Interrogative Approaches Identify Causes of Physical Impairment in Those Affected by Post COVID-19 Morbidity (Long COVID) - an International Multicenter Observational Study
Conditions: Long COVID, COVID Long-Haul
Sponsor: Sheffield Hallam University

 
 
Sensitivity: Internal 
Profiling the determinants of recovery to establish novel rehabilitation 
guidelines to improve clinically relevant and patient-reported outcomes in the 
post-COVID-19 period across 3 individual countries. 
 
Background  
The value of clinical cardiopulmonary exercise testing (CPET) 
within healthcare settings has been established in the last decad. 
CPET methods remain highly relevant in the COVID-19 endemic 
phase and should be used to assess those recovering from 
COVID-19 infection. This diagnostic tool could play an integral 
role in disease prognostication and evaluate the integrative 
response to incremental exercise. Date from such assessments 
can enable practitioners to characterise cardio-respiratory 
fitness and identify reasons for physical impairment or abnormal 
cardio-respiratory function. More than 50% of patients admitted 
to hospital will experience cardiorespiratory issues and 
significant morbidity during their recovery and will require 
significant rehabilitative support. In this context, measurements 
obtained from an assessment of cardio-respiratory responses to 
physiological stress could provide insight regarding the integrity 
of the pulmonary-vascular interface and characterisation of any 
impairment or abnormal cardio-respiratory function. Current 
approaches to rehabilitation are being developed on existing 
knowledge from Severe Acute Respiratory Syndrome (SARS) 
and Acute Respiratory Distress Syndrome (ARDS) related 
illness. These provide important insight but do not provide insight 
into the novel challenges provided by COVID-19.  
We bring together three clinical and academic research centres 
from around the world that collaborate as part of the Healthy 
Living for Pandemic Event Protection international network to 
conduct a minimum of 150 2-day CPET tests in patients that 
hospitalised with COVID-19. Patients will be engaged in testing 
in the UK (led by Faghy from the Human Science Research 
Centre, Derby and Maden-Wilkinson from the Research and 
Innovation for post-COVID-19 Rehabilitation centre, Sheffield), 
USA (led by Arena and Ozemek at the University of Illinois at 
Chicago) and India (led by Veluswamy and Babu at the Ramaiah 
Medical College, Bangalore). All tests will be conducted 
following standardised procedures documented by the American 
College of Sports Medicine.  
Acronym 
HL-PIVOT-LCR 
Short title 
HL-PIVOT: Long COVID Rehabilitation 
Chief Investigators 
Dr Mark Faghy (UK) 
Dr Cemal Ozemek (USA) 
Dr Sundar Kumar Veluswamy (India) 

 
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Aim 
Evaluate the integrative response to incremental exercise and 
increase diagnostic information relating to post-COVID-19 
morbidity. 
 
Assess cardio-respiratory responses to physiological stress and 
provide insight regarding the integrity of the pulmonary-vascular 
interface and characterization of any impairment or abnormal 
cardio-respiratory function. 
Trial Configuration 
Multi-Centre Observational Study 
Setting 
University Research Centre and Medical Facilities  
Number of 
participants 
150 (n=50 per centre). 
Eligibility criteria 
Eligibility 
• Aged 18 to 65 years old 
• Diagnosed with COVID-19  
• Still suffering from symptoms and experiencing functional 
limitations beyond 3 months after initial COVID-19 
infection (quantified as PCFS grade 1 or greater). 
• Sufficient English language comprehension and cognitive 
ability to understand the study protocol, give informed 
consent and follow instructions.  
Exclusion 
• <18 years of age 
• Admitted to or received treatment from Intensive Care 
Units   
• Unconfirmed COVID-19 test diagnosis  
• Pregnancy 
• Unable to perform cycle exercise.  
• Unable to understand verbal or written information in 
English 
• Achieving a grade 0 on the PCFS. 
• Unstable angina  
• Uncontrolled hypertension, that is, resting systolic blood 
pressure (SBP) >180mmHg, or resting diastolic blood 
pressure (BP) (DBP) >110mmHg  
• Orthostatic blood pressure drop of >20 mmHg with 
symptoms  
• Significant aortic stenosis (aortic valve area 120 bpm)  
• Acute pericarditis or myocarditis  

 
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• Decompensated HF  
• Third degree (complete) atrioventricular (AV) block 
without pacemaker  
• Recent embolism  
• Acute thrombophlebitis  
• Resting ST segment displacement (>2 mm)  
• Uncontrolled diabetes mellitus  
• Severe orthopaedic conditions that would prohibit 
exercise  
• Other metabolic conditions, such as acute thyroiditis, 
hypokalaemia, hyperkalaemia or hypovolaemia (until 
adequately treated)  
• Severe grade 3 rejection (cardiac transplantation 
recipients Appendix N) 
Description of 
interventions 
Consecutive day 2 day CPET and follow up for 7 days for 
subjective feelings/fatigue.  
Duration of study 
Study Duration:  
- Total trial duration 12 months 
o Recruitment 6 months (November 2022 to April 
2023) 
o Data Collection (November 2022-April 2023) 
o Analysis and reporting: 4 months (April 2023-
July 2023) 
- Participant Duration: 3 sessions (1 Familiarisation, 2 
CPET on consecutive days) and 1 week follow up 
Randomisation and 
blinding 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Study Investigators 
Chief Investigator: 
Dr Mark Faghy 
Senior Lecturer in Exercise Physiology 
School of Human Sciences 
University of Derby, UK 
 
Principle Investigator (Sheffield, UK) 
Dr Tom Maden-Wilkinson 
Senior Research Fellow 
Advanced Wellbeing Research Centre 
Sheffield Hallam University, UK 
 
Principle Investigator (Chicago, USA) 
Dr Cemal Ozemek 
Clinical Associate Professor 
Department of Physical Therapy 
University of Illinois at Chicago 
Chicago, USA 
  
Principle Investigator (Bengaluru, India) 
Dr Sundar Kumar Veluswamy 
Assistant 
Professor, 
Department 
of 
Physiotherapy 
Ramaiah Medical College, Bengaluru, 
India  
 
Co-Investigator: 
Dr. Ross Arena 
Professor 
Department of Physical Therapy 
University of Illinois at Chicago 
Chicago, USA 
 
Co-Investigator: 
Dr Ruth Ashton 
Lecturer in Exercise Physiology 
School of Human Sciences 
University of Derby, UK 
 
Co-Investigator: 
Prof. Rob Copeland 
Director, Advanced Wellbeing Research 
Centre 
Sheffield Hallam University 
 
 
Co-Investigator: 
Dr Thomas Bewick 
Consultant Respiratory Physician 
University Hospitals of Derby and Burton 
Derby, UK 
Co-Investigator: 
Dr Deepika Patel 
Assistant Professor 
Department of Physical Therapy 
University of Illinois at Chicago 
Chicago, USA 
 
Co-Investigator: 
Dr Emma Sharpe 
School of Human Sciences 
University of Derby 
Co-Investigator: 
Mr Alex Bugg 
Researcher, 
Advanced 
Wellbeing 
Research 
Centre, 
Sheffield 
Hallam 
University. 
 
