Prevention and Early Treatment of the Long-term Physical Effects of Coronarvirus-19 (COVID-19): a Randomised Clinical Trial of Resistance Exercise.
Phase: NA
Conditions: Covid19
Sponsor: NHS Greater Glasgow and Clyde

CISCO-21 Protocol – V1.1, 30/03/2021 Page 1 of 60  
  
 
Full Title: Prevention and early treatment of the long-term physical effects of COVID-
19: a randomised clinical trial of resistance exercise. 
  
Short title: CISCO-21 - Treat and Prevent Long COVID 
  
  
  
  
  
  
  
  
  
  
  
  
  
PROTOCOL VERSION NUMBER AND DATE:  
  
  
Version 1.1; 30/03/2021  
  
IRAS Number:  
294299 
ISRCTN Number / Clinical trials.gov Number:  
TBC 
Sponsors Number:  
GN20CA537 
  
This protocol has regard for the HRA guidance and order of content  
  
  
           
       
        
  
  
   
  
  
  
  
  

CISCO-21 Protocol – V1.1, 30/03/2021 Page 2 of 60  
  
 SIGNATURE PAGE  
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to 
the principles outlined in the Good Clinical Practice (GCP) guidelines, the Sponsor’s (Standard 
Operating Procedures (SOPs), and other regulatory requirements as amended.  
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of the Sponsor  
I also confirm that I will make the findings of the study publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this 
protocol will be explained.  
  
  
Chief Investigator: Prof Colin Berry 
 
Signature:    
 
 
 
  
Date:  
07/04/2021  
Name: (please print):  COLIN BERRY   
  
  
  
  
Position: PROFESSOR OF CARDIOLOGY AND IMAGING 
  
  
  
For and on behalf of the Study Sponsor (NHS Greater Glasgow and Clyde):  
 
Signature:   
 
  
Date:  
07/04/2021 
Name (please print):   MAUREEN TRAVERS  
  
  
Position: NHS GG&C Research Coordinator  
  
  
  
  
  
  
  

CISCO-21 Protocol – V1.1, 30/03/2021 Page 3 of 60  
  
  
  
KEY TRIAL CONTACTS  
Chief Investigator  
Professor Colin Berry  
Imaging and Cardiology  
BHF Glasgow Cardiovascular Research Centre  
126 University Place  
University of Glasgow  
Glasgow G12 8TA  
Office: +441413303325    
Cell: +447831698479  
Email: colin.berry@glasgow.ac.uk   
  
Department of Cardiology  
Queen Elizabeth University Hospital  
Govan Road, Glasgow  
Trial Co-ordination  
Project Management Unit  
Clinical Research and Development  
Ward 11, Level 1  
Dykebar Hospital  
Grahamston Road  
Paisley, PA2 7DE  
Contact: Diannt Taggart / Jurgen Van melckebeke  
Email: diann.taggart@ggc.scot.nhs.uk  / 
Jurgen.vanmelckebeke@ggc.scot.nhs.uk    
Sponsor  
NHS Greater Glasgow & Clyde  
Clinical Research and Development  
Ward 11, Level 1 
Dykebar Hospital  
Grahamston Road  
Paisley, PA2 7DE  
  
Contact: Dr Maureen Travers  
E-mail: maureen.travers@ggc.scot.nhs.uk    
Data Centre  
Glasgow Clinical Trials Unit  
Robertson Centre for Biostatistics  
University of Glasgow  
Contact: Sarah Weeden 
Tel: 0141 330 4744  
Email: sarah.weeden@glasgow.ac.uk     

CISCO-21 Protocol – V1.1, 30/03/2021 Page 4 of 60  
  
Key Protocol Contributors  
  
  
  
Dr David Anderson 
Consultant Respiratory Physician  
Queen Elizabeth University Hospital,   
NHS GGC, Glasgow  
Email: David.Anderson@ggc.scot.nhs.uk  
 
Dr Hannah Bayes  
Consultant Respiratory Physician  
Royal Infirmary, NHS GGC  
Email: Hannah.Bayes@ggc.scot.nhs.uk    
  
Mr David Boiskin 
Clinical Specialist Physiotherapist 
Department of Physiotherapy 
Queen Elizabeth University Hospital 
Email: David.Boiskin@ggc.scot.nhs.uk 
 
Ms Clare Burke 
Department of Physiotherapy 
Queen Elizabeth University Hospital 
Email: Clare.Burke@ggc.scot.nhs.uk 
 
Professor John GF Cleland  
Director, Glasgow Clinical Trials Unit 
Robertson Centre for Biostatistics  
University of Glasgow  
Email: John.Cleland@glasgow.ac.uk 
  
Professor Carl Goodyear 
Professor of Translational Immunology, 
RB421 Level B4, III - GBRC, University Place, Glasgow G12 8TA 
Email: Carl.Goodyear@glasgow.ac.uk  
 
Dr Stuart Gray  
BHF Glasgow Cardiovascular Research Centre 
126 University Place, Glasgow G12 8TA 
Email: Stuart.Gray@glasgow.ac.uk    
  
Dr Tracy Ibbotson 
Room 206, House 1, General Practice & Primary Care, 1 
Horselethill Road, Glasgow, G12 9LX.  
Email: Tracy.Ibbotson@glasgow.ac.uk 
  
Professor Chim Lang  
Clinical Professor and Consultant Cardiologist  
Ninewells - Mailbox 2, School of Medicine, University of 
Dundee, Ninewells Hospital & Medical School DD1 9SY 

CISCO-21 Protocol – V1.1, 30/03/2021 Page 5 of 60  
  
Email: C.C.Lang@dundee.ac.uk  
  
Professor Alex McConnachie  
Robertson Centre for Biostatistics,   
University of Glasgow, G12 8TA  
Email: alex.mcconnachie@glasgow.ac.uk   
  
Professor Frances Mair 
Norie Miller Professor of General Practice and Head of General 
Practice and Primary Care, University of Glasgow 
R302A Level 3, General Practice & Primary Care, 1 Horselethill 
Road, Glasgow G12 9LX 
Email: Frances.Mair@glasgow.ac.uk  
 
Dr Kenneth Mangion  
Lecturer in Cardiology, University of Glasgow  
Queen Elizabeth University Hospital,   
NHS GGC, Glasgow  
Email: kenneth.mangion@glasgow.ac.uk    
 
Dr Andrew Morrow 
MRC Clinical Research Fellow, Institute of Cardiovascular and 
Medical Sciences, University of Glasgow 
Queen Elizabeth University Hospital,  
NHS GGC, Glasgow  
Email: andrew.morrow@ggc.scot.nhs.uk  
 
Professor Naveed Sattar  
Institute of Cardiovascular and Medical Sciences,  
Queen Elizabeth University Hospital,  
NHS GGC, Glasgow  
Email: Naveed.sattar@glasgow.ac.uk   
 
Dr Robert Sykes 
Clinical Research Fellow, Institute of Cardiovascular and 
Medical Sciences, University of Glasgow 
Queen Elizabeth University Hospital,  
NHS GGC, Glasgow  
Email: robert.sykes@ggc.scot.nhs.uk  
 
Professor Rod Taylor 
MRC/CSO Social & Public Health Sciences Unit, Institute of 
Health and Wellbeing, University of Glasgow  
Email: Rod.Taylor@glasgow.ac.uk   
 
 
  
  

CISCO-21 Protocol – V1.1, 30/03/2021 Page 6 of 60  
  
TRIAL SUMMARY  
Study Title  
Prevention and early treatment of the long-term physical 
effects of COVID-19: a randomised clinical trial of resistance 
exercise. 
Other Title  
Treat and prevent Long COVID 
Acronym  
CISCO-21 
Study Design  
Randomised, controlled, open-label, parallel group, clinical trial 
Study Participants  
Patients with confirmed COVID-19 recovering in hospital, or 
having been discharged or not admitted, and with persisting 
symptoms (4 weeks or more as per NICE guidance). 
Research Question/Aims  
1. To undertake a pragmatic clinical trial of resistance-based 
exercise in addition to standard care versus standard care 
only to prevent and treat persisting symptoms post-COVID-
19. 
2. To rapidly translate and disseminate our research findings. 
3. To develop a national platform for rapid, multicentre 
clinical trials post-COVID-19.   
Eligibility 
Patients will be classified according by clinical presentation: 
A) Non-hospitalised - Positive diagnosis with persisting 
symptoms for at least 4 weeks from symptoms onset leading to 
medical review (A&E, Community COVID Hub) but not admission 
(Treatment group),  
B) Hospitalised, positive diagnosis, and with post-discharge, 
persistent symptoms for at least 4 weeks from symptoms onset 
(Treatment group),  
C) Hospitalised, positive diagnosis, and in convalescent phase in-
hospital (preventive group).  
Groups A & B = target population for treatment of persisting 
symptoms post-COVID i.e. Long-COVID;  
Group C = Target population for prevention of Long COVID.  
Inclusion criteria 
1. Virology PCR positive laboratory diagnosis of COVID-19, 
2. Within 6 months of diagnosis, 
3. Persistent symptoms for at least 4 weeks from 
symptoms onset (Groups A & B only) 
4. Presentation type - one of group A, B or C. 
 
