
during intervals (2:20-3:50) 
If HR has been over 85% of 
max ≥25% of the time during 
intervals (≥3:50) 
Specific 
dosage 
reduction  
for 6x1min 
If the intensity must be 
downgraded ≥10% in 5+ 
of the intervals 
If the intensity must be 
downgraded 10% in 3-4 of 
the intervals  
If the intensity must be 
downgraded 10% in < 3 of the 
intervals 
Specific 
dosage 
reduction  
for 10-20-30 
If HR has been over 85% 
of max < 15% of the time 
during the intervals (< 
2:15) 
If HR has been over 85% of 
max 15-24% of the time 
during intervals (2:15-3:40) 
If HR has been over 85% of 
max ≥25% of the time during 
intervals (≥3:40) 
Table 3: Red-amber-green system  
 
 
Safety 
Before performing any exercise the supervisor will evaluate whether the patient should participate based on 
an evaluation of the patient in relation to the contraindications and precautions identified below: 
 
Training contraindications and precautions: 
- 
Unstable angina or myocardial infarction (ECG is taking at baseline and the patient is asked for any 
angina-like symptoms before and after training) 
- 
Systolic blood pressure > 200 mmHg ± diastolic blood pressure > 100 mmHg (blood pressure is 
measured at baseline) 
 
Training termination criteria: 
- 
Onset of angina or angina-like symptoms. 
- 
Signs of poor perfusion: confusion, nausea, lightheadedness, central cyanosis 
- 
Patient requests to terminate (e.g. intolerable dyspnea) 
- 
Physical or verbal manifestations of severe fatigue 
 
 
Measurement 
Baseline (visit 1): (in the following order)  
• 
Age, sex, height, weight 
• 
Hours of sleep 
• 
Activity level before and after hospital discharge 
• 
Post-COVID-19 Functional Scale (PCFS) 
• 
Standard values in rest: blood pressure, SAT, HR 
• 
ECG 
• 
Body composition analysis (DXA scanning: total body fat mass, lean body mass and mineral bone 
mass density and BMI) 

 
 
• 
Pulmonary Function (dynamic spirometry, whole body plethysmography, diffusing capacity) 
• 
Cardiorespiratory fitness (VO2max, watt max and HRmax)  
 
Training days (visit 2, 3 and 4):  
• 
Saturation during training 
• 
ECG after end training 
• 
COVID-19 specific symptoms before and after the exercise training 
- 
Dyspnea, palpitations, chest pain 
• 
Training outcome (fill out the training scheme) 
o Median watt and median HR during the training (warm-up and cool-down excluded) 
o Time spent in predefined heart rate zones 
o Post-COVID-19 Functional Status scale 
o RPE during (6-20 Borg scale) and after ended training (1-10 Borg scale) 
o Dose-reduction based on defined success criteria 
o Adverse events and termination of training (termination of training is measured in % of 
completed training) 
o Primary outcome: Motivation: Likert scale 1-10 before and after the workout to determine 
how motivated the participants are before training and how tolerant and enjoyable the training 
has been.  
 
Analyses 
Feasibility of the protocols will be evaluated by a composite primary endpoint including i) participant 
adherence to the training dose (duration and intensity), ii) adverse events and iii) a 10-point Likert scale that 
will be compared for the three protocols using a χ2 test. Details of the composite primary endpoint can be found 
in the outcome section/the “red-amber-green” document. 
The protocols will secondarily be compared using ANCOVA modeling as well as paired T testing or χ2 test 
with respect to the individual endpoints e.g. Likert scale (key secondary outcome), rate of perceived exertion 
(RPE), Post-COVID-19 Functional scale (PFAS). The baseline value will be included as a confounder.