Co-Investigator: 
Dr Simon Goodwill, Principal Research 
Fellow, Advanced Wellbeing Research 
Centre, Sheffield Hallam University. 
Co-Investigator: 
Dr Caroline Dalton, Associate Professor, 
Advanced Wellbeing Research Centre, 
Sheffield Hallam University.  
 
Co-Investigator: 
 
 
 
 

 
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Contents 
 
1.0 Background .................................................................................................................... 7 
2.0 Aims and Objectives .................................................................................................... 7 
2.1 Primary Aim .................................................................................................................. 7 
2.2 Secondary Aims ........................................................................................................... 7 
3.0 Study Design .................................................................................................................. 8 
3.1 Study Sites ................................................................................................................... 8 
3.2 Sample Size ................................................................................................................. 8 
3.3 Eligibility and Exclusion .............................................................................................. 9 
3.4 Approach/Recruitment .............................................................................................. 10 
3.5 Ethical Considerations .............................................................................................. 10 
3.5.1 Consent ................................................................................................................ 10 
3.5.2 Deception ............................................................................................................. 10 
3.5.3 Debriefing ............................................................................................................. 10 
3.5.4 Withdrawal from the investigation .................................................................... 10 
3.5.5 Anonymity and Confidentiality .......................................................................... 11 
3.5.6 Protection of Participants ................................................................................... 11 
3.5.7 Observation Research ....................................................................................... 11 
3.5.8 Giving Advice ...................................................................................................... 11 
3.5.9 GDPR - Collecting Personal Data .................................................................... 11 
3.5.10 Basis for Collecting Data ................................................................................. 12 
3.5.11 Data Retention .................................................................................................. 12 
3.5.12 Rights of Data Subject ..................................................................................... 12 
4.0 Study Protocol ............................................................................................................. 12 
4.1 Baseline Clinical Data ............................................................................................... 13 
4.1.1 Anthropometrics (Session 1) ............................................................................. 13 
4.1.2 Questionnaires .................................................................................................... 13 
4.1.3 Functional Status ................................................................................................ 14 
4.1.4 Lung Function (Session 1) ................................................................................ 15 
4.1.5 Electrocardiogram (ECG) and Blood Pressure (Session 2 and 3) .............. 15 
4.1.6 Cardiopulmonary Exercise Test (CPET) (Session 2 and 3) ......................... 15 
4.2 Follow-up Assessments ............................................................................................ 17 
4.3 Safety of Graded Exercise Testing ......................................................................... 17 

 
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4.4 Risk Management ...................................................................................................... 17 
4.4.1 Cardiovascular Risk ........................................................................................... 17 
4.4.2 Musculoskeletal Risk .......................................................................................... 17 
4.4.3 Post-Exertional Malaise ..................................................................................... 17 
4.5 Statistical Analysis ..................................................................................................... 18 
4.6 Sponsor and Coordination ....................................................................................... 18 
4.7 Adverse Events and Reporting ................................................................................ 18 
4.7.1 Definition of Adverse Event (AE) ...................................................................... 18 
4.7.2 Non-serious AEs ................................................................................................. 19 
4.7.3 Abnormal Baseline Findings ............................................................................. 19 
4.7.4 Reporting Procedures for All AEs .................................................................... 19 
4.7.5 Definition of Serious Adverse Event (SAE) ..................................................... 20 
4.7.6 Reporting Procedures for All SAEs .................................................................. 20 
5.0 Data Protection and Patient Confidentiality ......................................................... 21 
6.0 Data Retention and Archiving .................................................................................. 21 
6.1 Amendments .............................................................................................................. 22 
6.2 Access to the Final Study Dataset .......................................................................... 22 
7.0 Financing and Insurance .......................................................................................... 22 
7.1 Participant Incentives ................................................................................................ 22 
7.2 Funding ....................................................................................................................... 23 
8.0 Public Patient Involvement ....................................................................................... 23 
9.0 End of Study ................................................................................................................. 23 
10.0 Discontinuation/Withdrawal of Participants from Study Treatment ............ 23 
11.0 Dissemination ............................................................................................................ 24 
11.1 Authorship eligibility guidelines and any intended use of professional writers
 ............................................................................................................................................ 24 
12.0 References .................................................................................................................. 24 
 
 
 

 
 
Sensitivity: Internal 
1.0 Background 
The value of clinical cardiopulmonary exercise testing (CPET) within healthcare 
settings has been established in the last decade [5]. CPET methods remain highly 
relevant in the COVID-19 endemic phase and should be used to assess those 
recovering from COVID-19 infection. This diagnostic tool could play an integral role in 
disease prognostication and evaluate the integrative response to incremental 
exercise. Date from such assessments can enable practitioners to characterise cardio-
respiratory fitness and identify reasons for physical impairment or abnormal cardio-
respiratory function. More than 50% of patients admitted to hospital will experience 
cardiorespiratory issues and significant morbidity during their recovery and will require 
significant rehabilitative support. In this context, measurements obtained from an 
assessment of cardio-respiratory responses to physiological stress could provide 
insight regarding the integrity of the pulmonary-vascular interface and characterisation 
of any impairment or abnormal cardio-respiratory function. Current approaches to 
rehabilitation are being developed on existing knowledge from Severe Acute 
Respiratory Syndrome (SARS) and Acute Respiratory Distress Syndrome (ARDS) 
related illness. These provide important insight but do not provide insight into the novel 
challenges provided by COVID-19.  
We bring together three clinical and academic research centres from around the world 
that collaborate as part of the Healthy Living for Pandemic Event Protection 
international network to conduct a minimum of 150 2-day CPET tests in patients that 
hospitalised with COVID-19. Patients will be engaged in testing in the UK (led by 
Faghy from the Human Science Research Centre, Derby and Maden-Wilkinson from 
the Research and Innovation for post-COVID-19 Rehabilitation centre, Sheffield), USA 
(led by Arena and Ozemek at the University of Illinois at Chicago) and India (led by 
Veluswamy and Babu at the Ramaiah Medical College, Bangalore). All tests will be 
conducted following standardised procedures documented by the American College 
of Sports Medicine. 
2.0 Aims and Objectives 
• Evaluate the integrative response to incremental exercise and increase 
diagnostic information relating to post-COVID-19 morbidity. 
• Assess cardio-respiratory responses to physiological stress and provide 
insight regarding the integrity of the pulmonary-vascular interface and 
characterization of any impairment or abnormal cardio-respiratory function. 
 