 

CISCO-21 Protocol – V1.1, 30/03/2021 Page 7 of 60  
  
Exclusion criteria 
1. Physiotherapy as part of standard care e.g. post-ICU, 
post-HDU,  
2. No expectation of being able to walk within 3 months 
3. Unable to provide informed consent,  
4. Unable to comply with the protocol. 
5. Known pregnancy 
 
Intervention  
Resistance exercise in addition to standard care 
Control  
Treatment as usual (standard care) without resistance exercise 
Primary outcome 
Incremental shuttle walk test (ISWT) at 3 months post-
randomisation 
Secondary outcomes 
1. Spirometry; 
2. Handgrip strength;  
3. Short Physical Performance Battery (SPPB) 
4. EQ5D, PHQ, Illness perception (Brief IPQ), Duke Activity 
Status Index (DASI), International Physical Activity 
Questionnaire (IPAQ-SF) short-form, Fatigue questionnaire, 
MRC dyspnoea score;  
5. Frailty assessed using 1) the Fried frailty phenotype:  five 
criteria: weight loss; exhaustion; grip strength; low physical 
activity; and slow walking pace; 2) Clinical Frailty Scale. 
6. Episodes of care (primary, secondary, physiotherapy, 
rehabilitation) up to 3 months (Visit 2), and in the longer 
term 
7. Hospitalisation for any reason up to 3 months (Visit 2), and 
in the longer term. 
Exploratory outcomes / sub-
studies  
1. Exercise dose achieved (1) daily log, (2) level attained and 
within subject change from baseline, 
2. Oxygen saturation, heart rate and respiratory rate at the 
start and end of the ISWT 
3. Adherence with exercise (log).  
4. Accelerometery (Glasgow only) 
5. Biobank tissues samples for biomedical research.   
 
Planned Sample Size  
220 randomised participants (n=110 per randomised group) 
Stratification of randomisation by clinical categories, A, B and C, 
history of COVID pneumonia, age, sex and site. 

CISCO-21 Protocol – V1.1, 30/03/2021 Page 8 of 60  
  
Planned Trial Period  
24 months  
Pre-start: secure approvals and study set up.    
Week 1:  participant enrolment, implementation    
Week 52: mid-point review    
Week 104: final report.  
Record linkage for long term follow up  
  
 
 

CISCO-21 Protocol – V1.1, 30/03/2021 Page 9 of 60  
  
ROLE OF STUDY SPONSOR AND FUNDER/SUPPORTER  
  
NHS Greater Glasgow & Clyde will be the sponsor of the trial. Sponsor will provide approvals, support 
regulatory submissions and ensure the requirements of the study are met as per the statement on the 
signature page of this protocol.   
  
The study is funded through the Chief Scientist Office.  
  
ROLES & RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES/ GROUPS & INDIVIDUALS  
Trial Management Group (TMG)  
The study will be coordinated from NHS Greater Glasgow & Clyde (NHS GG&C) by the Study 
Management Group (SMG). The SMG will consist of the chief investigator, project manager and 
representatives from both NHS GG&C and other organisations relevant to the study. The role of the 
group is to monitor all aspects of the conduct and progress of the study, ensure that the protocol is 
adhered to and take appropriate action to safeguard participants and the quality of the trial itself.   
  
Trial Steering Committee (TSC) 
The role of the TSC is to provide overall supervision of the trial and ensure that it is being conducted 
in accordance with the principles of GCP and the relevant regulations. The TSC will: 
 
review the trial protocol and agree substantial protocol amendments 
 
provide advice to the investigators on all aspects of the trial 
 
include an independent chairperson, at least 2 other independent members, and the Co-
sponsor and a patient or carer representative   
 
Decisions about continuation or termination of the trial or substantial amendments to the protocol 
will be the responsibility of the TSC who will advise the sponsor. The TSC will meet at the start of the 
study, and 6-monthly thereafter. The TSC will have its own charter outlining the role and 
responsibilities of its members. The TSC may invite other attendees from the trial team to present or 
participate in discussions on particular topics. These attendees will be non-voting members. 
 
Independent Data Monitoring Committee (IDMC) 
An IDMC will be established to include a minimum of two independent medical experts (covering 
cardiovascular disease and/or COVID-19; one of the academic clinicians will act as chair) and an 
independent biostatistician. The Glasgow CTU will liaise with the committee and ensure that the 
committee is provided with adequate information about study progress and results. 
 
The IDMC will have a formal charter; this will outline the responsibilities of the IDMC members, 
Glasgow CTU and the co-sponsors. Responsibilities include: 
 
• 
To protect the safety of patients recruited to the trial. 
• 
Advising the TSC and sponsor if it is safe and appropriate to continue with the study. 
• 
Examining information provided by the Glasgow CTU on study recruitment, adverse events 
and outcomes and providing recommendations for the Project Office to forward to the TSC, 
ethics committees, regulatory bodies, study sponsors, and the funder. 

CISCO-21 Protocol – V1.1, 30/03/2021 Page 10 of 60  
  
The IDMC will receive unblinded reports on study safety data and on study progress and outcomes. 
The IDMC may recommend to the TSC and co-sponsors that the study should stop prematurely 
because of concerns about patient safety. The IDMC will meet approximately every six months. No 
formal interim analyses are planned. The IDMC will take into account all of the results and the 
consistency and biological plausibility of the findings. These analyses will have no impact on the 
required sample size for the study. 
  
PROTOCOL CONTRIBUTORS   
  
The protocol has been developed by a group with extensive clinical and research experience relevant 
to this study – our list of contributors can be found on Pages 4 and 5 of this protocol.  The team 
includes internationally leading experts in clinical trials (Berry, Cleland, Lang, Sattar, Taylor), 
biomarkers (Goodyear, Sattar), pulmonary rehabilitation (Anderson, Bayes), exercise physiology 
(Gray), primary care (Mair), and biostatistics (McConnachie).   
  
The study will be supported by the Robertson Centre for Biostatistics, University of Glasgow and 
Clinical Research & Development and the Project Management Unit, NHS GGC.  
 
  
KEYWORDS 
 
• 
Coronavirus-19 (COVID-19) 
• 
SARS-CoV-2 
• 
Resistance exercise 
• 
Health status 
• 
Exercise capacity 
• 
Rehabilitation 
• 
Cardiovascular disease 
• 
Clinical trial 
 
 

CISCO-21 Protocol – V1.1, 30/03/2021 Page 11 of 60  
  
LIST OF ABBREVIATIONS  
  
AE  
Adverse event  
AR  
Adverse reaction  
BMI  
Body Mass Index  
CA  
Competent authority  
CAD  
Coronary artery disease  
CHI  
Community health index  
CI  
Chief investigator  
CRF  
Case report form  
CRP  
C-reactive protein  
CT 
Computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Events  
CTPA 
Computed tomography pulmonary angiography 
CTU  
Clinical trials unit  
CXR 
Chest X-ray 
DASI  
Duke Activity Status Index   
ECG  
Electrocardiogram  
eGFR  
Estimated Glomerular Filtration Rate  
EQ5D  
European quality of life 5-domain  
EU  
European Union  
GCP  
Good clinical practice  
GDPR  
General data protection regulation  
GP  
General Practitioner  
ICAM  
Intercellular adhesion molecule-1  
ICF  
Informed consent form  
ISWT 
Incremental shuttle walk test 

CISCO-21 Protocol – V1.1, 30/03/2021 Page 12 of 60  
  
ICMJE  
International Committee of Medical Journal Editors  
ICH GCP  
International Conference on Harmonization of Good Clinical Practice  

CISCO-21 Protocol – V1.0 Dated 04/02/2021 Page 13 of 60  
  
 
IPQ 
Illness perception questionnaire 
ISF  
Investigator site file  
LPLV  
Last Patient Last Visit  
LV  
Left ventricle  
MI  
Myocardial infarction  
MRC  
Medical Research Council  
NHS  
National Health Service  
NHS GGC  
National Health Service Greater Glasgow & Clyde  
NHS R&D  
National Health Service Research & Development    
NICE  
National Institute for Health and Care Excellence  
NT-proBNP  
N-terminal pro-brain natriuretic peptide  
PCR 
Polymerase chain reaction  
PHQ-9 
Patient health questionnaire - 9 
PPI  
Patient and Public Involvement  
PROMS 
Patient reported outcome measures 
RCPGP 
Royal College of General Practitioners 
REC  
Research Ethics Committee  
SAE  
Serious adverse event  
SDV  
Source data verification  
SIGN 
Scottish Intercollegiate Guideline Network 
SMG  
Study management group  
SOP  
Standard Operating Procedure  
SOT  
System organ term  
SSI  
Site specific information  
RUSAE  
Related Unexpected Serious Adverse Event  

