Kinetics of Physiological and Symptomatic Responses to CardioPulmonary Exercise Testing (CPET) in Subjects With Persistent Exercise Intolerance After COVID-19: an Open-Source Exercise Network
Conditions: COVID-19
Sponsor: Association pour la Complementarite des Connaissances et des Pratiques de la Pneumologie

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
1/23 
STUDY PROTOCOL 
Kinetics of physiological and symptomatic responses to CardioPulmonary Exercise Testing (CPET) in subjects with 
persistent exercise intolerance after COVID-19: an Open-Source Exercise Network 
 
Study data manager 
Association pour la Complémentarité Connaissances et Pratiques de la Pneumologie (aCCPP) 
Coordinator 
 
Principal 
investigators 
Prof. Bernard Aguilaniu (Univ. Grenoble Alpes) 
 
Prof. Pierantonio Laveneziana (Univ. Hospital La Pitié-Salpétrière, Paris) 
Prof. Frédéric Costes (Univ. Hospital of Clermont-Ferrand) 
Investigators 
Pulmonologists, Cardiologists and Physiologists involved in the realization and the diagnostic 
interpretation of the Cardio Pulmonary Exercise Testing -CPET) that it is within public or private 
structures (Univ. Hospitals, General Hospitals, private practices or mixed).  
 
About 40 investigators are expected. 
Protocol date 
June 9, 2023 
Protocol version 
1.2     
 
 
 
 
 
 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
2/23 
Synopsis  
 
Title of the study 
Kinetics of physiological and symptomatic responses to CardioPulmonary Exercise Testing 
(CPET) in subjects with persistent exercise intolerance after COVID-19: an Open-Source Exercise 
Network 
Study data manager 
Association pour la Complémentarité Connaissances et Pratiques de la Pneumologie 
Coordinator 
Principal investigators 
Prof. Bernard Aguilaniu 
Prof. Pierantonio Laveneziana 
Prof. Frédéric Costes
University Grenoble Alpes 
Univ. Hospital La Pitié-Salpétrière, Paris 
Univ. Hospital of Clermont-Ferrand 
      
Coordinator Prof. Bernard Aguilaniu (Univ. Grenoble Alpes) 
 
Members/Investigators: 
Prof. Pierantonio Laveneziana - Univ. Hospital La Pitié-Salpétrière Paris 
Prof. Frédéric Costes - Univ. Hospital Clermont-Ferrand 
Dr. David Debeaumont - Univ. Hospital Rouen 
Dr. Yan Martinat - Centre Médical Parot Lyon 
Dr. Frija-Masson Justine - Univ. Hospital Bichat Paris 
Dr. Motiejunaite Justina - Univ. Hospital Bichat Paris 
 
Members/Consultants: 
Prof. Anestis Antoniadis - IMAG Univ. Grenoble Alpes 
Prof. François Péronnet - Univ. Montréal-Canada 
Centers and 
investigators 
Pulmonologists, Cardiologists and Physiologists involved in the realization and the diagnostic 
interpretation of the Cardio Pulmonary Exercise Testing -CPET) that it is within public or private 
structures (Univ. Hospitals, General Hospitals, private practices or mixed).  
About 40 investigators are expected. 
Current status 
Since the first wave of COVID-19, pulmonologists, cardiologists and physiologists are regularly 
consulted for intolerance to exercise expressed by dyspnea and/or frank fatigability sometimes 
associated with muscular or thoracic pain. When these complaints persist beyond 3 months after 
the first symptoms, it is legitimate to perform a CPET: 
 
Either to evaluate the functional impact of an identified organ deficiency (e.g. myocarditis, 
pulmonary fibrosis, etc.), 
 
Or, in the absence of formal arguments for an identified organ deficiency, to observe 
possible abnormalities in physiological responses during an incremental exercise test, 
likely to explain the persistence of symptoms and intolerance to exercise.  
 
The recent literature highlights the presence of non-specific ventilatory and cardio-circulatory 
abnormalities leading to various physio-pathological observations. These reports concern today 
relatively small numbers of patients mixing subjects whose clinical forms of COVID, comorbidities 
and habitus are very diverse. Moreover, the hypotheses or conclusions proposed by these studies 
are influenced by the medical specialty of the practitioner who observes them. 
Thus, it seems necessary to collect a very large number of clinical and physiological observations in 
order to draw up a factual report of the disorders observed without any interpretative 
preconception. 
It is reasonable to assume that, with time, health professionals will be frequently confronted with 
patients with exercise intolerance after COVID-19 and that the management of the disease will be 
more codified. For this, it seems necessary to collect and secure as much data as possible in order 
to improve the understanding of persistent symptoms and in particular the potential diversity of 
phenotypic presentations.  
Objectives 
Primary objective:  

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
3/23 
Physiological responses and symptoms during CPET in subjects diagnosed with COVID who have 
persistent symptoms responsible for exercise intolerance 
Homogeneous patient subgroups will consider: 
 
the initial clinical presentation of COVID, 
 
any persistent symptoms other than exercise intolerance, 
 
clinical characteristics prior to COVID-19 infection (co-morbidities – regular habitual 
physical activity). 
 
Secondary objectives: 
- 
To model the kinetics of ventilatory pattern responses in order to characterize the behavior of 
excessive hyperventilation and, possibly, chaotic breathing. 
- 
To test, through different statistical models, the possibility of predicting the persistence of 
dyspnoea as a function of exercise variables, pre-existing clinical data of the COVID, clinical 
presentation of the acute COVID. 
Concerned population 
Inclusion criteria: 
 
Age ≥ 18 years 
 
Patients with persistent symptoms 3 months after the onset of COVID-19 infection, 
regardless the severity of the initial illness 
 
Patients with an ICU stay, primarily following rehabilitation management; that is, in 
practice, at least 6 months after COVID 
 
Patients followed by a pulmonologist, cardiologist or physiologist in a public or private 
facility or in private practice, allowing for CPET 
 
Patients who have performed a CPET before December 31, 2022 
 
Patients informed of the possible anonymized processing of the data collected during CPET 
for research purposes; and who gave informed consent 
Exclusion criteria: 
 
Age < 18 years 
 
Patients unable to perform CPET for locomotor reasons 
 
Patients with severely reduced functional work capacity   
 
Patient deprived of liberty by judicial or administrative decision 
 
Patients unable to give informed consent 
Study type and 
methodology 
French-speaking, multicentric, observational, descriptive cohort study with retrospective data 
collection, not affecting the management of patients and in line with the French MR004 reference 
methodology. 
 