2.1 Primary Aim  
• Evaluate the integrative response to incremental exercise and increase 
diagnostic information relating to post-COVID-19 morbidity.  
 
2.2 Secondary Aims 
• Examine the relationship between COVID-19 symptom prevalence and 
exercise tolerance 
• Examine the prevalence of post-exertional malaise in people with long covid.  
• Examine the role of vaccination history (COVID-19) on exercise tolerance.  

 
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• Assess cardio-respiratory responses to physiological stress and provide insight 
regarding the integrity of the pulmonary-vascular interface and characterization 
of any impairment or abnormal cardio-respiratory function. 
3.0 Study Design 
A multicentre, cross-sectional, observational study. 
 
3.1 Study Sites 
 
UK Sites: 
 
The study and data collection will be conducted at the following sites:  
 
• University of Derby Kedleston Road, Derby, DE22 1GB 
• Sheffield Hallam University, Olympic Legacy Park, Sheffield, S9 3TY  
• Northumbria University, Northumberland Building, Newcastle upon Tyne, 
NE1 8ST  
• University of Exeter, Stocker Rd, Exeter, EX4 4PY 
 
International Sites: 
 
Ramaiah Medical College, Bengaluru, India 
In India, the study will be conducted at the Centre for Rehabilitation, and the 
Department of Physiotherapy at the Ramaiah Medical College Hospitals. Patients will 
be recruited through telephonic follow-up of patients discharged from the Ramaiah 
Medical College Hospitals as well as through the Post COVID Clinic of at Ramaiah 
Memorial Hospital. 
 
University of Illnois, Chicago.  
In the USA, study visits will be conducted at the University of Illinois’ Physical Therapy 
Faculty Practice, Chicago, IL, USA. Patients will be recruited from the University of 
Illinois Hospital through the pulmonology and cardiology clinics as well as through 
word of mouth and social media. 
 
3.2 Sample Size 
A minimum of 150 patients admitted to hospital with a positive COVID-19 infection will 
be recruited for WP2. Patients for WP2 will be recruited to the study from three 
international centres (UK; led by Faghy, Royal Derby and Burton Hospital Trust and 
the Research and Innovation for post-COVID-19 Rehabilitation Centre; USA led by 
Arena, University of Illinois at Chicago; India led by Veluswamy , Ramaiah Medical 
College, Bengaluru. In line with the consensus in current literature, patients will not be 
treated in intensive care units. Those requiring rigorous treatment via intensive care 
units will experience profound complications in the post-COVID-19 period and trials 
involving these groups have already been established by clinical centres (Imperial 

 
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College London). Currently the Office for National Statistics estimates that 1.2 million 
people in the UK are suffering with Long COVID. 
 
3.3 Eligibility and Exclusion 
Eligibility criteria includes: 
• Aged 18 to 65 years old 
• Diagnosed with COVID-19  
• Still suffering from symptoms of COVID-19, 3 months after initial infection 
• Sufficient English language comprehension and cognitive ability to 
understand the study protocol, give informed consent and follow instructions. 
 
Exclusion criteria includes: 
• <18 years of age 
• Admitted to or received treatment from Intensive Care Units  
• Unconfirmed COVID-19 test diagnosis  
• Unable to understand verbal or written information in English 
• Achieving a grade 0 or 1 on the PCFS. 
• Unstable angina  
• Uncontrolled hypertension, that is, resting systolic blood pressure 
(SBP) >180mmHg, or resting diastolic blood pressure (BP) (DBP) >110mmHg  
• Orthostatic blood pressure drop of >20 mmHg with symptoms  
• Significant aortic stenosis (aortic valve area 120 bpm)  
• Acute pericarditis or myocarditis  
• Decompensated HF  
• Third degree (complete) atrioventricular (AV) block without pacemaker  
• Recent embolism  
• Acute thrombophlebitis  
• Resting ST segment displacement (>2 mm)  
• Uncontrolled diabetes mellitus  
• Severe orthopaedic conditions that would prohibit exercise  
• Other metabolic conditions, such as acute thyroiditis, hypokalaemia, 
hyperkalaemia or hypovolaemia (until adequately treated)  
• Severe grade 3 rejection (cardiac transplantation recipients Appendix N). 
 

 
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3.4 Approach/Recruitment 
Participants will be recruited from existing patient databases and Long COVID clinics 
in the UK as well as through social media.  
 
3.5 Ethical Considerations 
3.5.1 Consent 
Eligible patients will be identified at the designated PIC sites (STH, Sheffield; UIC, 
USA and Ramaiah, India) by individuals knowledgeable about the research. The 
researcher will introduce themselves to the patient and/or patient representatives and 
explain the nature of their visit to the patient. The researcher will proceed, if the patient 
agrees, to discuss the nature, objective, risks, and benefits of the proposed research. 
This will include the provision of written information regarding the research study, 
implications, expected outcomes, risks, and benefits. The patient will be allowed to 
ask questions throughout this process. 
 
Once patients have indicated their willingness to participate in the research, they will 
be invited to a session at their local site. Consent will be obtained by members of the 
research team and documented using the study consent form. Informed consent will 
be obtained before the participant undergoing any activities that are specifically for the 
study. All study documentation (i.e. participant information sheet, participant consent 
form) will be kept in the Trial Master File. 
 
The right of the patient to refuse to participate in the study without giving any reason 
must be respected. Equally, the patient will be free to withdraw their consent to 
participate in the study without providing any reasons and without prejudicing his or 
her further treatment. 
 
3.5.2 Deception 
No deception will occur within this project. All research aims and procedures will be 
articulated to the patient and included within the PIS. 
 
3.5.3 Debriefing 
All participants will be given the opportunity to hear about the results of the study in 
the form a short summary upon completion. This will be provided by the chief 
investigator and all participants will be able to 'opt out' of this opportunity should they 
wish to. 
 
Regardless all participants will be thanked for their participation at the final visit. 
 
3.5.4 Withdrawal from the investigation 
Patients will be free to withdraw their consent to participate in the study at any time 
without providing any reasons and without prejudicing his or her further treatment. 
 
Withdrawal from the investigation can be done at any time by contacting the chief 
investigator and/or members of the study team using the contact details provided on 
the PIS. 
 

 
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3.5.5 Anonymity and Confidentiality 
Information related to participating in the study will be kept confidential and managed 
in accordance with the Data Protection Act, NHS Caldecott Principles, The Research 
Governance Framework for Health and Social Care and the conditions of Research 
Ethics Committee approval. 
 
Staff involved in the study will ensure that all participants’ confidentiality is maintained 
at all times.  
 