CISCO-21 Protocol – V1.0 Dated 04/02/2021 Page 14 of 60  
  
SUSAR  
Suspected Unexpected Serious Adverse Reaction   
TIA  
Transient ischaemic attack  
TMF  
Trial master file  
UK  
United Kingdom  
ULN  
Upper limit of normal  
WHO  
World Health Organisation  
  
  
 

CISCO-21 Protocol – V1.0 Dated 04/02/2021 Page 15 of 60  
  
 TABLE OF CONTENTS  
 
SIGNATURE PAGE .................................................................................................................................... 2 
TRIAL SUMMARY ..................................................................................................................................... 6 
FLOW DIAGRAM ................................................................................................................................... 16 
SCHEDULE OF ASSESSMENTS ................................................................................................................ 17 
STUDY PROTOCOL ................................................................................................................................. 19 
1.  
BACKGROUND ........................................................................................................................... 19 
2.  
RATIONALE ................................................................................................................................ 21 
3.  
RESEARCH QUESTION / AIM(S) ................................................................................................. 23 
4.  
STUDY DESIGN........................................................................................................................... 25 
5.  
SETTING ..................................................................................................................................... 25 
6. 
STUDY POPULATION ..................................................................................................................... 26 
7. 
TRIAL PROCEDURES ....................................................................................................................... 27 
8. 
SAFETY REPORTING ....................................................................................................................... 36 
9. 
Statistical Analysis ......................................................................................................................... 40 
10. DATA HANDLING ............................................................................................................................. 42 
11. MONITORING, AUDIT & INSPECTION ............................................................................................. 42 
12. ETHICAL AND REGULATORY CONSIDERATIONS .............................................................................. 43 
13.  
DISSEMINATION POLICY ............................................................................................................ 47 
14.  
REFERENCES .............................................................................................................................. 48 
15.   
APPENDICES .............................................................................................................................. 50 
 
 
  
  
 
 

CISCO-21 Protocol – V1.0 Dated 04/02/2021 Page 16 of 60  
  
 
FLOW DIAGRAM 
 
 
 
 
CONSORT 2010 Flow Diagram 
 
 
 
 
 
 
 
Assessed for eligibility (n ~ TBC) 
  Registry - not meeting inclusion criteria 
for randomisation (n=TBC) 
   Declined to participate (n= TBC) 
Other reasons (n= TBC)
Analysed 
(n= 
TBC, 
minimum) 
 Excluded from analysis (withdrawals) (n= 
TBC) 
Lost to follow-up (give reasons) (n= TBC) 
Discontinued intervention (give reasons) (n= 
TBC) 
Allocated to intervention (n=110) 
 Received allocated intervention (n=TBC) 
 Did not receive allocated intervention (give 
reasons) (n= TBC) 
Lost to follow-up (give reasons) (n= TBC) 
Discontinued intervention (give reasons) (n= 
TBC) 
Allocated to control (n=110) 
 Received allocated intervention (n= TBC) 
 Did not receive allocated intervention (give 
reasons) (n= TBC) 
Analysed 
(n= 
TBC, 
minimum) 
 Excluded from analysis (withdrawals) (n= 
TBC) 
Allocation 
Analysis 
Follow-Up 
Randomized 1:1 (n=220) 
Enrolment 

 
SCHEDULE OF ASSESSMENTS  
 Visit 
1 
2 
3 
Timeline 
Day 1 
3 months 
(+6weeks) 
E-linkage 
Trial Activity 
 
Setting 
Enrolment   
  
Hospitalised, non-hospitalised COVID-19   
Outcome 
evaluation 
CRF 
  
1 & 10 years 
  
 
Screening – Inclusion/Exclusion Criteria including DASI questionnaire 
 
 
 
Written Informed Consent  
 
 
 
General health status check  
 
 
 
Medical History / clinical status2 
 
 
 
Vital signs (heart rate, rhythm, BP, height, weight, waist circumference, 
oxygen saturation, at baseline and during follow-up) 
 
 
 
Cardiovascular risk factors, risk score 
 
 
 
Routine blood samples as per standard of care  
 
 
 
Spirometry 
 
 
 
Handgrip strength 
 
 
 
Short Physical Performance Battery (SPPB) 
 
 
 
Accelerometer (Glasgow only) 
 
 
 
PROMS including EQ5D, PHQ, Illness perception (Brief IPQ), Duke Activity 
Status Index (DASI), International Physical Activity Questionnaire (IPAQ-SF) 
short-form, Fatigue questionnaire 
 
 
 
Frailty 1) Fried 5-criteria phenotype, 2) Clinical Frailty Scale 
 
 
 
Training - Hospital, CRF, on-line, telephone 
 
 
 
Randomisation 
 
 
 
Training (resistance exercise) 
 
 
 
Incremental shuttle walk test (ISWT) 
 
 
 

 
Exercise dose (log, level, adherence) 
 
√ 
 
Episodes of care (primary, secondary, physiotherapy, rehabilitation) 
 
 
 
Research blood sample 
 
 
 
Data collection – clinical endpoints (collected via hospital Portal/Trakcare 
systems) and e-record linkage 
 
 
 
  
All visits should be performed within the documented visit time (e.g. 3 months +6 weeks). The aim is to meet these visit windows but any that are out-with 
will be dealt with at the analysis stage, as appropriate, and therefore will not be considered protocol deviations. If the visit date is extended beyond 3 
months, the participant should continue with the exercise regimen until the day of the visit. 
1. Informed consent must be obtained before the patient undertakes any study assessments.   
2. Clinical activity is defined as ‘Standard Care’(including safety), ‘Research’, or for the UK NHS, ‘NHS Support’, ‘NHS Treatment’  
3. The research blood sample should be undertaken at the 3-month visit. 
4. The participants will be contacted by the Research Staff by telephone one week after enrolment, regardless of the randomised group in order to 
assess patient wellbeing and adherence with the resistance exercise intervention. If there are concerns, then the participant will be invited to the 
Clinical Research Facility for review. 
5. Consent covers the randomised study and participation in an optional follow-up using electronic linkage of NHS and government records for episodes 
of care and death (and their causes) and medication in the longer term. 
 
Standard care blood samples e.g. FBC, U&E, HbA1c, D-Dimers, NTproBNP, lipids, CRP, high sensitivity troponin  
Research blood samples: Exploratory analyses may include - Haemostasis - Claus Fibrinogen, D-Dimer, FVIII (one stage), VWF antigen, VWF:GP1ba, 
Antithrombin activity, Protein C activity, Free protein S; Cardiac - NT-proBNP, hs-troponin; Vascular cytokines - ET-1, ICAM, VCAM, p-selectin, IL-6, VWF, Nox3; 
Vascular cells and microparticles; Metabolic status - HbA1C, lipids; Blood RNA (Tempus™ or PAXgene®) including for RT-PCR of SARS-CoV-2 and RNA for 
vascular biology; Inflammation – hs-CRP, ST2; Immune response antibodies; Collagen metabolites; DNA - The buffy coat will be stored for DNA analysis e.g. 
candidate gene SNPs, other variants. Residual blood will be saved for future analyses of interest.  These analyses will be undertaken in University laboratories 
or in laboratories of external collaborators (industry or academic, UK or abroad) by agreement with the Sponsor.          
 
  

CISCO-21 Protocol – V1.1, Dated 30/03/2021  
 
 
 
 
Page 19 of 60  
  
STUDY PROTOCOL  
 
Prevention and early treatment of the long-term physical effects of COVID-19: a randomised 
clinical trial of resistance exercise. 
  