The following processes are defined in this protocol: 
 
on-site collection of clinical and physiological data from patients process;  
 
anonymization and migration process of these data (collected on each investigation site) 
to the centralized CPET-studies.com platform which will return an anonymized file 
dedicated to statistical analysis. 
Recruitment 
Investigator Recruitment 
From June 1, 2022, pulmonologists, cardiologists and physiologists performing CPET in public or 
private structures (Univ. Hospital, General Hospital, private practice or mixed activity) will be 
invited to participate in this study. 
 
Patient Recruitment 
From February 1, 2023, each investigator will be able to identify the files of patients who meet the 
inclusion criteria of the protocol by going back to January 2, 2020.  
From February, 2023, each investigator will be able to ensure the migration on the CPET-
studies.com platform of clinical and physiological data collected between January 2, 2020 and 
December, 2023. 
Data collection  
Physiological data collection 
Physiological measurements made during CPET (source data) will be stored locally on each 
investigator's ergospirometer until the time of migration.  

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
4/23 
They include continuous recording of ergospirometer measurements and discontinuous recording 
of blood pressure, symptoms and blood gases. 
In order to get rid of some of the variability of the results  the export will only concern the measured 
data. Additional physiological data will then be obtained by applying the appropriate physiological 
calculation formulas in a strictly identical way whatever the brand of the ergospirometer. All these 
data (measured and calculated) will be transformed by the CPET-STUDIES application into a file 
called Finalized File. 
 
Collection of clinical data  
The clinical data of the patients will be collected on the medical file or a dedicated file (Excel or 
Word) by each practitioner. They will be filled in by the referring physician who alone knows the 
name and surname of his patients on the online platform. The identifying data of each patient will 
then be pseudonymized so that no one other than the referring physician can access them. All data 
is hosted by a health data host certified for the 6 HDS levels. 
Clinical data are: sex, weight, age, height, date of COVID, physical activities before COVID, 
comorbidities, COVID-related symptomatology, usual treatments, Hospital Anxiety and Depression 
Scale (HADS) and Chalder fatigue scale questionnaires. 
 
Access to the platform will be secured by identification with a login and a password  
The patient's physiological and clinical data will be encrypted and pseudonymized when migrated 
and/or entered on the CPET-STUDIES.COM platform. 
The content of the Finalized File will then be imported into a database, which contains only the 
clinical data associated with the patient's pseudonym. 
Patient information 
As is commonly done on admission to hospitals, a signed informed consent form will be attached 
to the administrative and medical file of the patient. 
In the absence of the signed informed consent form, patients who have undergone CPET will be 
contacted and informed of the modalities of this study, and asked to sign the informed consent 
form (see Appendix 1). 
This will be done as long as it does not involve a disproportionate effort. 
Overview and duration 
of the study 
The data collection will be carried out from February 1, 2023 to December 31, 2023 or during 10 
months.  
The data concerned cover the period from January 2, 2020 to December 31, 2022 (35 months). 
These data were stored by the investigators on-site as part of their usual practice. 
The migration of locally stored data to the CPET-STUDIES.COM platform will take place between 
February, 2023 and December 31, 2023. 
Data analysis method 
Analyses will be performed using R software, with all required software packages, and JAGS, in their 
most up-to-date version at the time of analyses.  
No hypotheses will be tested for either the primary or secondary objectives. A descriptive analysis 
of all evaluation criteria will be performed on the total population and on subgroups to be defined 
a priori according to the sample. 
The variables collected at the end of the steady state, at maximal exercise, and during recovery 
(2 min) will be expressed as mean, standard deviation (SD), median, quartiles. 
Modeling of the kinetics of certain variables (VE TV-BF-HR- RER) will be performed and then a 
mathematical model will be developed to quantify and compare these kinetics between subgroups. 
Comparisons of kinetics between subgroups will be made using recently developed mixed-effects 
functional analysis of variance (FANOVA) methods. 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
5/23 
The kinetics of some variables will be expressed as a function of developed power (in watts), 
metabolic power (VO2 in L/min), ventilatory flow (in L/min), HR expressed in absolute value, in % of 
the max HR reached and in % of the predicted value according to the formula maxHR = 210-0.65 x 
age). 
At the request of the scientific committee, additional analyses may be carried out, in particular with 
regard to the measurement of operating volumes during exercise. 
Number of patients 
1 000 patients with exercise intolerance following COVID are expected. 
Financial partners 
Financial support from the Pharmaceutical Group Menarini France and AstraZeneca 
 