On all study documentation participants will be identified only by a unique patient study 
identification number on the CRF and central electronic database (Redcap). 
 
3.5.6 Protection of Participants 
All components of the research activity has been approved by local NHS REC and the 
HRA (via the IRAS system) and all planned activities have also been approved by the 
clinical research support team. All participants will be informed and aware of the 
expectations taking part in the research and will be provided with regular opportunity 
to ask questions relating to their involvement. 
 
3.5.7 Observation Research 
This study will comprise of a 2-week cohort observation. Whilst the study design is 
adopting an observational approach participants will be made aware of all research 
activities. 
 
3.5.8 Giving Advice 
No advice will be provided by the research team. If patients raise questions relating to 
clinical issues relating to their health, they will be directed to 
contact their GP. 
 
The PIS also provides links to NHS helpline/advice pages which patients will be 
directed too. 
 
Research will not be undertaken in public places. 
 
3.5.9 GDPR - Collecting Personal Data 
Researchers will be collecting data from participants in this study. This data has been 
specifically chosen to achieve the aforementioned aims and study outcomes and in 
the public interest of enhancing clinical understanding academic research. No 
information that is not directly associated with the research questions will be collected. 
 
This is the legal basis on which we are collecting your data and while this allows us to 
use your data, it also means we have obligations towards you to: 
• Not seek more information from you than what is essential and necessary for 
the study; 
• Make sure that you are not identified by the data by anonymising it using ID 
codes; 
• Use your anonymised data only for the purposes of this study and for any 
relevant publications that arise from it; 

 
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• Store data safely in password-protected databases to which only the named 
researchers have access; 
• Not keep your information for longer than is necessary (usually for seven 
years); 
• Safely destroy your data by shredding or permanently deleting them. 
• Researchers on the project with access to the data are supervised by highly 
qualified and experienced staff and have been very careful to ensure the 
security of your data.  
 
The study was approved for its ethical standards by Health Research Authority (IRAS 
313936) and the University of Derby Human Sciences Research Ethics Committee. 
 
3.5.10 Basis for Collecting Data 
Consent 
 
3.5.11 Data Retention 
Study records will be stored for 15 years according to the Research & Innovation Office 
SOP for archiving, in a secure off-site storage. Direct access to source documents and 
data will be granted to authorised representatives from the sponsor, host institution 
and the regulatory authorities to permit trial-related monitoring, audits, inspections and 
reviews. 
 
3.5.12 Rights of Data Subject 
All rights have been addressed via the utilisation of the GCP guidelines and via HRA 
approval. 
 
4.0 Study Protocol 
Each test will be interpreted following published guidelines provided by the American 
College of Sports Medicine. Upon the conclusion of each test, the key descriptive 
characteristics and findings will be recorded to facilitate the use of cohort analyses. 
Data will be stratified according to the demographic (age, gender, ethnicity, pre-
COVID-19 functional status and important physiological parameters for a given 
workload (absolute and relative oxygen consumption or VO2 peak, O2 pulse, alveolar-
arterial O2 gradient, arterial to end-tidal CO2 difference and the relationship between 
carbon dioxide output and ventilation (VE/VCO2 slope)). These approaches will be 
used to identify differences, trends and patterns in key defining variables that might 
lead to longstanding impairment/morbidity. Study day 1 will be conducted 7-10 days 
post baseline measures to ensure no symptoms of post exertional malaise and/or 
excessive fatigue from baseline assessments. Patients will wear accelerometers 
during this period to compare baseline and follow up.  

 
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4.1 Baseline Clinical Data 
Data collected will include demographics, the pre-admission symptoms, pre-
admission therapy, preadmission exercise tolerance and performance status 
(retrospective assessment by the patient and/or representative 6 weeks preceding 
admission) level of educational attainment, past-medical history, time and route of 
admission, and in-hospital routine physiological observations (including heart rate, 
blood pressure, oxygen saturation, respiratory rate and temperature). Blood 
biomarkers that are part of clinical profiling such as CRP, total blood count, D-Dimers 
and IL-6 as well as exploratory markers for Long covid mechanisms including 
inflammatory responses and clotting factors. This will also be performed pre and post 
(30mins) exercise bouts..  
 
4.1.1 Anthropometrics (Session 1) 
Participants will be asked to provide an approximate date of onset of COVID-19 and 
whether they have received any COVID-19 vaccinations and the manufacturer of the 
vaccine. Body Mass (kg) and height (m) will be assessed. 
 
4.1.2 Questionnaires 
4.1.2.1 Symptom Profile 
Symptom profile will be measured twice at the baseline assessment (Day 0), to 
capture a) retrospective assessment by the patient of their symptom status at 
symptom onset (essentially their baseline symptoms), and b) their current symptom 
status at the point of testing. 
 
4.1.2.2 Quality of Life 
The EQ-5D-5L is routinely used in the assessment of the quality of life in respiratory 
research and is available in more than 130 languages (EQ-5D-5L). It comprises five 
dimensions (Previously 3): mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has five levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. 
 
4.1.2.3 Sleep Behaviour 
Participants will complete the Pittsburgh Sleep Quality Index (PSQI). The PSQI is a 
self-report measure to assess sleep quality over a 4 week in period, throughout the 
Session 3 (+1 day) 
Symptom Profile* 
ECG  
Resting HR + BP 
CPET Lactate and BP 
Recovery following 
CPET 
HRV 
 
7 Day follow up 
Accelerometery 
Patient Log/Diary 
HRV  
  
Baseline 
Anthropometrics  
Questionnaires 
Symptom Profile*  
Lung Function 
TUG 
6MWT 
  
Session 2 
Symptom Profile* 
ECG  
Resting HR + BP 
CPET Lactate and BP 
Recovery following 
CPET 
HRV 
  

 
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intervention. The measure consists of 19 individual items, with a 0-3 interval scale and 
creates 7 components that produce one global score. The PSQI is reliable and valid 
in the assessment of sleep problems. 
 
4.1.2.4 Fatigue 
Fatigue is a common complaint in patients recovering from an acute respiratory 
infection and is not adequately captured in general quality of life or specific recovery 
questionnaires. Participants will complete 2 separate measures of fatigue at Visit 1 
and Visit 2); (A) the Fatigue Assessment Scale (FAS), a self-reported questionnaire 
validated to assess presence and severity of fatigue; and (B) MFI-20. A 20 item self-
reported questionnaire assessing fatigue across five aspects. 
 
4.1.2.5 MRC Dyspnoea Scale 
The Medical Research Council (MRC) Dyspnoea Scale (MRC) is a measure to grade 
the effect of breathlessness on the person’s daily activities. The MRC is simple to 
administer and is a short 1-5 stage scale (1 item) and allows the person to state the 
extent to which their breathlessness affects their mobility. 
 