1.  
BACKGROUND  
The COVID-19 pandemic is having an unprecedented impact on our health and social services, and on 
the population, society, and the economy [1,2]. COVID-19 is a systemic illness, and complications 
include pneumonia and pulmonary thromboembolism [3]. In our CSO-funded Cardiovascular Imaging 
in SARS-CoV-2 (CISCO-19) study [4; pilot data], most hospitalised patients experience persisting health 
problems after the acute illness. COVID-19 is associated with an increase in cardiovascular risk [3-5], 
that potentially may be reduced by evidence-based cardiovascular interventions. A report in the BMJ 
(May 2020) from the ISARIC-4C framework described the results for 17,702 patients admitted to 208 
acute hospitals in the UK, including several hospitals in NHS Scotland [3]. A history of cardiac disease 
was among the most common morbidities (31%, 5469/17702), and a multivariable predictor of all-
cause mortality (hazard ratio (95% confidence interval) 1.16 (1.08 to 1.24); p<0.001). These results 
provide a strong link between cardiovascular disease and the prognosis of COVID-19.  
Systemic inflammation, direct infection of endothelial cells by SARS-CoV-2 and dysfunction of 
angiotensin converting enzyme-2 (ACE2), cause endothelial dysfunction (aka ‘endothilitis’) [4,6,7]. 
Consequent microvascular dysfunction, thrombosis, and occlusion likely play a key role in multi-organ 
dysfunction, especially in the lung, heart, and kidney. A key objective of CISCO-19 is to assess coronary 
microvascular function [4]. We have found that myocardial injury, such as might occur due to 
myocarditis, is uncommon [4, pilot data]. On the other hand, impairments in blood flow in the heart 
appear to affect around 1 in 3 patients, and estimated oxygen consumption (VO2max), a measure of 
aerobic exercise capacity, is persistently reduced during the convalescence phase (1 month) [4]. 
Bringing these findings together with the current published evidence, COVID-19 patients have a risk 
of persisting symptoms, coronary and systemic microvascular dysfunction may be an underlying 
mechanism for persisting exertional breathlessness, chest pain, and fatigue [4-7].  
COVID-19 patients may experience a loss of metabolically active tissue [8]. Hospitalisation may be 
prolonged, and they are at risk of substantial weight loss, including sarcopenia and cachexia [9]. The 
mechanisms of cachexia are multifactorial and include tissue catabolism secondary to the acute 
infection, systemic inflammation, cytokine activation, and loss of mobility [10]. These problems may 
be especially relevant in older patients with COVID-19, and those with pre-existing chronic health 
problems, of whom there are many. Even a short period of immobilisation, in-hospital or at home, 
bed rest and the inactivity of sustained quarantine can have clinically relevant effects on muscle and 
metabolic health. A reduction in physical activity for just 2 weeks can result in significant losses in 
muscle mass and function [11] and peripheral insulin sensitivity [12]. A systematic review has 
identified generalised impairments in physical function after COVID-19 [13]. This is important, as 
muscle mass is a strong predictor of prognosis in many chronic conditions, and frailty, which associates 
with multimorbidity and socioeconomic deprivation, may be especially relevant [14]. 
Pharmacological methods to increase muscle mass are few and the main method to improve muscle 
mass and function is via resistance exercise. We have recently developed a resistance exercise 
intervention [15] which we have employed in people with type 2 diabetes (see pilot data). On top of 
its effects on muscle mass and function, which are not seen with other forms of exercise, resistance 
exercise is pragmatic in COVID-19 as it can be easily adapted to the patients’ capabilities and 

CISCO-21 Protocol – V1.1, Dated 30/03/2021  
 
 
 
 
Page 20 of 60  
  
performed in patients from the spectrum of bed-bound to ambulatory with the need for little 
equipment. Resistance exercise has similar broad ranging health benefits, such as reducing blood 
pressure and improving glycaemic control (PMID: 30045740; 30969369) and be associated with a 
reduction in CVD risk (PMID: 30376511). Importantly for this study, resistance training during periods 
of reduced activity can attenuate the declines in muscle mass and function (PMID: 26265753). 
Many patients who have survived COVID-19 describe persisting health problems. NICE, the Scottish 
Intercollegiate Guidelines Network (SIGN) and the Royal College of General Practitioners (RCGP) have 
defined Long COVID as ‘signs and symptoms that develop during or following an infection consistent 
with COVID-19 which continue for more than 12 weeks and are not explained by an alternative 
diagnosis’ [16]. Using clinical data from the over four million people who downloaded the COVID 
Symptom Study app [17] developed by the health science company, ZOE, Spector and colleagues at 
Kings College London have provided insights into persisting health problems of COVID-19 patients who 
were not admitted to hospital. Their preliminary and, arguably, somewhat ‘crude’ data show that 
more than 1 in 8 individuals still have problems after one month from the date of diagnosis, around 1 
in 20 have persisting symptoms at two months and 1 in 50 have symptoms at 3 months. Given the 
scale of the COVID-19 pandemic, many thousands of individuals will be affected. These Long COVID 
sufferers reported a range of symptoms, including up to 20 different symptoms beyond those used 
for the initial diagnosis of acute infection. These results underline that COVID-19 is a multisystem 
disease that requires a multidisciplinary approach to treatment. 
Since SARS-CoV-2 is a new virus, the initial research focus has been to investigate the acute illness 
through observational studies and trials of acute therapy. In the CSO Rapid Research programme, we 
secured funding for the CISCO-19 heart, lung, and kidney imaging study (ClinicalTrials.gov Identifier: 
NCT04403607) based in the West of Scotland [4]. This on-going study involves recruiting 160 patients 
in hospital, imaging at 28 days post-discharge and then again at 1 year. The study involves stress 
perfusion cardiovascular magnetic resonance (CMR) to quantify myocardial blood flow, and CT 
coronary angiography (CTCA). Patient reported outcome measures (PROMS), covering symptoms, 
quality of life, and functional status), and blood samples are being collected at each visit. COVID-
HEART, a national BHF-NIHR Flagship study, was modelled on CISCO-19. These, and other BHF-NIHR 
studies, will describe the natural history of COVID-19. ISARIC-4C is a UK-wide, secondary care COVID-
19 study [3]. PHOSP is a national consortium funded by the UKRI studying long-term health outcomes 
in patients who have been hospitalised for COVID-19. PHOSP involves 3 tiers, including routine clinical 
data (Tier 1), research assessments measured at standard care clinic visits (Tier 2; n=4,000 patients) 
and de novo, linked studies (Tier 3). The PHOSP Tier 2 assessments may occur at 6 weeks (phone call), 
3 months (the first face-to-face consult), and 6 and/or 12 months, where clinically indicated. In the 
main, these national flagship projects have focused on characterisation of the disease and 
implementing frameworks to support research. To date, randomised trials have focused on the acute 
phase of the illness. They include RECOVERY (NCT04381936), TACTIC-E (NCT04393246) and DEFINE 
(NCT04473053).  
Clinical management of patients following COVID-19 in the NHS will generally align with practice 
guidelines from the British Thoracic Society and other key stakeholders such as NICE, RCPGP and SIGN. 
Local practice may vary according to circumstances. In NHSGGC, patients who have been admitted 
with radiological and/or virology confirmed COVID-19 would be invited for a CXR 12 weeks post-
discharge and if there are persisting abnormalities on the X-ray, the patient would be invited to a 
phone consultation. Patients would attend out-patient clinics according to clinical need and logistical 
considerations. 
As we learn more about the natural history of COVID-19, it is clear that many patients (millions 
worldwide) are left with persisting symptoms such as exercise intolerance, breathlessness, fatigue, 
[3,4,17] that may represent persisting dysfunction of the heart, lungs, peripheral tissues, and their 

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microcirculation [3,4]. It is also possible that COVID-19 was just an intercurrent event that interacted 
with and exposed an underlying health problem (e.g. chronic lung disease, or iron deficiency). A post-
viral syndrome that might be anticipated to affect some patients, as is the case with other viral 
illnesses, is also relevant. NICE, SIGN and RCGP have highlighted the paucity of randomised trial 
evidence to show whether treatment of the convalescent phase after COVID-19, with or without 
hospitalisation, reduces longer-term disability [16]. We believe there is a knowledge-gap relating to 
the prevention and early treatment of longer-term health problems post-COVID-19. The recent CSO 
call into the long-term effects (LTE) of COVID-19 presents an ideal opportunity to build on CISCO-19. 
We will develop a clinical trial which in turn will set the framework for additional, linked clinical trials 
for national implementation across NHS Scotland, and potentially the UK. Our CSO LTE trial proposal 
complements our parallel application for BHF-NIHR flagship prioritisation for a “COVID-19 Rapid 
Cardiovascular Trials Platform” (under review, submission October 30, 2020). 
 
  
2.  
RATIONALE   
Many people have long-lasting symptoms after COVID-19, such as breathlessness, fatigue and chest 
pain. So far, research studies of treatments for COVID-19 have focused on the life-threatening acute 
illness; few studies look at treatments to improve long-term health after COVID-19. COVID-19, 
particularly when this requires a hospital admission, can lead to weight loss and muscle wasting, 
contributing to worse outcomes. Muscle strengthening (resistance-based) exercise could improve 
outcomes in the long-term. 
The rationale for our study has two main parts. The first (primary) addresses a gap in therapy, notably, 
for a non-pharmacological intervention. To address this gap, we have set out to develop a lifestyle 
intervention that may be helpful to patients with persisting symptoms in the recovery (or 
convalescence) phase after COVID-19. Specifically, we will train participants to undertake a pragmatic 
resistance-based exercise intervention that they can learn and apply according to their circumstances 
in-hospital or in the community. The rationale is predicated on providing patients with a personalised 
therapy option and empowering them in the self-management of their recovery following illness due 
to COVID-19 infection. 
The second area of need is the general lack of evidence-based medicines for patients who have 
persisting symptoms after COVID-19. To address this gap, there is a need for rapid trials to evaluate 
multiple therapeutic candidates to urgently provide doctors (and their patients) with clinical evidence 
to inform treatment decisions. To address this gap, we aim to create a platform for rapid trials of new 
treatments after COVID-19. We wish to seize the opportunity afforded by this trial to set-up a 
transferable framework for future trials in COVID-19. The rationale is to provide a low-cost trials 
resource to facilitate the rapid set-up and cost-efficient delivery of multiple other trials. This will be 
a parallel work strand during the trial. We will develop a Working Group of stakeholders from across 
the NHS and Universities in Scotland and our COVID-19 PPI Group (which includes co-applicants and 
collaborators). Key considerations include repurposing novel therapy, potential for efficacy, safety, 
endpoint, sample size, feasibility interim analyses, power, MHRA and costs. As part of the plan of 
work in application (Aim 3), the researchers and PPI Group will scope these potential interventions 
within the context of a platform trial with a view to identifying candidates to follow-on after the 
exercise intervention trial. This will cut the costs of doing future trials and allow more patients the 
opportunity to contribute to medical research that will improve outcomes for people recovering from 
COVID-19. 