 
 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
6/23 
Table of contents 
Synopsis ........................................................................................................................................................ 2 
1. Introduction ............................................................................................................................................... 9 
2. Objectives of the study ............................................................................................................................... 9 
2.1. Primary objective................................................................................................................................. 9 
2.2. Secondary objectives ........................................................................................................................... 9 
3. Investigators and organization of the study ................................................................................................ 9 
3.1. Study data manager ............................................................................................................................. 9 
3.2. Coordinating investigator and principal investigators of the study ........................................................ 9 
3.3. Steering committee of the study .......................................................................................................... 9 
Coordinating investigators:  ............................................................................................................................. 10 
Other members: ............................................................................................................................................... 10 
3.4. Centers and investigators ................................................................................................................... 10 
3.5. Management center and statistical analysis ....................................................................................... 10 
4. Design of the the study ............................................................................................................................. 10 
4.1. Constitution of the cohort and data collection .................................................................................... 10 
4.2. Data migration .................................................................................................................................. 11 
5. Population of the study ............................................................................................................................ 11 
5.1. Recruitment procedures .................................................................................................................... 11 
5.2. Number of Patients ............................................................................................................................ 11 
5.3. Eligibility Criteria ............................................................................................................................... 11 
5.4. Exclusion Criteria ............................................................................................................................... 11 
5.5. Previous and/or concomitant treatments ........................................................................................... 11 
6. Evaluation criteria .................................................................................................................................... 11 
6.1. Primary endpoint ............................................................................................................................... 11 
6.2. Secondary endpoints ......................................................................................................................... 11 
7. Procedures of the study ............................................................................................................................ 11 
7.1. Recruitment of pulmonologists, cardiologists, physiologists and patients ............................................ 12 
7.2. Data collection................................................................................................................................... 12 
7.2.1. Clinical data ............................................................................................................................................ 12 
7.2.2. Physiological Data ................................................................................................................................... 12 
7.3. Data transmission and migration ........................................................................................................ 12 
7.4. Dissemination or publication of the study results ............................................................................... 13 
8. Statistical analysis .................................................................................................................................... 14 
9. Sample size .............................................................................................................................................. 14 
10. Legal and ethical considerations ............................................................................................................. 14 
10.1. Ethical considerations ...................................................................................................................... 14 
10.2. Information to patients .................................................................................................................... 14 
10.3. Pharmacovigilance ........................................................................................................................... 14 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
7/23 
10.4. Protocol amendment ....................................................................................................................... 14 
10.5. Archiving ......................................................................................................................................... 14 
10.6. Financial Partner .............................................................................................................................. 15 
Appendix 1: Informed Consent Form ............................................................................................................. 16 
Appendix 2: CPET post-COVID questionnaire ................................................................................................. 18 
Appendix 3: Borg scale ................................................................................................................................. 20 
Appendix 4: Methodology of the CPET .......................................................................................................... 21 
Appendix 5: HADS questionnaire .................................................................................................................. 22 
Appendix 6: Chalder faigue scale .................................................................................................................. 23 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
8/23 
List of abbreviations 
CNIL 
Commission nationale informatique et liberté 
English: French National Commission on Informatics and Liberty 
ECG 
Electrocardiogram 
e-CRF 
Electronic case report form 
SD 
standat deviation 
IC 95 % 
Confidence Interval 95 % 
        TLC 
Total Lung Capacity 
FRC 
Fonctinal Residual Capacity 
IC 
Inspiratory Capacity 
FEV1 
Forced Expiratory Volume in 1 sec  
FVC 
Forced Vital Capacity 
SVC 
Slow Vital Capacity 
Tlco 
Transfer Lung carbon monoxyd 
HR 
Heart rate 
BF 
Breathing Frequency 
6MWT 
6 min walking Test  
CPET 
Cardio Pulmonary Exercise Testing 
VO2 
Oxygen  
RER 
Respiratory Exchange Rate 
VA 
Alveolar Ventilation Flow 
VE 
External Ventilatory Flow 
RV 
Residual Volume 
TV 
Tidal Volume 
 
 
 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
9/23 
1. Introduction 
Since the first wave of COVID, pulmonologists, cardiologists and physiologists are regularly consulted for intolerance to exercise 
expressed by dyspnea and/or frank fatigability sometimes associated with muscular or thoracic pain. When these complaints 
persist beyond 3 months after the first symptoms, it is legitimate to perform a CPET: 
 
Either to evaluate the functional impact of an identified organ deficiency (e.g. myocarditis, pulmonary fibrosis, etc.), 
 
Or, in the absence of formal arguments for an identified organ deficiency, to observe possible abnormalities in 
physiological responses during an incremental exercise test, likely to explain the persistence of symptoms and intolerance 
to exercise  
 
The recent literature highlights the presence of non-specific ventilatory and cardio-circulatory abnormalities leading to various 
physio-pathological observations. These preliminary reports concern today small numbers of patients mixing subjects whose 
clinical forms of COVID, comorbidities and habitus are very diverse. Moreover, the hypotheses or conclusions proposed by these 
studies are influenced by the medical specialty of the practitioner who observes them. 
 
Thus, it seems necessary to collect a very large number of clinical and physiological observations in order to draw up a factual 
report of the disorders observed without any interpretative preconception. 
2. Objectives of the study 
2.1. Primary objective  
Kinetics of physiological responses and symptoms during CPET: to describe by homogeneous subgroups of patients, the 
physiological responses and symptoms during CPET in COVID-19 subjects with persistent symptoms responsible for exercise 
intolerance. 
Homogeneous patient subgroups will consider: 
 
the initial clinical presentation of COVID, 
 
any persistent symptoms other than exercise intolerance, 
 
clinical characteristics prior to COVID-19 infection (co-morbidities – regular habitual physical activity). 
 
2.2. Secondary objectives  
 
To model the kinetics of ventilatory pattern responses in order to characterize the behavior of excessive 
hyperventilation and, possibly, chaotic breathing. 
 
To test, through different statistical models, the possibility of predicting the persistence of dyspnoea as a function of 
exercise variables, pre-existing clinical data of the COVID, clinical presentation of the acute COVID. 
3. Investigators and organization of the study 
3.1. Study data manager 
The study data manager is the association aCCPP represented by its Caretaker President, Vice-President Dr. Philippe Eric Kelkel 
from the General Hospital Métropolole Savoie. 
 
3.2. Coordinating investigator and principal investigators of the study  
The principal investigators of the study are: 
 
Prof. Pierantonio Laveneziana, pulmonologist, Univ. Hospital La Pitié-Salpêtrière, 47-83, bd de l'hôpital, 75651 Paris 
Cedex 13, FRANCE. 
 
Prof. Frédéric Costes, pulmonologist, Department of Sports Medicine and Functional Explorations, Gabriel-Montpied 
Hospital, Univ. Hospital of Clermont-Ferrand. Clermont Auvergne Univ., INRA, UMR 1019, Human Nutrition Unit, 
Clermont-Ferrand, FRANCE. 
 
The principal coordinating-investigator is Prof. Bernard Aguilaniu, Univ. Grenoble Alpes, FRANCE. 
 