4.1.2.6 Post-COVID-19 Functional Status (PCFS) Scale 
The Post-COVID-19 Functional Status (PCFS) Scale will be assessed upon discharge 
from the hospital and during each face-to-face visit to monitor direct recovery and to 
assess functional sequelae. The PCFS will evaluate the ultimate consequences of 
COVID-19 on functional status and supplement other instruments that measure quality 
of life, tiredness, or dyspnoea in the acute phase. The PCFS covers the full spectrum 
of functional outcomes and focuses on both limitations in usual duties/activities and 
changes in lifestyle in six scale grades. Briefly grade 0 reflects the absence of any 
functional limitation, and the death of a patient is recorded in grade D. Upward of grade 
1, symptoms, pain or anxiety are present to an increasing degree. This has no effect 
on activities for patients in grade 1, whereas a lower intensity of the activities is 
required for those in grade 2. Grade 3 accounts for inability to perform certain activities 
forcing patients to structurally modify these. Finally, grade 4 is reserved for those 
patients with severe functional limitations requiring assistance with activities of daily 
living (ADL). 
 
4.1.2.7 Cognition 
The Montreal Cognitive Assessment (MoCA) will be conducted at Visit 1.  To allow 
accurate interpretation, highest educational level/attainment will be recorded during  
data collection  
 
4.1.3 Functional Status 
Two different assessments of lower extremity functional capacity will be conducted at 
each visit these are (A) the 6-minute walk test (6MWT) and (B) the timed up and go 
test (TUG). The 6MWT is a standardised and widely used measure of functional status 
in individuals with chronic disease such as chronic obstructive pulmonary disease, 
cystic fibrosis, congestive cardiac failure, peripheral vascular disease, and elderly. It 
has been previously used to assess response to interventions and predict morbidity 
and mortality. Participants will be given a shortened practice attempt (1-2 minutes) at 
the beginning of each of their assessment visits. This will not be recorded but will be 
performed to allow familiarisation with the assessment and repeated at each visit for 

 
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consistency. Patients suffering from excessive fatigue/Post exertional malaise from 
the 6MWT will be excluded from the study to prevent further onset of these symptoms.  
 
The TUG is reliable and reproducible and has been validated as a predictor of frailty 
and risk of falls in elderly adults. The TUG has several advantages over other 
measures, mainly its reproducibility and shorter assessment time. Its use at predicting 
functional status following pneumonia has not been assessed previously. 
 
Participants will also be asked to self-report their return to functional activity and 
employment at each contact with the research team (telephone consultations and 
follow-up visits.) Each participant will be asked at each contact with the research team 
if they have returned to perform their activities of daily living to the same level as 6 
weeks before admission, and if they have returned to their occupation (if employed.) 
The patient-reported date of return to these activities will also be recorded. 
 
4.1.4 Lung Function (Session 1) 
Full lung function tests including FEV1, FVC, PEFR, flow-volume curves, MIP, and 
MEP will be conducted during first visit. These spirometry measurements will be 
conducted by a suitably qualified individual, proficient in the use of the specific 
equipment and according to published standards. 
 
4.1.5 Electrocardiogram (ECG) and Blood Pressure (Session 2 and 3) 
Participants will then be fitted with: a 12-channel electrocardiography (ECG) device 
(Custo Cardio 200, Customed, Ottobrunn, Germany); a blood pressure cuff positioned 
over the brachial artery (Tango M2, SunTech, Eynsham, UK). Measurements will be 
taken following 10 minutes of supine rest, during sit to stand task and monitored 
continuously throughout the CPET.  
 
4.1.6 Cardiopulmonary Exercise Test (CPET) (Session 2 and 3) 
Cardiopulmonary exercise testing will be performed to measure VO2 peak and other 
parameters representative of cardiovascular reserve (McGregor et al., 2016). Tests 
will be conducted using a standard bicycle ramp protocol in accordance with American 
Thoracic Society guideline (Ross et al., 2003). In accordance with pilot data, we will 
stratify individuals starting load based on their 6MWT distance, Strata I: 6MWD < 350 
(starting load of 10 watts; with subsequent increments of 5 watts), Strata II: 6MWD 
350 – 400 (starting load of 20w with subsequent increments of 5w and Strata III: 
6MWD > 400 (starting load of 30w with subsequent increments of 5W) 
 
Participants will then complete a maximal graded exercise test on a friction-loaded 
cycle ergometer (Monark 894E Ergomedic Peak Bike, Monark, Varberg, Sweden). 
The cycle ergometer friction wheel will be calibrated according to manufacturer 
recommendations prior to the study. The cycle ergometer will be set up according to 
each participant’s body size and personal preference. The knee angle at the bottom 
of the pedal stroke will be ~25°, which is optimal for movement economy and injury 
prevention. Knee angle will be measured using a universal goniometer. The cycle 
ergometer handlebars will be positioned so that the participant can comfortably 
maintain an upright posture. The cycle ergometer set-up will be identical for each visit.  
 

 
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A step-wise incremental exercise test will be performed at a cadence of 60 revolutions 
per minute (rpm) (±10%). The exercise protocol will begin with a 3-minute rest period, 
followed by a step-wise incremental protocol, designed to achieve volitional 
exhaustion within 8-12 minutes of exercise onset. The exercise protocol will be 
individualised based on participants’ predicted exercise capacity, as described above. 
Heart rate and pulmonary gas exchange data will be measured continuously. Blood 
pressure and rating of perceived exertion (RPE) (6 to 20 scale) will be measured 
during the final 15 second period of each minute. For blood pressure measurements, 
participants will be asked to relax their arm and shoulder muscles whilst their forearm 
is rested on the researcher’s shoulder (padded with a folded towel). This will ensure 
that the participant’s arm is positioned near heart level to reduce measurement error. 
At the end of the exercise test, participants will complete a cooldown consisting of 
unloaded pedalling at 20rpm for 5-10 minutes. All data will be exported for offline 
analysis using Microsoft Excel (Washington, USA).  
 
Criteria for the assessment of a good participant effort will include peak respiratory 
exchange ratio (RER) >1.10, peak HR≥85% predicted and RPE ≥18.31 (Balady et al., 
2010). Prior to the test, participants will be monitored for 5 minutes to allow passive 
data collection and for a total of 10 minutes after completion.  
We will analyse over 30s averages to allow for differences in Gas analysis systems 
and monitor heart rate throughout test and 10 minutes seated recovery. Blood 
Pressure monitoring continuously (every 30s). Blood lactate concentration will be 
monitored through fingertip sampling at the end of each stage and at 5-minute intervals 
for 30 minutes following volitional fatigue.   
 