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Our team is multidisciplinary, multi-ethnic, gender-balanced and drawn from across NHS Scotland, 
and the University of Glasgow. We are currently leading the CISCO-19 study (ClinicalTrials.gov 
Identifier: NCT04403607), funded by the CSO, in the West of Scotland, using medical imaging of the 
hearts, lungs, and kidneys of patients, to understand the impact of COVID-19 [4]. We have consulted 
with members of the public, including people with COVID-19, in designing this study.  
We will also undertake exploratory research into the vascular biology of COVID-19 infection. This 
work will be undertaken in collaboration with scientists in the University of Glasgow, including ICAMS 
and the MRC Centre for Virus Research. A blood sample at 3 months will be collected and stored in 
the NHS Biorepository. 
In order to assess the natural history, longer-term follow-up for health outcomes will be undertaken 
using electronic record linkage to patient records omitting the need for participants to undergo 
further research visits after the end of the trial. If after initial analysis longer term, follow up via 
national records is felt to be worthwhile additional funding will be sought for this.  
Alignment with other national / international initiatives 
Our Tier 3 PHOSP proposal is intended to link with COVID-HEART and other studies in NHS Scotland 
that include consent to be contacted about future research. Co-enrolment would be desirable to 
synergise the studies. If funded, our trials programme will bring in new resource to enhance 
enrolment into existing studies, specifically, by engaging more sites, and more research staff. The 
primary outcome of the exercise intervention coincides with the Tier 2 visit in PHOSP. Our consortium 
includes the lead investigators of BHF-NIHR prioritised studies. Prof Berry contributed to the concept 
and protocol of COVID-HEART. He is PI for CISCO-19, a Trial Steering Committee member of PHOSP 
and Co-Local PI for CAPACITY-COVID.  
Future trials 
Our proposal will create a trials framework ready for use in real-time with the potential to extend and 
develop contingent on future research funding. Having set up the multicentre clinical trial, we wish 
to make available the framework to support other interventions (see below). They are anticipated to 
include interventions for which substantial safety data already exist but for which efficacy data are 
lacking in this patient population. Developing these new trials, from concept through to funding, is a 
specific aim that is nested within the current proposal. This plan builds on the existing infrastructures 
already in use for CISCO-19 and other COVID-19-related research developed by clinical researchers 
at the Universities of Glasgow and Dundee. The proposal will link with existing, national research 
studies including the BHF-NIHR prioritised COVID-HEART and PHOSP studies in which the CI (Berry) 
already has leadership roles (Co-Lead, COVID-HEART; TSC Member, PHOSP), and potentially facilitate 
a UK wide trials platform. Our vision is to provide other researchers with an eCRF that is already 
immediately available for use. The eCRF platform would then be customised to the needs of the study. 
This approach should facilitate rapid set up of multiple new trials and greatly reduce costs. 
  
 
 

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3.  
RESEARCH QUESTION / AIM(S)  
3.1  Objectives  
  
1) 
To undertake a clinical trial of pragmatic resistance-based exercise in addition to 
standard care versus standard care only to prevent and treat persisting symptoms 
post-COVID-19. 
2) 
Rapidly translate and disseminate our research findings. 
3) 
Develop a national platform for rapid, multicentre clinical trials post-COVID-19.   
  
3.2  Questions  
  
1. 
Does resistance-exercise intervention improve functional capacity and health status post-
COVID-19?  
 Hypothesis: A personalised yet pragmatic approach to resistance-based exercise as an adjunct 
to standard care improves health status and functional capacity, as compared to standard care 
without resistance-based exercise. 
 
2. 
Do the results of this trial elucidate mechanisms of disease in Long COVID? 
 Hypothesis: Improvements in functional capacity with resistance-based exercise identify 
reversible impairments in skeletal muscle function in patients after COVID-19. 
 
3. 
Is a national clinical trials platform for post-COVID patients in NHS Scotland feasible? 
Hypothesis: A clinical trials infrastructure permits the rapid implementation of novel 
therapeutic interventions in patients with Long COVID. 
 
3.3 Primary outcome 
 
 
Incremental shuttle walk test (ISWT) at 3 months. 
 
Incremental shuttle walk test (ISWT) [20]. This is a validated measure of functional capacity, with test-
retest reliability and evidence of being responsive to rehabilitation interventions. The ISWT is used as 
a Tier 2 evaluation in the PHOSP-COVID study. By adopting the ISWT as the primary outcome measure, 
our study will complement PHOSP, align with the protocol (for those patients who have been enrolled), 
and potentially, enhance co-enrolment into this observational study. 
 
Oxygen saturation, heart rate and respiratory rate will be measured at the start and end of the ISWT. 
They will be exploratory outcomes. 
 
 
 

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3.4  Secondary outcomes 
 
1. 
Spirometry; 
2. 
Handgrip strength;  
3. 
Short Physical Performance Battery (SPPB) 
4. 
EQ5D, PHQ, Illness perception (Brief IPQ), Duke Activity Status Index (DASI), 
International Physical Activity Questionnaire (IPAQ-SF) short-form, Fatigue 
questionnaire, MRC dyspnoea score;  
5. 
Frailty assessed using 1) Fried frailty phenotype:  five criteria: weight loss; exhaustion; 
grip strength; low physical activity; and slow walking pace; 2) Clinical Frailty Scale 
6. 
Episodes of care (primary, secondary, physiotherapy, rehabilitation)  
7. 
Hospitalisation for any reason.  
 
The secondary outcomes are intended to align with PHOSP assessments at 3-months. 
 
 
3.5  
Exploratory outcomes 
  
1) Exercise dose achieved (1) daily log, (2) level attained and within subject change from 
baseline, 
2) Vital parameters of cardio-respiratory function e.g. oxygen saturation, heart rate, respiratory 
rate at baseline and during follow-up 
3) Adherence with exercise (log) 
4) Accelerometery (Glasgow site) 
5) Biobank tissues samples for biomedical research 
 
Research blood samples: Exploratory analyses may include - Haemostasis - Claus Fibrinogen, D-
Dimer, FVIII (one stage), VWF antigen, VWF:GP1ba, Antithrombin activity, Protein C activity, Free 
protein S; Cardiac - NT-proBNP, hs-troponin; Vascular cytokines - ET-1, ICAM, VCAM, p-selectin, 
IL-6, VWF, Nox3; Vascular cells and microparticles; Metabolic status - HbA1C, lipids; Blood RNA 
(Tempus™ or PAXgene®) including for RT-PCR of SARS-CoV-2 and RNA for vascular biology; 
Inflammation – hs-CRP, ST2; Immune response antibodies; Collagen metabolites; DNA - The 
buffy coat will be stored for DNA analysis e.g. candidate gene SNPs, other variants. Residual 
blood will be saved for future analyses of interest.            
 
 
 

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4.  
STUDY DESIGN 
This trial has a prospective, randomised, open-label, parallel group design.  The trial is designed to 
assess the superiority of resistance-exercise intervention as compared with standard care without this 
intervention in patients recovering after COVID-19. 
 
 
  
5.  
SETTING 
 
All patients presenting at participating hospitals and Primary Care settings e.g. community assessment 
centres (CAC), Community Health Centres (CHC) or Community Test Centres (CTC), with COVID-19 can 
be considered for inclusion. Also, patients enrolled in CISCO-19, OBELIX, RECOVERY and ISARIC studies, 
and other relevant studies, who fulfil the inclusion/exclusion criteria for CISCO-21, with the permission 
of the study CI and local PI, may be approached re co-enrolment in the CISCO-21 study. A screening 
log with the reasons for not being enrolled, will be prospectively completed. 
 
Research collaborators include, in the University of Glasgow, the Institute of Cardiovascular and 
Medical Sciences, the MRC-University of Glasgow Centre for Virus Research, the Robertson Centre 
for Biostatistics and the Electrocardiography Core Laboratory.  
 
5.1  
Standard care 
Clinical management of patients following COVID-19 in the NHS will generally align with practice 
guidelines from the British Thoracic Society and other key stakeholders such as NICE, RCPGP and SIGN. 
Local practice may vary according to circumstances. In NHSGGC, patients who have been admitted 
with radiological and/or virology confirmed COVID-19 would be invited for a CXR 12 weeks post-
discharge and if there are persisting abnormalities on the X-ray, the patient would be invited to a 
phone consultation. Options for the evaluation of patients with persisting symptoms include to 
provide an oxygen saturation monitor, a functional assessment of physical capacity, and/or an 
invitation to attend an out-patient clinic according to clinical need and logistical considerations. 
 