3.3. Steering committee of the study 
The steering committee is composed of 9 members. 
 
 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
10/23 
Coordinating investigators:  
Prof. Bernard Aguilaniu 
Prof. Pierantonio Laveneziana 
Prof. Frédéric Costes
Univ. Grenoble Alpes, FRANCE 
Univ. Hospital La Pitié-Salpêtrière, Paris, FRANCE 
Univ. Hospital of Clermont-Ferrand, FRANCE
 
Other members: 
Steering committee facilitator: Prof. Bernard Aguilaniu (Univ. Grenoble Alpes, FRANCE) 
 
- 
Dr. David Debeaumont 
 
Univ. Hospital Rouen, FRANCE 
- 
Dr. Yan Martinat 
 
 
Medical Center Parot, Lyon, FRANCE 
- 
Dr. Frija-Masson Justine 
 
Univ. Hospital Bichat, Paris, FRANCE 
- 
Dr. Motiejunaite Justina 
 
Univ. Hospital Bichat, Paris, FRANCE 
- 
Prof. Anestis Antoniadis 
 
IMAG Univ. Grenoble Alpes and Cape Town Univ. SA, FRANCE 
- 
Prof. François Péronnet 
 
Univ. of Montréal-Canada, CANADA 
 
3.4. Centers and investigators 
The investigators are Pulmonologists, Cardiologists and Physiologists involved in the realization and the diagnostic interpretation 
of the Cardio Pulmonary Exercise Testing - CPET within public or private structures (Univ. Hospitals, General Hospitals, private 
practices or mixed).  
 
About 40 investigators are expected. 
 
3.5. Management center and statistical analysis 
The data management of the study will be carried out by the aCCPP. 
A telephone number and an e-mail address will be made available to the participating physicians. The management center will 
respond to each specific request throughout the study. 
Data management is provided by the aCCPP and its contractors. 
 
Statistical analysis will be performed by Prof. Anestis Antoniadis, IMAG Univ. Grenoble Alpes, and Prof. Sophie Lambert Lacroix, 
MultiDisciplinary Institute in Artificial Intelligence (MIAI) Grenoble Alpes University. 
4. Design of the the study 
This study is a French-speaking, multi-center, observational, descriptive cohort with retrospective data collection on patients with 
COVID who present persistent symptoms responsible for intolerance to exercise. 
This study does not affect patient management in any way: no additional examinations will be performed, nor will any treatment 
be administered specifically for this study.  
 The (retrospective) data collection will be carried out from July 15, 202 to December 31, 2023 (10 months). 
 The data involved cover the period from January 2, 2020 to December 31, 2022 (i.e., 29 months). 
 These data were stored by the investigators on-site as part of their usual practice. 
 
The migration of the data collected and stored locally on the CPET-STUDIES.COM platform will take place between February 1, 
2022 and May 31, 2023. 
 
4.1. Constitution of the cohort and data collection 
 From June 1, 2022, pulmonologists, cardiologists and physiologists performing functional exercise tests (CPET), in public 
or private structures (univ. hospital, general hospital, private practice or mixed) will be officially invited to participate in 
this study by e-mail. 
 Between June 1, 2022 and November 31, 2023, each physician willing to participate in the study will transmit his signed 
investigator participation form to the management center, and will receive in return the study documents as well as the 
instructions to implement in their ergospirometer a standardized export file.  
 This study will take place over a period of 18 months from June 1, 2022 to December 31, 2023. The data collection 
concerns patients who had a consultation between January 2, 2020 to December 31, 2022. Therefore, the investigating 
physicians will identify the files of patients who meet the inclusion criteria of the protocol (§ 5.3), going back to January 
2, 2020.  

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
11/23 
 Once these steps are validated, the investigator will be able to migrate the data (Physiological CPET and Clinical) to the 
CPET-STUDIES.COM platform, where it will be pseudonymized before any processing. 
 
4.2. Data migration 
Data migration will be performed on the dedicated CPET-STUDIES.COM platform between February 1, 2023 and December 31, 
2023. 
5. Population of the study 
5.1. Recruitment procedures 
All patients with exercise intolerance during COVID, diagnosed between January 2, 2020 and December 31, 2022, who have been 
informed that the physiological data collected during the CPET and the clinical data necessary for its interpretation may be used 
for clinical research, can be enrolled. 
 
5.2. Number of Patients 
This study is expected to collect data from approximately 1 000 patients. 
 
5.3. Eligibility Criteria 
Patients with the following characteristics can be enrolled in this study: 
 
Age ≥ 18 years 
 
Patients with persistent symptoms 3 months after the onset of COVID-19 infection, regardless the severity of the initial illness 
 
Patients with an ICU stay, primarily following rehabilitation management; that is, in practice, at least 6 months after COVID 
 
Patients followed by a pulmonologist, cardiologist or physiologist in a public or private facility or in private practice, allowing 
for CPET 
 
Patients who have performed a CPET before January 1, 2023 
 
Patients informed of the possible anonymized processing of the data collected during CPET for research purposes; and who 
gave informed consent 
 
5.4. Exclusion Criteria 
Patients with the following characteristics will not be enrolled in this study: 
 
Age < 18 years 
 
Patients unable to perform CPET for locomotor reasons 
 
Patients with severely reduced functional work capacity   
 
Patient deprived of liberty by judicial or administrative decision 
 
Patients unable to give informed consent 
 
5.5. Previous and/or concomitant treatments 
As the study is non-interventional, no treatment is prohibited. 
6. Evaluation criteria 
6.1. Primary endpoint 
To describe by homogeneous patient subgroups, physiological responses and symptoms during CPET in COVID subjects with 
persistent symptoms responsible for exercise intolerance. 
 
Homogeneous patient subgroups will consider: 
 
the initial clinical presentation of COVID, 
 
any persistent symptoms other than exercise intolerance, 
 
clinical characteristics prior to COVID-19 (co-morbidities - physical activity level). 
 
6.2. Secondary endpoints 
- 
To model the kinetics of ventilatory pattern responses in order to characterize the behavior of excessive hyperventilation and, 
possibly, chaotic breathing. 
 