4.1.6.1 Pulmonary Gas Exchange Measures 
Breath-by-breath pulmonary gas exchange data will be smoothed using a middle five 
of seven breath average. Key variables of interest include: the first ventilatory 
threshold (VT1), the respiratory compensation point (RCP), peak oxygen consumption 
(V̇ O2peak) and end-tidal CO2. V̇ O2peak is defined as the mean V̇ O2 over the last 30 
seconds of the exercise test, adjusted for body mass (ml·kg−1·min−1). VT1 will be 
determined by using the V-slope method to identify the deflection point in the 
relationship between V̇ CO2  and V̇ O2 – indicating a disproportionate rise in CO2 
production due to increasing anaerobic glycolytic activity (65). VT1 will be confirmed 
using the nadir of the ventilatory equivalent (VE) for V̇ O2 (VE/V̇ O2) (65). The RCP will 
be determined using the V-slope method to identify the deflection point in the 
relationship between VE and V̇ CO2 – which marks the onset of hyperventilation caused 
by excessive blood lactate accumulation (65). The RCP will be confirmed using the 
nadir of VE/V̇ CO2  (65). The VT1 and the RCP will be confirmed by two researchers at 
each site. Where agreement is not reached, a third researcher will adjudicate. End-
tidal CO2 is the partial pressure of CO2 measured at the end of each breath. 
 
Exercise termination criteria 
Chest pain suggestive of ischaemia 
Fall in systolic blood pressure >20 mmHg from the highest value during exercise 
>225 mmHg systolic blood pressure 
>130 mmHg diastolic blood pressure 
Hypotension (<100 mmHg systolic) 

 
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Severe desaturation: SpO2 ⩽ 80% when accompanied by symptoms of severe hypoxaemia 
Sudden pallor 
Loss of coordination 
Mental confusion 
Dizziness or faintness 
Signs of respiratory failure 
 
 
 
4.2 Follow-up Assessments 
Using a custom developed application alongside commercially available heart rate 
monitoring devices, participants will be asked to provide accelerometery (asked 
through the participants phone), heart rate variability (iHeart) and a subjective wellness 
score for each day following baseline and CPET investigations each for a period of 3 
days. This custom developed software has been developed at the Advanced 
Wellbeing Research Centre to provide objective and subjective assessment of fatigue 
in people suffering with long covid and has successfully been piloted with over 200 
individuals. Where smartphone data is not possible, individuals will be asked to wear 
an accelerometer and subjectively report their wellness through patient diary.  
 
4.3 Safety of Graded Exercise Testing 
Graded exercise testing is a safe procedure which is routinely used in clinical, exercise 
and research settings. Numerous studies that have assessed the safety of graded 
exercise testing (mostly in cardiac patients) indicate that the risk of exercise-induced 
complications and mortality is very low. The reported mortality rate ranges from 0 to 1 
death per 10,000 tests, and the non-fatal adverse event rate ranges from 0 to 5.2 per 
10,000 tests. 
 
4.4 Risk Management  
4.4.1 Cardiovascular Risk 
Participation in aerobic exercise may increase the risk of cardiovascular complications 
such as cardiac ischaemia, arrythmia or hypotension. The use of an appropriate 
graduated warm-up and cool-down is recommended to minimise these risks (ACSM, 
2021). In the proposed study, participants’ physiological response to exercise will be 
closely monitored during and after exercise. Exercise will be stopped if any adverse 
signs or symptoms occur (see table above). The researcher is experienced in the 
provision of clinical exercise tests and is trained in cardiopulmonary resuscitation.  
 
4.4.2 Musculoskeletal Risk 
Participation in aerobic exercise may increase the risk of musculoskeletal injury such 
as a muscle strain. This risk will be minimised by conducting a graduated warm-up 
and by following the cycle ergometer manufacturer guidelines regarding correct 
positioning of participants.  
 
4.4.3 Post-Exertional Malaise 
Post exertional malaise has been identified in patients with long covid especially with 
incremental exercise and exertion. We will screen for individuals’ experiences PEM 

 
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prior to the study and follow up with individual participants following baseline 
measurement sessions before proceeding with repeated day CPET. Those individuals 
who show symptoms of PEM will be provided with guidance of pacing and provided 
with access to published materials around managing fatigue as per UK NHS long covid 
clinic guidance (World Physiotherapy, 2021).  
 
4.4.4. Bruising. 
 
Bruising may occur following venepuncture sampling, participants will be advised of 
this through PIS and management if bruising occurs (Rest and cold exposure). 
 
4.5 Statistical Analysis 
Statistical analysis will be supervised by Dr Emma Sharpe at the University of Derby 
and conducted using SPSS version 26. This study is a prospective observational 
cohort study, designed to identify suitable tools and measures across different 
domains for assessing patient recovery from COVID-19.  
 
Descriptive statistics will be calculated for all outcomes of interest. These will be 
presented as proportions and means with standard deviations or medians with 
interquartile ranges, depending on the distribution of data. 
 
Within group differences will be compared using parametric (students t-test) and non-
parametric (Mann-Whitney U, Chi square) tests, depending on normality of 
distribution.  
 
4.6 Sponsor and Coordination 
The University of Derby, UK will act as the sponsor for the research and Dr Mark Faghy 
will act as the Chief Investigator. With site principal investigators as follows: 
• Advanced Wellbeing Research Centre, Sheffield UK - Dr Tom Maden-
Wilkinson 
• Ramaiah Medical College, Bengaluru, USA - Dr Sundar Kumar Veluswamy 
• University of Illinois, Chicago - Dr Cemal Ozemek  
 
4.7 Adverse Events and Reporting 
4.7.1 Definition of Adverse Event (AE) 
Any untoward medical occurrence in a clinical study where participants are 
administered a medicinal product, which does not necessarily have to have a causal 
relationship with participation in this study. 
 
An AE includes: 
• Exacerbation of pre-existing illness 
• Increase in frequency or intensity of a pre-existing episodic event or condition 
• Condition detected or diagnosed after study intervention even though it may 
have been present before the start of the study 
• Continuous persistent disease or symptoms present at baseline that worsens 
following the start of the study 
 

 
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An AE does not include: 
• Medical or surgical procedure (e.g. surgery, tooth extraction) but the condition 
that leads to the procedure is an AE 
• Pre-existing disease or conditions present or detected at the start of the study 
that did not worsen 
• Situations where an untoward medical occurrence has occurred (e.g. 
hospitalisations for cosmetic elective surgery) 
• Disease or disorder being studied, or sign or symptom associated with the 
disease or disorder unless more severe than expected for the participant’s 
condition 
• 
Overdose of concurrent medication without any signs or symptoms 
 
4.7.2 Non-serious AEs 
All such events, whether expected or not, should be recorded. 
 
4.7.3 Abnormal Baseline Findings 
Abnormal findings at that are deemed to be a clinically significant abnormality may be 
reported as an AE, according to the judgement of the Chief Investigator taking into 
account any associated clinical symptoms/signs from the below measures during pre; 
mid and post time frame. 
 