 
 
 

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6. 
STUDY POPULATION  
 
6.1 Clinical strata 
 
Since COVID-19 is an acute illness with a recovery period that may be prolonged, we recognise that 
different approaches are needed to reflect the stage and trajectory of recovery from COVID-19. 
Patients will be classified according to the clinical management of their illness: 
A. Non-hospitalised - Positive diagnosis with persisting symptoms leading to medical review 
(A&E, SATA, Community COVID Hub) but not admission,  
B. Hospitalised, positive diagnosis, post-discharge, persistent symptoms,  
C. Hospitalised, positive diagnosis, convalescent phase in-hospital.  
Groups A & B = target population for treatment of persisting symptoms post-COVID i.e. Long-COVID; 
Group C = Target population for prevention of Long COVID.  
 
6.2 Inclusion criteria  
 
1) Virology PCR positive laboratory diagnosis of COVID-19, 
2) Within 6 months of diagnosis, 
3) Persistent symptoms for at least 4 weeks from symptoms onset (Groups A & B only) 
4) Presentation type - one of group A, B or C;  
 
 
6.3 Exclusion criteria  
 
1. Physiotherapy as part of standard care e.g. post-ICU, post-HDU,  
2. No expectation of being able to walk within 3 months 
3. Unable to provide informed consent,  
4. Unable to comply with the protocol. 
5. Known pregnancy 
 
NB Since the primary outcome is the ISWT at 3 months, a patient who will not be able to walk during 
the follow-up period would therefore not be able to complete the primary outcome evaluation. 
Accordingly, a patient who will be unable to walk should not be enrolled.  Patients who are ‘bed-
bound’ may be enrolled provided there is a reasonable belief that they will be able to walk 3 months 
later. 
 
 
6.4 Stratification of randomisation 
Participants who fulfil eligibility criteria and provide written informed consent will have randomisation 
stratified by clinical strata groups (A – C), history of COVID-19 pneumonia (yes / no), age, sex and site. 

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7. 
TRIAL PROCEDURES 
 
Please see Schedule of Assessments  
 
7.1 Screening and recruitment 
Screening will be undertaken in A&E, the Acute Medical Assessment Units and medical wards. 
Patients who attend Community Assessment Centres, Community Test Centres or Health Centres 
and have a diagnosis of COVID-19 confirmed may also participate. Patients with a history of COVID-
19 who have been discharged following this episode of care may also be sent the PIS and consent 
form. These centres may display posters about the study such that the patients may contact the 
research centre if their symptoms persist during their convalescence. Posters may also be placed in 
public areas in the hospitals and community health centres. 
 
A screening log will be prospectively recorded and entered into the eCRF. 
 
Patients who are enrolled in observational studies may be eligible to participate. For example, the 
Cardiovascular Imaging in SARS-CoV-2 (CISCO-19) study is an observational cohort study and patients 
are invited to give informed consent to be contacted about future studies. Therefore, patients who 
have been enrolled into CISCO-19 and who fulfil eligibility criteria may be eligible to participate in 
this next-stage clinical trial. 
 
7.2   Informed consent 
Only patients who are sufficiently well to understand the information about the study (including the 
potential for benefit and known risks), as described by the attending clinical research nurse and/or 
clinician, would be eligible to participate. Potential participants will be identified and screened using 
the clinical inclusion and exclusion criteria defined in this protocol, and approached as follows:  
Patients in  
Group A - Non-hospitalised, with symptoms persisting for at least 4 weeks post diagnosis: Potential 
participants in this patient group will be identified and invited to take part in the study when they 
attend A&E or Community Assessment Centre, Community Test Centre or Community Health Centre 
with persistent symptoms. They can be given a PIS at this visit, or agree for their contact details to be 
passed on the research team and a PIS sent out to them. Alternatively, they may be identified at a 
later date from review of records by the usual care team and sent a letter of invitation and a PIS at 
this point.  
Group B- hospitalised with COVID-19, with symptoms persisting for at least 4 weeks post diagnosis, 
and discharged. Potential participants will be approached by their usual care team re the study pre –
discharge, or agree for their contact details to be passed to the research team and a PIS sent out to 
them. Again. if patients are identified as potentially eligible from a review of records at a later date 
the can be sent an invitation letter with a PIS for the study with contact details of the research team. 

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In groups A and B we would also like to be able to follow up the letter with a phone call after 2 weeks 
to see how patients are and if are interested in joining the study 
 
Group C- hospitalised with COVID-19 and convalescent in hospital: Potential participants would be 
approached by a member of their usual care team re taking part in the study and if interested asked 
to agree to speak to a member of the research team about this.  
 
Potential participants for all groups will be given as much time as they need to decide whether to take 
part in the study. 
 
In all cases clinical staff will be available to discuss the study with the patient and his/her family and 
friends. If the patient agrees to take part in the study, then the consent form will be signed by the 
patient and the member of staff obtaining the consent. The decision to include a patient in the study 
will be documented in the medical notes. No further scheduled study assessments can be performed 
until written informed consent has been obtained.   
 
Withdrawal criteria: A participant may withdraw from the study at any time. There are no specific 
withdrawal criteria, although clinicians can withdraw patients as appropriate and record the reasons. 
All patients will be followed up for clinical outcomes, unless consent is specifically withdrawn. 
 
Participants consenting for the study will be invited to provide consent for long-term follow-up of their 
electronic medical records (with no additional patient contact). Consent will be sought to use study 
data in other ways such as in pooled analyses of anonymised data such as for natural history studies, 
meta-analyses and health outcomes research. 
 
 
7.3  
Recruitment plan 
 
Healthcare staff who participate in this study should adopt a consecutive approach to enrolment in 
order to minimise selection bias and provide a study cohort that is representative of patients treated 
during usual care. The results are intended to have external relevance and be transferable to clinical 
practice. This approach will also facilitate timely delivery of the trial. 
 
The sample size estimate takes account of a degree of participant withdrawals from the study, 
incomplete data, and problems with data acquisition.  
 
 
7.4  
Clinical evaluation 
 
7.4.1 Clinical status 
Information on medical history and COVID-19 will be collected. The information will be collected at 
baseline and again at 3 months. The information will as far as possible align with the CISCO-19 study 
(Appendix), and will include:   
  
1. 
Cardiovascular history  

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2. 
Medical history/therapy, including history of COVID-19 pneumonia and physiotherapy 
3. 
Vital signs and anthropometry (heart rate, rhythm, blood pressure, height, weight, waste 
circumference, oxygen saturation) 
3. 
Comorbidity including the components of the Charlson Index   
4. 
Scottish Index of Multiple Deprivation derived from the post code  
5. 
Cardiovascular risk factors e.g. smoking history, cardiovascular risk scores.  
6. 
Respiratory history – Asthma, bronchiectasis, COPD (including bronchitis and emphysema), 
chronic rhinosinusitis, hypersensitivity pneumonia, lung cancer, lung fibrosis, chronic pleural 
disease, pneumoconiosis, pulmonary eosinophilia, pulmonary vascular disease (PTE, 
pulmonary hypertension, cor pulmonale), sarcoidosis, sleep apnoea syndrome), other *WHO 
Common Chronic Respiratory disease list. 
7. 
Post-COVID lung disease (convalescence) - fibrosis, pulmonary hypertension, PTE 
8. 
COVID-19 – diagnosis and treatment   
9. 
12-lead ECG (if available) 
10. 
Imaging (if available) – CXR, CT chest / CTPA, cardiac 
11. 
COVID-19  
prognostic  
risk  
score  e.g.  
ISARIC-4  
and WHO severity 
score. 
 
Smoking  
status  will  
be  
defined  
as  
per  
established  
definitions: 
https://www.cdc.gov/nchs/nhis/tobacco/tobacco_glossary.htm 
 
 
7.4.2 Clinical strata 
For the purposes of classifying sub-groups within the target population, participants will be 
categorised into one of 3 groups 
A) Non-hospitalised - Positive diagnosis with persisting symptoms leading to medical review (A&E, 
SATA, Community COVID Hub) but not admission,  
B) Hospitalised, positive diagnosis, post-discharge, persistent symptoms at 4 weeks or longer (PHOSP 
contact), 
C) Hospitalised, positive diagnosis, convalescent phase in-hospital.  
Groups A & B = target population for treatment of persisting symptoms post-COVID i.e. Long-COVID; 
Group C = Target population for prevention of Long COVID. 
 