- 
To test, through different statistical models, the possibility of predicting the persistence of dyspnoea as a function of exercise 
variables, pre-existing clinical data of the COVID, clinical presentation of the acute COVID. 
7. Procedures of the study 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
12/23 
7.1. Recruitment of pulmonologists, cardiologists, physiologists and patients 
The recruitment of investigating physicians for this study is based on a voluntary basis. 
The list of potential investigating centers corresponds to certain pulmonology, cardiology and physiology departments involved in 
the realization and diagnostic interpretation of CPET; whether within public or private structures (univ. hospital, general hospital, 
liberal or mixed activity). 
Pulmonologists, cardiologists and physiologists will be invited to participate in the study by an e-mail from the investigating 
coordinator. An investigator participation form to be completed by the physicians agreeing to participate in the study will be 
attached to this e-mail. Physicians agreeing to participate in the study will return the completed form to the study management 
center before November 31, 2003.  
 
All patients meeting the enrollment criteria and having had exercise intolerance during COVID, diagnosed between January 2, 
2020 and December 31, 2022, will have been informed that the physiological data collected during the CPET and the clinical data 
necessary for its interpretation will be possibly exploited for an observational research (see above 5.1. Recruitment procedures). 
 
7.2. Data collection  
7.2.1. Clinical data 
Clinical data recorded (see Appendix 2) include: 
 
Patient  
- 
Sex, month and year of birth, weight, height,   
- 
Pre-COVID physical activity level (PA): sport (h/week), PA at work, daily PA, time spent sitting,  
- 
Main comorbidities (pulmonary, hypertension, cardiovascular, metabolic, chronic renal pathologies, psychiatric pathologies, 
cancers), 
- 
Common treatments (therapeutic class) with potential effects on exercise tolerance. 
 
COVID pathology 
- 
Date of COVID,  
- 
Severity of initial COVID: oxygen requirement, parenchymal extension on CT-scan, non-respiratory symptoms, 
- 
Post-COVID symptoms: dyspnea, fatigue, cough, muscle and/or joint pain, anxiety, agueusia, anosmia, headache, neurological 
symptoms, gastrointestinal symptoms, palpitations, dizziness. 
 
Additional data available 
- 
Cardiovascular assessment: HR, cardiac ultrasound, MRI, 
- 
Anxiety/depression questionnaire scores and Chalmers fatigue questionnaire, 
- 
Resting respiratory function: FEV1, FVC, SVC, CI, Tlco. 
- 
Helium VA 
- 
 
Symptoms during CPET  
The Borg scale should be used (see Appendix 3) for the collection of symptoms during CPET. This scale is used to assess the intensity 
of breathlessness and muscle fatigue during exercise in patients. 
 
7.2.2. Physiological Data 
In order to get rid of some of the variability of the results, the export of physiological  data will only concern the measured data. 
Additional physiological data will then be obtained by applying the appropriate physiological calculation formulas in a strictly 
identical way whatever the brand of the ergospirometer is. All these data (measured and calculated) will constitute a file called 
Finalized File. 
 
This Standardized file will constitute the physiological source data used to reach the research objectives of the study. 
The content of the Standardized file is imported into a database, which contains only the patient’s data. 
Eventually, the anonymized clinical and exercise physiological (CPET) data will be transferred to a spreadsheet for statistical 
analysis. In no case will the statisticians have access to the patient's personal information. 
 
7.3. Data transmission and migration 
A new CPET Open Source Data platform (CPET-STUDIES.COM), designed by HYLAB with the help of the software development 
company ASCANIO, is intended to collect clinical and physiological data.  
The CPET-STUDIES.COM application transforms the files’ original data into a Finalized File. 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
13/23 
Access to the platform will be secured by identification with a login and a password  
 
The patient's physiological and clinical data will be encrypted and pseudonymized when migrated and/or entered on the 
CPET-STUDIES.COM platform, 
 
The content of the Finalized File will then be imported into a database, which contains only the clinical data associated 
with the patient's pseudonym. 
 
Clinical data: 
Pseudonymized data will be stored separately from the rest of the study and will be encrypted. Moreover, for security reasons, 
data extraction tools will not decrypt these pseudonomyzed data.  
 
Physiological data : 
Physiological data in the export file will be migrated to a Finalized File which will, in a homogeneous manner, perform: 
- cycle-by-cycle averaging of measured variables over the last 20 and 30 seconds of each minute; 
- the calculations required to obtain new variables of interest (called calculated variables).  
 
This Finalized File will constitute the SOURCE data for this study, exploitable for the research objectives of the study. 
 
Finally, the anonymized data (clinical and EFX) will be transferred to the R statistical software. Under no circumstances will the 
statistician have access to the personal information of the patient. 
 
7.4. Dissemination or publication of the study results 
It is not in the public interest that the results of a study are never made available or considered, especially by public decision-
makers or authorized representatives of the community where the study was conducted. Withholding information or refusing to 
disclose results can only be justified in exceptional circumstances; for example, when methodological problems encountered 
during the study render the results meaningless. When it is not possible to present or publish all the results or conclusions of an 
epidemiological study for reasons of limited space or insufficient time to allow such presentation or publication, the person in 
charge of the study must guarantee that all persons who might be interested in all the results or conclusions will have access to 
them upon request.  
The main results must be communicated to those who participated in the study or their representatives, as well as to other 
members of the community where the study was carried out In this respect, the scientific committee undertakes to transmit the 
results of the study to all the investigating physicians who participated in it. 
 
Intermediate results 
Intermediate results should always be explicitly stated as such. Intermediate results, as well as raw or previously processed data 
or any data, results, analyses or conclusions that may be derived from these intermediate results, may not be transmitted to third 
parties or used in other studies unless such transmission or use is explicitly provided for in the protocol and is specifically approved 
by the study’s manager.  
In the event that the study is discontinued for any reason, the presentation or publication of any preliminary or partial results or 
findings from the study may occur subject to compliance with prior validation procedures. Data or results from the discontinued 
study should be identified as such in subsequent publications and presentations.   
 