4.7.4 Reporting Procedures for All AEs 
Aim: to describe adverse events relating to study and the reporting process 
 
Adverse event (AE) and Serious Adverse Event (SAE) will use the local NHS Trust 
reporting procedures but reported to the University of Derby Research and Knowledge 
Exchange Office as soon as possible. 
 
All AEs should be reported on the CRF. Any questions concerning adverse event 
reporting should be directed to the Chief Investigator in the first instance. Participants 
will be asked to report AE’s and SAE’s during all follow up sessions. All participants 
will be provided with contact details for a trial phone, where they can communicate 
AE/SAE throughout the study and will be operated during working hours (Monday to 
Friday 9-5). Outside of these working hours, participants are encouraged to leave a 
voicemail and the study team will contact them back as soon as possible during 
working hours. 
 
The following information will be recorded: description, date of onset and end date and 
severity. Follow-up information should be provided, as necessary. AEs considered 
related to the study as judged by a medically qualified investigator (Tom Bewick, CI) 
or the sponsor will be followed until resolution or the event is considered stable. All 
related AEs that result in a participant’s withdrawal from the study or are present at 
the end of the study, should be followed up until a satisfactory resolution occurs. It will 
be to the responsibility of the Chief Investigator’s clinical judgement whether an AE is 
of sufficient severity to warrant removal from the study. The relationship of AEs to the 
study will be assessed by a medically qualified investigator. All such events, whether 
expected or not will be recorded. 
 

 
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4.7.5 Definition of Serious Adverse Event (SAE) 
Any untoward and unexpected medical occurrence or effect that: 
• Results in death 
• Is life-threatening – refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe 
• Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
 
An SAE form will be completed and forwarded to the sponsor or delegated 
representative within 24 hours. However, relapse and death and hospitalisations for 
elective treatment of a pre-existing condition do not need reporting as SAEs. All SAEs 
should be reported to the study sponsor local Research Ethics Committee where in 
the opinion of the Chief Investigator, the event was: 
• 
‘Related’, i.e. resulted from the administration of any of the research 
procedures; and 
• ‘Unexpected’, i.e. an event that is not listed in the protocol as an expected 
occurrence 
 
4.7.6 Reporting Procedures for All SAEs 
Reports of related and unexpected SAEs should be submitted within 15 days of the 
Chief Investigator becoming aware of the event, using the ‘COREC SAE’ form for non-
CTIMP studies. Local investigators should report any SAEs as required by their Local 
Research Ethics Committee and/or Research & Development Office. Fatal or life-
threatening SAEs must be reported within 7 days which will be reported to the 
Competent Authorities MHRA and the Research Ethics Committee. 
 
SAE reports must be sent to R&I using one of the following methods: 
 
i. Email: UKREO@Derby.ac.uk 
ii. Hand Delivered (Not Mailed): South Tower, Kedleston Road 
iii. Telephone: 01332 59 7815 (If written report not immediately possible) 
 
The intensity of the AE will initially be assessed according to the following definitions: 
• Mild: An event easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities 
• Moderate: An event sufficiently discomforting to interfere with everyday 
activities 
• Severe: An event that prevents everyday activities 
 
All AE and SAE Reporting documentation (i.e. NHS National Patient Safety Agency, 
National Research Ethics Service, Report of Adverse Event (AE) and Serious Adverse 
Event) physical copies of these will be kept in the Trial Master File. 
 

 
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5.0 Data Protection and Patient Confidentiality 
All investigators and study site staff will comply with the requirements of the Data 
Protection Act 2018 with regards to the collection, storage, processing, and disclosure 
of personal information and will uphold the Act’s core principles. This includes a trial 
independent monitor which will carry out the monitoring of the study data as an on-
going activity. 
 
Staff involved in the study will ensure that all participants’ confidentiality is maintained. 
The participants will be identified only by initials and surname (for purposes of address 
on the telephone), and a unique patient study identification number on the CRF and 
central electronic database. All documents will be stored securely and only accessible 
by staff involved in the study and authorised personnel. The study will comply with the 
Data Protection Act (in the UK) and with local legal requirements alongside the 
principles of ICH-GCP (worldwide); in line with this, all data will be anonymised as 
soon as it is practical to do so. The fully anonymised study data will be stored for at 
least five years following the closure of the study and thereafter disposed of in line with 
regulatory requirements. No participant will be individually identified in any subsequent 
publications relating to this study. 
 
The study database will be kept on Microsoft Excel© 2016 and hosted on the 
University of Derby internal server. The server and database are protected by several 
measures including anti-virus and anti-spyware applications, firewalls, encryption 
technology and permissions. Data will be entered onto the paper CRF and retained 
and stored securely until the study end date, at which point the CRFs will be sent 
securely to the coordinating centre for entry onto the electronic study database. The 
data will be securely stored in line with ICH-GCP standards and data protection 
principles. The data stored will be checked for missing or unusual values and for 
consistency within participants over time. If any problems are identified, the 
appropriate CRFs will be reviewed in discussion with relevant local site personnel and 
queried for confirmation or correction as required until resolution. 
 
The Chief and Principal Investigators, sponsor, and authorised staff will have access 
to participants’ data. The Chief Investigator and/or Principal Investigators will facilitate 
access to study records for monitoring, audits, and regulatory inspections. 
 
6.0 Data Retention and Archiving 
In compliance with the ICH/GCP guidelines, regulations and following the University 
Hospitals NHS Trust Code of Research Conduct and Research Ethics the Chief 
Investigator will maintain all records and documents regarding the conduct of the 
study. These will be retained for at least 15 years (or for longer if required). If the Chief 
Investigator is no longer able to maintain the data records, an alternative person will 
be nominated to take over this responsibility. 
 
The Trial Master File and Trial documents held by the Chief Investigator on behalf of 
the Sponsor shall be finally archived by the sponsor local NHS Trust. This archive shall 
include all study databases and associated meta-data encryption codes. 
 