7.5  Blood Sampling  
7.5.1  
Sample collection 
Samples required for medical management will at all times have priority over samples taken for 
research.  Wherever possible, taking additional research blood samples should be timed to coincide 
with routine clinical sampling time-points.  
Sampling time-points:  

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Visit 1 - Enrolment (post-consent), standard care bloods (if not available),  
if omitted at Visit 1,  
Visit 2 – 3 months + 6 weeks following enrolment 
Blood samples required at each timepoint: standard care and research samples – see footnote, 
Schedule of Events.   
Blood samples (25 ml) for central laboratory tests of circulating molecules implicated in the 
pathophysiology acute MI or myocardial injury, potentially complicated by COVID-19. Sample 
collection kits will be provided for these research bloods, including PAXgene tubes. Samples will be 
collected and dealt with as per study Sample Handling Manual. These samples will be batched and 
analysed in line with available funding.  
Routine standard of care bloods will be assayed in local NHS laboratories as per standard procedures 
irrespective of site. Recent publications describe cardiovascular complications leading to hospital 
readmissions post-COVID-19 (Ayoubkhani et al (2021); the OpenSAFELY study (Tazare J et al 2021), 
pointing to significant cardiovascular risk of patients with persisting symptoms.  
Research samples will be handled as per instructions in Sample Handling Manual.  Samples will be 
archived at the NHS GGC Biorepository using a LIMS. Initial exploratory analysis will be at University 
of Glasgow, 
Results of routine blood samples will be uploaded to NHS Clinical Portal / Trakcare systems for review 
by clinicians.   
7.5.2 Sample analysis  
Analysis of samples for vascular cytokines will be carried out in the Sattar/ Welsh laboratory, University 
of Glasgow.  
 
The haemostasis and coagulation analyses will be undertaken in the NHS Haemostasis Laboratory (Dr 
Catherine Bagot), Department of Haematology, Glasgow Royal Infirmary. Immunology will be analysed 
in the NHS (Prof Rory Gunson) and/or University laboratories e.g. Prof Carl Goodyear, MRC CVR. 
  
Sample collection, shipping, processing and analysis will be as per study sample manual and local SOPs  
7.6   
Oxygen saturation, respiratory rate and heart rate 
Oxygen saturation, respiratory rate and heart rate should be measured at each visit, including at the 
start and end of the shuttle walk test. 
7.7 
Spirometry 
Lung function should be assessed using spirometry  at Visits 1 and Visit 2. 
The basic measurement will be a peak expiratory flow rate (PEFR), forced vital capacity (FVC) and 
forced expiratory volume in one second (FEV1)  

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7.8 
Muscle strength 
  
Hand grip strength will be assessed as a measure of physical function at Visits 1 and 2. Handgrip 
strength will be recorded using a handheld dynamometer. For handgrip strength, measurements are 
performed until 3 measurements are within 5% of each other. Typically, 3 - 6 manoeuvres in each 
hand are performed. Responses in the dominant hand will be recorded. 
7.9  
Short Physical Performance Battery (SPPB) 
The SPPB is a series of brief, simple physical tests including of the ability to stand for 10 seconds with 
the feet in 3 different positions (together side-by-side (score 0 – 1), semi-tandem (score 0 – 1), and 
tandem (score 0 – 2)), two timed trials of a 3m or 4m walk (fastest recorded) and the time to rise from 
a chair 5 times. The score ranges from 0 to 12 (higher scores reflect better extremity function). The 
gait and chair subtests score from 0 to 4.  
 
SPPB will be supported by an SOP that takes account of information, training and standardisation. 
7.10 
Accelerometer  
Accelerometery reflects body motion during daily activities. In a sub study focused to participants in 
Glasgow (Groups A and B), a portable accelerometer, styled as a watch, will be provided at baseline 
and again 3 months. An all-comers approach will be adopted with invitation to consecutively 
presenting patients. The device should be worn for 7 days lead. 
 
GENEActiv accelerometer will be used and supported by a SOP with instructions and contact details if 
there are any issues. Of the available variables, the following are the parameters that will be obtained 
using the information collected via these devices: 
 
 
Total Physical activity 
 
Light Intensity Physical Activity 
 
Moderate Intensity Physical Activity 
 
Vigorous Intensity Physical Activity 
 
Sleep duration 
 
Sleep efficiency 
7.11 
Questionnaires  
  
Patient reported outcome measures will be collected at each visit in order to assess their associations 
with the measurements (parameters) of cardiopulmonary injury / function.  This would be with the 
intention to gain insights into the clinical significance of the research findings, and to assess temporal 
changes over time.  
  
 
EQ-5D: Health status and quality of life  
 
 
Anxiety/depression (PHQ4)  
 

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 
Illness perception (Brief IPQ): Describes the participants self-reported health burden and 
perception  
 
 
Duke Activity Status Index (DASI): To assess the functional status (exercise capacity); this index 
is validated against the Bruce treadmill exercise test, and both are prognostically validated.  
 
 
International Physical Activity Questionnaire (IPAQ-SF): provides information on current / 
recent activity levels.  
 
 
Fatigue questionnaire. 
 
 
MRC Dyspnoea score. 
 7.12  Frailty 
Frailty will be assessed using two scales, 1) the Fried frailty phenotype, five criteria: weight loss; 
exhaustion; grip strength; low physical activity; and slow walking pace (Appendix) and 2) the Clinical 
Frailty Scale. The Fried frailty phenotype includes distinct components whereas the Clinical Frailty 
Scale is a simple ordinal score that is more straightforward to complete. There is no frailty threshold 
for inclusion in the study, aside from the eligibility criterion that the patients should be able to walk. 
7.13 
Randomisation 
Participants will be randomly assigned (1:1) to the intervention or control group. The randomisation 
sequence will be pre-determined before the start of the trial. 
Participants who fulfil eligibility criteria and provide written informed consent will have randomisation 
stratified by group (clinical strata, Group A, B or C; see section 7.4, above).  
The randomisation procedure will be undertaken by trained staff will use a web-based randomization 
tool hosted by the CTU.  
7.14 
Resistance exercise intervention  
Intervention = a resistance-based exercise intervention for patients during the convalescence phase 
in-hospital through to 3-months post-discharge, a duration reflecting chronic, maintenance treatment 
studies. To maximise enrolment of eligible patients, the intervention may be initiated in-hospital or in 
the community post-discharge. Resistance bands may be used according to the exercise guideline. 
Patients recovering from COVID-19 may spend many days in-hospital leading up to discharge. Patients 
will be placed within one of three broad categories of baseline physical capabilities (bed bound, up-
to-sit, and ambulant) at the beginning of the intervention. Within the latter 2 categories, there will be 
progression of effort options and patients will be able to move between (up or down) these three 
categories.  
The exercise regimens are generic and designed not to require expert physiotherapy input, therefore, 
the availability of NHS physiotherapists, which may be at times limited, will not be a barrier to 
implementation. If the study was successful it is hoped it could be adopted by ward staff. Progress will 
be reviewed and changes in the exercise plan will be adjusted according to a standard operating 

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procedure. The participants may progress through the physical capability groups during the recovery 
phase from their illness. 
Peripheral locomotor muscle training  
Participants will be invited to train daily. Patients will be invited to perform the number of repetitions 
that leads to a validated resistance exercise specific Rating of Perceived Exertion (RPE) of 8-10 (PMID: 
12569225). The use of RPE to prescribe and progress resistance exercise has been shown to be as 
efficacious as other more complex methods but reported to be the most tolerable and enjoyable 
method (PMID: 31107348). Once patients can reach 15-20 repetitions of each exercise they will be 
advised to move to the next level within each category and once able to do this for the top level within 
the category, to move to the next category. Similarly, if patients are not able to manage 5 repetitions 
of each exercise they will move down a level and, if at the bottom level within a category, down a 
category. 
The overall  exercise programme pack is provided a single document. The exercise programme has 
been developed by Dr Stuart Gray (Physiologist, University of Glasgow) with guidance from our PPI 
group (Dr Tracy Ibbotson, Prof Frances Mair, Primary Care), Drs Hannah Bayes and David Anderson 
(Rehabilitation, NHSGGC), Prof Rod Taylor (MRC Unit) and Clare Burke and David Boiskin 
(Physiotherapy, NHSGGC QEUH).  
A training package will be provided to the site research staff (research nurses, fellows). The pack will 
be given to patients during an initial face to face session where the nurse/therapist will help to select 
the most suitable category and level of exercise for the patient, and to demonstrate these and ensure 
patients are comfortable performing the exercises. Every 2 weeks a member of the research team will 
contact the patients to ensure they are happy with the exercises and to help overcome any issues that 
have arisen. If the patient is in hospital, the contact may be daily, as needed. 
Implementation at sites will be overseen and supported by a Working Group that includes these 
colleagues in an advisor role. The site research staff will be trained on the practical aspects of the 
exercises. Training will be given through in-person site visit. 
Intervention group: An instructional pack (with video links and pictures) and an exercise log will be 
provided to empower each patient.  We have put together a draft of the exercise programme pack for 
patients. This has been reviewed by our PPI group (4 Nov 2020) and feedback incorporated to reflect 
co-design of the programme. Based on our experience in the CISCO-19 study, we believe the exercise 
intervention will be feasible for most patients who have capacity to follow and adhere to verbal and/or 
written instructions. We aim for a widely generalisable intervention that can be taken up by most 
post-COVID-19 patients. 
The programme is intended for patients in-hospital or at home and allowing for transition between 
the two. Our exercise intervention is supported by a systematic review of resistance training [18]. 
Specific protocols [15]: taking account of feedback to ensure simplicity, safety and remove barriers to 
implementation, household objects e.g. bottle of water, tin of food, which would be available to all 
participants, or exercise tension bands are also an option, according to patient preference. This 
demarcates our intervention from Physiotherapy and can be facilitated by other healthcare staff 
including nursing staff (hospital-based, community) and medical staff (including GPs). 
LONG COVID-19 EXERCISE MANUAL (developed by Dr Stuart Gray, Prof Colin Berry and informed by 
feedback from the NHS GGC Patient Group, October – November 2020),  