Obligation to publish 
All results of a study, whether the funders are public or private, are the scientific responsibility of the physician in charge of the 
study, not of the funder, and the results must always be made public if they have sufficient scientific validity.  
 
Any request to hide results, to change or attenuate the content of a report, or to postpone the publication of results, will be 
categorically rejected. 
 
Obligation to peer review 
The general rule is to submit the results of a study to an independent peer review before making them public or submitting them 
to the media. 
 
Impartiality of publications 
Publications should describe all aspects of the study in an honest and balanced way without taking into account other interests, 
especially non-scientific ones. Scientific committee members should not exaggerate the results of the study in order to increase 
their chances of obtaining more funding for future research or to make their articles more attractive to the editor of a journal . A 
certain bias of selecting results that agree with the view of the physician in charge of the study and ignoring those that contradict 
it must be avoided. Authors of epidemiological articles must comply with the rules of quality journals in which possible conflicts 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
14/23 
of interest are disclosed. The definition and order of authorship should be consistent with scientific publication practices. In this 
study, the list of investigating physicians will be systematically associated with all publications. 
8. Statistical analysis 
The source data will be collectively analyzed for subgroup studies defined according to scientific criteria by a committee dedicated 
to this study. 
Analyses will be performed using R software, with all required software packages, and JAGS, in their most up-to-date version at 
the time of analyses.  
No hypotheses will be tested for either the primary or secondary objectives. A descriptive analysis of all evaluation criteria will be 
performed on the total population and on subgroups to be defined a priori according to the sample. 
The variables collected at the end of the steady state, at maximal exercise, and during recovery (Rec + 2') will be expressed as 
mean, standard deviation (SD), median, quartiles. 
Modeling of the kinetics of certain variables (VE-TV-BF-HR) will be performed and then a mathematical model will be developed 
to quantify and compare these kinetics between subgroups. Comparisons of kinetics between subgroups will be made using 
recently developed mixed-effects functional analysis of variance (FANOVA) methods. 
The kinetics of some variables will be expressed as a function of developed power (in watts), metabolic power (VO2 in L/min), 
ventilatory flow (in L/min), HR expressed in absolute value, in % of the max HR reached and in % of the predicted value according 
to the formula maxHR = 210-0.65 x age). 
 
9. Sample size 
 1 000 patients with exercise intolerance after COVID are expected for the enrollment period. 
10. Legal and ethical considerations 
10.1. Ethical considerations 
This study has been filed with the Commission Nationale Informatique et Liberté – CNIL and is registered in the public directory 
maintained by the French Health Data Hub. 
 
10.2. Information to patients 
As is commonly done on admission to hospitals, a signed informed consent form will be attached to the administrative and medical 
file of the patient. 
 
In the absence of an informed consent form, patients who have undergone CPET will be contacted and informed of the modalities 
of this study in order to sign an informed consent form (Appendix 1). 
This will be done as long as it does not involve a disproportionate effort. 
 
10.3. Pharmacovigilance 
In accordance with the Jardé law, pharmacovigilance reports of serious adverse events (SAEs) concerning drugs will not be 
collected during the study, nor transmitted to the pharmaceutical companies concerned. 
Adverse events and SAEs will be managed by the investigators according to their usual practices. 
 
10.4. Protocol amendment 
Any modification of the protocol will have to be discussed and approved by the steering committee and will be subject to an 
amendment. 
Minor changes (editorial corrections to improve comprehension, spelling corrections, administrative changes ...) will result in an 
increase of the number after the dot in the version number: version 1.1 instead of version 1.0. 
Major changes will result in an increase of the number before the dot in the version number: version 2.0 instead of version 1.0. 
Major changes will be reported to the appropriate authorities. 
 
10.5. Archiving 
The study data manager, who is also the study management center, will retain all study data for the following periods: 
 
Patient data: Retention in the controller's information system for up to 2 years after the last publication or, in the absence 
of publication, until the final research report is signed. 
 
Professional data: 15 years maximum from the end of the last research in which the health professional participated. 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
15/23 
Following this, these data will be archived on paper or computer for a maximum of 20 years in accordance with the Cnil 
deliberation n° 2018-155 of May 3, 2018 (MR-004). 
 
10.6. Financial Partner 
This study will be conducted with the financial support of the Pharmaceutical Companies Menarini France and AstraZeneca.

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
16/23 
Appendix 1: Informed Consent Form 
 
Informed Consent Form 
June 9, 2023 
 
Kinetics of physiological and symptomatic responses to CardioPulmonary Exercise Testing (CPET) in subjects with 
persistent exercise intolerance after COVID-19: an Open-Source Exercise Network 
 
Dear Madam, Dear Sir, 
Dr. ______________________________ (LAST NAME, First name), practicing at the hospital/clinic ____________________________________,  
offers you to participate in a research study to better understand persistent exercise intolerance after COVID. By analyzing information from a 
large cohort, it is possible to identify subgroups of people with common clinical characteristics that will allow a more detailed understanding of 
the mechanism and determinants of persistent symptoms, and consequently to propose more adapted treatments.  
The physician with whom you have performed a cardiopulmonary exercise test (CPET) is participating in this study which is organized under the 
aegis of a scientific committee composed of pulmonologists, cardiologists and physiologists.   
Study data manager: 
 
 
Coordinator:  
Principal investigators: 
aCCPP Association 1901  
Association pour la Complémentarité des Connaisances et des Pratiques de la Pneumologie 
Pr Bernard Aguilaniu (Grenoble Alpes University Hospital) 
Pr PierAntonio Laveneziana (La Pitié Salpétrière Paris University Hospital) 
Pr Frédéric Costes (Clermont-Ferrand University Hospital) 
 