 
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6.1 Amendments 
Amendments to the study protocol will be handled according to the Health Research 
Authority’s guidelines for Non-CTIMP studies. Decisions to amend the protocol will be 
the responsibility of the Sponsor in consultation with the Chief Investigator and 
Principal Investigator. The Sponsor will have responsibility for determining the 
category of each amendment (Substantial versus Non-Substantial). All substantial and 
non-substantial amendments will be reported directly to the local Hospitals Trust 
Research Ethics Committee. It will be authorised by the Sponsor and Chief 
Investigator before submission. The appropriate documentation, clearly detailing 
changes, will be emailed to the responsible REC for review. Should a protocol 
amendment be made that requires REC approval, the changes in the protocol will not 
be instituted until the amendment and revised participant consent forms and 
participant information sheets (if appropriate) have been reviewed and received 
approval from the REC and R&I departments. A protocol amendment intended to 
eliminate an apparent immediate hazard to participants may be implemented 
immediately providing that the MHRA, R&I and REC are notified as soon as possible, 
and approval is requested. Minor protocol amendments only for logistical or 
administrative changes may be implemented immediately and therefore the REC will 
be informed. 
 
6.2 Access to the Final Study Dataset 
The study database will be kept on Microsoft Excel© 2016 and hosted on the local 
University server. The server and database are protected by many measures including 
anti-virus and anti-spyware applications, firewalls, encryption technology and 
permissions. Data will be entered onto the paper CRF and retained and stored 
securely until the study end date, at which point the CRFs will be sent securely to the 
coordinating centre for entry onto the electronic study database. 
 
The data will be securely stored in line with ICH-GCP standards and data protection 
principles. The data stored will be checked for missing or unusual values and for 
consistency within participants over time. If any problems are identified, the 
appropriate CRFs will be reviewed in discussion with relevant local site personnel and 
queried for confirmation or correction as required until resolution. The Chief and 
Principal Investigators and authorised staff will have access to participants’ data. The 
Chief Investigator and/or Principal Investigators will facilitate access to study records 
for monitoring, audits, and regulatory inspections. 
 
7.0 Financing and Insurance 
This study is funded by GILEAD Sciences: COVID-19 RFP Program to the value of 
£174,885.46. 
 
Indemnity and insurances will be provided by the University of Derby who is acting as 
the sponsor for this study. 
 
7.1 Participant Incentives 
There will be no financial recompense for the participants time, however all expenses 
(parking and travel) will also be covered by the study. 
 

 
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7.2 Funding 
The study is funded by GILEAD Sciences: COVID-19 RFP Program 
 
8.0 Public Patient Involvement 
This protocol has been reviewed as part of the PPI groups at Royal Derby Hospital, 
UK and Patient involvement in Research Group (PIRG) at the Advanced Wellbeing 
Research Centre, UK.  
 
9.0 End of Study 
The end of the study is the date of the home visit (post-study follow up) of the last 
participant enrolled. 
 
10.0 Discontinuation/Withdrawal of Participants from Study 
Treatment 
Each participant has the right to withdraw from the study at any time. Participants may 
be withdrawn from the study either at their request or at the discretion of the Chief 
Investigator. Participants will be made aware (via The Participant Information Sheet 
and Participant Consent Form) that withdrawing the data which has been collected 
cannot be erased and may still be used in the final data analysis and study 
dissemination (i.e. published journal). The Chief Investigator may withdraw a 
participant from the study at any time if they consider that the participant’s health is 
compromised by remaining in the study or the participant is not sufficiently 
cooperative. The reasons for any participant withdrawal will be recorded on the study 
completion form of the CRF. The data collected from withdrawn participants will be 
included in the study report. 
 
Besides, the Chief Investigator may discontinue a participant from the study at any 
time if they consider it necessary for any reason including but not limited to: 
• Ineligibility (arising during study or retrospective having been overlooked at 
screening) 
• Significant protocol deviation 
• Significant non-compliance with study requirements 
• An AE which results in the inability to continue to comply with study procedures 
• Progression of illness that renders participants unable to comply with study 
procedures. 
• Consent is withdrawn 
• Lost to follow up 
 
The reason for withdrawal will be clearly stated and recorded in the CRF. 
 
If the participant is withdrawn due to an AE, the Chief Investigator will arrange for a 
follow-up telephone call until the AE has resolved or stabilised. 
 

 
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11.0 Dissemination 
All data arising from this study will be owned by the named academics from the 
University of Derby. On completion of the study, the data will be analysed and reported 
into a final study report. The full study report will be accessible via the Chief 
Investigator. 
 
There shall be no publication or dissemination of the conclusions of the study, 
including all or any part of the results of the study, without the prior written consent of 
the Chief Investigator and the Sponsor, such consent not to be unreasonably withheld 
or delayed. There shall be no publication or other dissemination of the conclusions of 
the study until the Sponsor has approved the conclusions of the study. 
 
There are no plans to notify the participants of the outcome of the study. Participants 
may specifically request results from the PI; this information would be provided after 
study results have been published. The study protocol, full study report, anonymised 
participant-level dataset, and statistical code for generating the results will not be 
made publicly available. 
 
Manuscripts resulting from the research will be conceived, written, and published at 
the discretion of the Chief Investigator, in conjunction with the Principal Investigator 
and other members of the research team as appropriate. This activity will be 
independent of the Research Funder, who will not have any control over the content 
or results of any publications. It is anticipated that the research will lead to publications 
in subject-specific international peer-reviewed journals and presentations at 
international conferences. 
 
11.1 Authorship eligibility guidelines and any intended use of professional 
writers 
Authorship will be determined by the research team on the final study report and 
subsequent publications, following the International Committee of Medical Journal 
Editors guidance for authorship of manuscripts submitted for publication. Professional 
writers will not be employed. 
 
12.0 References 
 
American College of Sports Medicine,, et al. ACSM's Guidelines for Exercise Testing 
and Prescription. Tenth edition. Philadelphia: Wolters Kluwer, 2018. 
 
Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman D, Franklin 
B, Guazzi M, Gulati M, Keteyian SJ, Lavie CJ, Macko R, Mancini D, Milani RV; on 
behalf of the American Heart Association Exercise, Cardiac Rehabilitation, and 
Prevention Committee of the Council on Clinical Cardiology; Council on Epidemiology 
and Prevention; Council on Peripheral Vascular Disease; and Interdisciplinary Council 
on Quality of Care and Outcomes Research. Clinician’s guide to cardiopulmonary 
exercise testing in adults: a scientific statement from the American Heart 
Association. Circulation. 2010;122:191–225. 

 
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McGregor G, Nichols S, Hamborg T, et al. High-intensity interval training versus 
moderate- intensity steady-state training in UK cardiac rehabilitation programmes 
(HIIT or MISS UK): study protocol for a multicentre randomised controlled trial and 
economic evaluation. BMJ Open 2016;6:e012843. doi:10.1136/bmjopen-2016- 
012843  
Ross RM. ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir 
Crit Care Med 2003;167:1451; author reply 51 
World Physiotherapy. World Physiotherapy Response to COVID-19 Briefing Paper 9. 
Safe rehabilitation approaches for people living with Long COVID: physical activity and 
exercise. London, UK: World Physiotherapy; 2021.