Information collected - Regulations - Publication 
This is an observational study that consists of collecting physiological information from your exercise test and clinical information about your 
health. This information will be collected on an electronic medium that will allow statistical analysis of all 600 records that we wish to collect. 
The main data on your health status are: 
Age - weight, height, sex 
History of chronic disease (e.g. cardiovascular, respiratory or metabolic diseases, etc.), 
Date of COVID and initial and persistent symptoms 
This observational study, which complies with the French MR-004 reference methodology, is published in the French Health Data Hub national 
directory. The Declaration of conformity to the reference methodology MR-004 was made to the National Commission for Information 
Technology and Civil Liberties (CNIL) on April 25, 2022 and bears the reference n°2226149 v 0.  
Therefore, your voluntary participation does not require any additional visit or examination compared to your usual care. If you do not want 
your data to be analyzed, this will not influence in any way the care provided by your doctor. At any time, you may revoke your decision to 
participate in the study and this decision will not affect your medical follow-up. 
All data collected are pseudonymized, i.e., identifying information does not appear at any time in the study documents and publications. 
They are saved under the responsibility of the aCCPP, promoter of the research. 
The aCCPP is responsible for processing your personal data for scientific research purposes in the context of this study (art. 9.2(j) of 
Regulation (EU) No. 679/2016 of the European Parliament and of the Council of 27 April 2016 on the protection of individuals with regard to the 
processing of personal data and on the free movement of such data, hereinafter referred to as the "GDPR" or "Regulation"). This processing is 
implemented on the basis of the legitimate interest of the aCCPP to undertake scientific research in the field of pulmonology (Art. 6.1(f) GDPR).  
The data of this research will be kept in the information system of the controller until 2 years after the last publication or in the absence of 
publication, until the signature of the final report of the research. They will then be archived on paper or digital storage medium for a maximum 
period of 20 years. 
In addition, all research projects carried out by the aCCPP are published on the website: https://colibri.semaphore-sante.fr/. From this site, 
you can consult the projects in progress, ask questions and also oppose that your personal data contribute to a specific research project. The 
data collected during this study, aggregated and thus strictly anonymized, will be published in scientific medical journals by the scientific 
committee. You will be informed of the results through the investigating physician of the medical department in which you are being treated, if 
you wish, as soon as they are available. 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
17/23 
Rights of data subjects 
In accordance with Article 13 of the GDPR, we inform you that your data will be processed in accordance with the Regulation and with the rules 
of confidentiality to which the aCCPP association attaches particular importance. You have several rights regarding the information about you: 
 
You can ask to have access to the information concerning you in order to obtain a copy of it and the indication of the uses which are 
made of it (right of access); 
 
You can ask to correct and update information about you (right to rectification); 
 
You may object to the use of this information for research (right to object). This opposition prevents any use or conservation of these 
data; 
 
You can obtain the erasure of this data (right to erasure); 
You can exercise these rights at any time with the aCCPP, for the attention of the Data Protection Officer (DPO), 19 avenue Marcelin Berthelot, 
38 100 Grenoble - FRANCE, dpo@colibri-pneumo.fr, which undertakes to act on them as soon as possible or within a maximum period of one 
month (article 12.3 of the RGPD). You can also exercise these rights with the doctor who is following you in the study and who alone knows your 
identity.  
 
If you consider that the processing of your personal information constitutes a violation of the General Data Protection Regulation, you 
may lodge a complaint with the CNIL (right to lodge a complaint with a supervisory authority). 
 
Consent 
I freely consent to participate in the study entitled: 
“Kinetics of physiological and symptomatic responses to CardioPulmonary Exercise Testing (CPET) in subjects with persistent exercise 
intolerance after COVID-19: an Open-Source Exercise Network” 
 
I have read the informed consent form explaining the purpose of this study, how it will be conducted and what my participation will 
entail, 
 
I have received appropriate answers to all my questions, 
 
I have understood that my participation is free and that I can interrupt it at any time without incurring any responsibility or any 
prejudice to the quality of the care I will receive. I will then indicate to the doctor who is treating me whether or not I wish the data 
collected up to the moment of my decision to be used, 
 
My consent does not relieve the physician who is following me in the study of any of his responsibilities and I retain all my rights 
guaranteed by law. 
 
Patient’s signature 
 
LAST NAME First name : 
Date:  
Signature: 
Investigating physician’s signature 
 
LAST NAME First name : 
Date:  
Signature: 
 
 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
18/23 
Appendix 2: CPET post-COVID questionnaire 
 
 
 
Date COVID 
Date CPET (EFX) 
month/year 
day/month/year 
 
 
 
 
Main comorbidities 
Pulmonary
Disease 
Arterial 
hypertension
Cardiac
Disease 
Metabolic
Disease 
Chronic renal 
failure 
Chronic 
Hepatic failure 
Psychiatric
condition 
Cancer 
No 
No 
No 
No 
No 
No 
No 
No 
YES 
YES 
YES 
YES 
YES 
YES 
YES 
YES 
Obstructive 
Myocardiopathy 
DT2 
Anxiety Treated 
Cured 
Interstitial 
Coronary disease 
DID 
Dépression Treated 
Remission 
Vascular 
Valvular disease 
Thyroid Insufficiency 
Psychosis 
Progression  
Others 
Congénital Disease 
Others 
Cognitive disorder 
Chronic Heart Failure 
Others 
 
 
 
COVID:  initial clinical presentation 
Besoin en O2  
CT-scan Parenchyma Extension 
Symptomes non respiratoires 
No 
No 
No 
YES 
YES 
YES 
0.5-6 L/min 
Mild           < 10 % 
Prolonged fever  
> 6 L/min 
Moderate  10-24 % 
Fatigue 
Hight Flow 
Moderate-to-severe        25-49 % 
Joints/muscle pain/stiffness 
Invasive ventilation 
Severe       ≥ 50 % 
Headache 
Anosmia and/or agueusia 
Gastrointestinal 
Neurological 
Cardiac/Pericardial 
 
 
 
Anonymized Center Code
Anonymized patient code 
Sex 
Age 
Weight 
Height 
///// 
///// 
M/F 
years 
kg 
cm 
Physical Activity Level  before COVID-19 
Sport (h/week) 
Work Activities 
Daily Physical Activities 
Seating Time  
No 
No  
YES 
YES 
< 4 h 
< 4 h 
With movement 
Mainly Domestic  (Inside) 
4 –  7 h 
4-6 
h 
Without movement 
Leisure Time Activities  (Outside ≥ 60 min /J) 
>  7 h 
6 à 10 h 
   
> 10 h 
Sport competition 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
19/23 
Symptoms Post COVID 
Dyspnoea
Fatigue
Cough
Muscle/
Joint pain
Anxiety
Agueusie
Anosmia
Headhache Neurological
Gastro
intestinal
Palpitations
Vertigo
Others
 
 
 
 
 
 
 
 
 
 
 
 
 
No 
No 
No 
No 
No 
No 
No 
No 
No 
No 
No 
No 
No 
Yes 
Yes
 
+ /++/ +++ 
Yes
 
+ /++/ +++
Yes
 
+ /++/ +++ 
Yes
 
+ /++/ +++
Yes
 
+ /++/ +++
Yes
 
+ /++/ +++
Yes
 
+ /++/ +++
Yes
 
+ /++/ +++ 
Yes
 
+ /++/ +++ 
Yes
 
+ /++/ +++ 
Yes
 
+ /++/ +++ 
Yes
 
+ /++/ +++ 
Gasping for 
breath 
 
 
 
 
 
 
 
 
 
 
 
 
Shortness of 
breath 
 
 
 
 
 
 
 
 
 
 
 
 
Chest 
tightness 
 
 
 
 
 
 
 
 
 
 
 
 
Incomplete or 
unsatisfactory 
breathing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Evaluation 
ECG 
Echocardiography 
MRI 
No 
No 
No 
Yes 
Yes 
Yes 
Normal 
Normal 
Normal 
Abnormal 
Abnormal 
Abnormal 
 
Questionnaires Scores 
Hosp. Anxiety and Depression Scale 
Chalmers 
Anxiety 
Depression 
Fatigue 
Not Done 
Not Done 
Not Done 
Value 
Value 
Value 
 
Rest Pulmonary Function 
FEV1 
FVC 
SVC 
TlCO 
(L.) 
(L.) 
(L.) 
(mlco/min/mmHg) 
Value 
Value 
Value 
Value 
 
Treatments with potential effects on exercise responses 
Pulmonary 
Cardiovascular 
Others 
No 
No 
No 
Yes 
Yes 
Yes 
Bronchodilatators 
Betablockers 
To be specify 
 
Calcium inhibitors 
 
 
Maximal Borg Scale 
Dyspnoea 
Fatigue 
Muscular pain 
0  to 10 
0 to 10 
0 to 10 
 
 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
20/23 
Appendix 3: Borg scale 
 
The Borg scale should be used during exercise after giving the following explanation to the patient: 
- 
This scale will assess the intensity of your breathlessness and muscle fatigue during exercise.  
- 
I will ask you at regular intervals to indicate the intensity of your breathlessness and then immediately afterwards, the 
intensity of your muscular fatigue.  
- 
To answer you will have to indicate with your finger the situation that best corresponds to what you feel, either by showing 
the number from zero to 10, or by indicating the words that best express this intensity.  
- 
So I let you read the scale:  
o 
0 corresponds to no breathlessness or fatigue 
o 
10 corresponds to the maximum intensity ever felt for breathlessness (or muscular fatigue) 
o 
Right now (at rest), indicate the intensity of your breathlessness..., indicate your muscular fatigue 
 
 
 
 
 
 
0 Rest
0,5 Very, Very Easy (barely noticeable)
1 Very, Very Easy
2 Easy
3 Moderate
4 Somewhat Hard
5 Hard
6
7 Very Hard
8
9
10 Maximal
BORG scale

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
21/23 
Appendix 4: Methodology of the CPET  
 
The main recommendations are: 
a. No need to record ventilatory measurements in the resting state  
b. Continuous recording of ventilatory and ECG measurements; and discontinuous (see below) recording of blood 
pressure, symptoms and blood gases during the following 3 phases: 
- 
A steady state phase of 3 minutes at constant load 20-30-40 or 50 watts, depending on clinical situation and body 
mass. 
- 
An incremental phase of 10-15 or 20 watts depending on the clinical situation and body mass. 
- 
A recovery phase for a minimum of 3 minutes without load, pedaling without load. 
 
c. 
Borg Dyspnea then Borg Muscle Fatigue  
 
At the end of the steady state,  
 
Every 2 minutes,  
 
At maximal exercise, 
 
At 3 minutes post exercise (Borg D + Borg F). 
 
c. 
Capillary or arterial blood gases including lactatemia if possible  
 
At the end of steady state, 
 
At maximal exercise, 
 
Intermediate stages depending on clinical situation 
 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
22/23 
 Appendix 5: HADS questionnaire 
 

CPET Post-COVID 
Protocol-June 2023-Version 1.2 
23/23 
Appendix 6: Chalder faigue scale 
 
Completion of the Chalder fatigue scale 
Explanation to be given:  
"Indicate for each question how you are currently doing compared to your status before COVID infection” 
 
 
Scoring of responses 
Less than usual = 0 
No more than usual  = 1 
More than usual = 2 
Much more than usual = 3 
 
2 
Possible scores: 
 Total of the 11 questions:  
≤ 11/33 = no difference / before COVID 
 
 Answers YES/NO 
 
Every response  0 or 1 = 0 (so the 2 left colums) 
Every response 2 or 3 = 1 (so the 2 right colums) 
Increased fatigue (YES) if the sum of the 2 right columns is > 4  
Craig Jackson. The Chalder Fatigue Scale (CFQ11) Occupational Medecine 2015 
Less than 
usual
No more 
than usual
More than 
usual
Much more 
than usual
1. Do you have problems with 
tiredness?
2. Do you need to rest more?
3. Do you feel sleepy or 
drowsy?
4. Do you have problems 
starting things?
5. Do you lack energy?
6. Do you have less strenght 
in your muscles?
7. Do you feel week?
8. Do you have difficulties 
concentrating?
8. Do you make slips of the 
tongue when speaking?
8. Do you find it difficult to 
find the right word?
8. Do you have memory 
difficulties?
PHYSICAL SYMPTOMS
MENTAL SYMPTOMS