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SUMMARY: Exercises are personalised options according to the circumstances of the individual 
patient: Bed-bound, up-to-sit, ambulant. The resistance exercise options are described in a manual. 
Setting: Hospitalised patients, in their room on the ward and continued until post-discharge up to 3 
months. Participants may be recruited post-discharge and would then come to hospital for consent 
and baseline assessment and thereafter would carry out exercises at home. 
Timing and duration of interventions: Convalescence phase through to 3 months post-discharge. This 
time window is intended to follow-on from the acute therapy (and trials). The window focuses on the 
period when patients are recovering on the medical wards, through to 3 months post-discharge, which 
is when the first clinical assessment takes place in PHOSP (Tier 2). Our observations from the current 
landscape of clinical trials in the UK is that this time-period is not fully covered by the existing studies, 
hence our strategic focus for this enrolment window (post-ICU/HDU through to 3 months), which is a 
critical time for patients in their paths to recovery. Informed consent into our trial will complement 
co-enrolment into PHOSP (which is an observational study).  
Patients who have been treated in ICU or HDU receive Physiotherapy as part of standard care, 
therefore, these patients would only be eligible for enrolment if the physiotherapy has completed. 
This reflects our plan for ‘prehabilitation’ without overlap with standard care NHS Physiotherapy. The 
focus for our trial(s) would mainly be during the post-ICU period to post-discharge e.g. 3 months (Tier 
2, PHOSP), and options for longer term follow-up assessments, also aligned with PHOSP, will be 
feasible. Our aim is to synergise with PHOSP (aligning timing and endpoints), enhance enrolment and 
the compliance with follow-up. 
7.15  Incremental shuttle walk test 
Primary outcome: Incremental shuttle walk test (ISWT) [20]. This is a validated measure of functional 
capacity, with test-retest reliability and evidence of being responsive to rehabilitation interventions. 
The ISWT is used as a Tier 2 evaluation in PHOSP. By adopting the ISWT as the primary outcome 
measure, our study will complement PHOSP, align with the protocol (for those patients who have been 
enrolled), and potentially, enhance co-enrolment into this observational study. Use of ISWT should be 
registered with the University of Leicester (Prof Sally Singh), including use of the digital timer for the 
test. Our staff have local experience since the PHOSP-COVID study is running in Dundee and Glasgow. 
Oxygen saturation, heart rate and respiratory date at the start and end of the ISWT, and reflect 
exploratory outcome measurements. 
7.16 
Data Retrieval and eCRF Input  
A study clinician and/or delegated member of staff will be responsible for accessing the relevant 
patient data (A&E admission paperwork, discharge paperwork) and blood sample results on the 
NHSGG&C hospital systems, including Clinical Portal and/or Trakcare. The data provided on these 
systems will be considered as source data.   
  
Patients will be allocated a unique patient number at the point of consent, and this is how they will be 
identified within the eCRF.   
  
The eCRF will be developed and managed by the Robertson Centre for Biostatistics.  

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7.17  Record linkage  
 Patient contact is necessary for the study visits which will be minimised by telephone contact during 
the study period. At the other time-points, patient contact will not be necessary if access to 
electronic medical records is feasible and the data are clear. When patient contact is unsuccessful 
the GP may be contacted, and electronic health records will be checked including for the assessment 
of events, and medication use in the longer term. The follow-up will be by telephone, or by letter or 
clinic review as clinically appropriate.   
In the longer term, additional follow-up of health outcomes, and related health information e.g. 
primary care attendances, pharmacy prescriptions, will be assessed by electronic case record linkage 
using the Community Health Index (CHI) number in Scotland.  
Episodes in primary and secondary care, death, and causes in primary and secondary diagnostic 
positions, will be assessed using electronic health records held by the NHS and government / public 
sector agencies.  
 

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8. 
SAFETY REPORTING  
 
8.1  Definitions   
8.1.1 Adverse Event (AE)   
Any untoward medical occurrence in a subject to whom a trial specific procedure has been 
administered, including occurrences which are not necessarily caused by or related to that trial specific 
procedure.  
  
8.1.2  
Serious Adverse Event (SAE)  
Any adverse event or adverse reaction that:  
  
a) Results in death  
b) Is life threatening  
c) Requires hospitalisation or prolongation of existing hospitalisation  
d) Results in persistent or significant disability or incapacity  
e) Consists of a congenital anomaly or birth defect  
f) Is otherwise considered medically significant by the investigator  
g) Important adverse events/reactions that are not immediately life-threatening or do not result 
in death or hospitalisation but may jeopardise the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above. 
  
8.1.3  
Related Unexpected Serious Adverse Event (RUSAE)  
Any SAE thought to be related to a trial specific procedure performed on that subject that is thought 
to be unexpected; that is the event is not listed within the protocol or would not be expected to occur 
when carrying out the trial specific procedure in normal clinical practise.  
 
8.2 Serious adverse event recording and reporting  
Where an SAE requires recording; full details including the nature of the event, start and stop dates, 
severity, relationship to research product and/or trial procedures, and the outcome of the event will 
be recorded in the patient’s medical notes and CRFs.  These events will be monitored and followed up 
until satisfactory resolution and stabilisation.  
  
Each SAE should be assessed to determine if related to the research specific procedures and assessed 
for expectedness.  Where an event meets the criteria of an SAE and is both:  
  
• 
Related: that is, it resulted from any of the research procedures, AND   
  
• 
Unexpected: that is against the procedure events listed below as an expected occurrence.   
  
The SAE meets the criteria of a Related and Unexpected Serious Adverse Event (RUSAE) and is subject 
to expedited reporting to the Sponsor.  

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 8.3  
 Expected Events Related to Phlebotomy Procedures  
 
There is little risk to participants taking part in this study; however, there may be complications 
relating to the phlebotomy procedures such as:  
  
• 
Haematoma   
• 
Nerve injury   
• 
Arterial puncture - If this occurs, remove the needle and apply direct pressure for at least 10 
minutes; if a pulsatile mass persists, consider arterial duplex ultrasonography  
• 
Syncope   
• 
Phlebitis or cellulitis   
  
These events would be considered expected within this study.  
8.4  
Expected Events related to resistance exercise  
  
Complications of exercise intervention may be soft tissue strain, falls or exhaustion.  
8.5  
 Reporting to the Sponsor  
  
All RUSAEs must be reported to the Pharmacovigilance Office immediately (within 24 hours) using the 
generic non-CTIMP SAE form which is available from http://www.glasgowctu.org/data/SAE_non-
CTIMP.pdf. The SAE form should be completed and signed by appropriately delegated staff.    If 
necessary, a verbal report can be given by contacting the PV Office on 0141 330 4744. This must be 
followed up as soon as possible with an electronic report.    
If all of the required information is not available at the time of initial reporting, the CI (or designee) 
must ensure that any missing information is forwarded to the PV Office as soon as this becomes 
available. The report should indicate that this information is follow-up information for a previously 
reported event.  
8.6  
 Reporting of RUSAEs to the Ethics Committee  
  
The PV office will report all RUSAEs to the ethics committee within 15 days of the PV office becoming 
aware of the event, via the ‘report of serious adverse event form’ for non-CTIMPs published on the 
Health Research Authority web site. http://www.hra.nhs.uk/documents/2015/02/safety-report-
form-non-ctimp.docx. The form should be completed in typescript and signed by the Chief Investigator.   
8.7 
Pregnancy reporting (site responsibilities) 
 
Pregnancy is an exclusion criterion. If after enrolment the participant becomes pregnant, this is not 
considered an AE or SAE in this trial unless a negative or consequential outcome is recorded for the 
mother or child/foetus. However, the patient would then be invited to withdraw from the study. If 
the outcome meets the serious criteria, this would be considered an SAE and must be reported as per 
SAE reporting procedure above. 

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8.8 
Recording and reporting of SAEs where eCRF access is not possible 
 
If recording in the eCRF is not possible a paper SAE form should be completed: 
 
 
The SAE form is downloaded from www.glasgowctu.org, printed off, completed and signed. 
The form is then faxed to the Glasgow Clinical Trials Unit Pharmacovigilance (PV) Office on 
+44(0)141 357 5588. If faxing is not possible a copy of the SAE form should be scanned and 
emailed to: pharmacovig@glasgowctu.org. If this website is unavailable a paper copy of the 
SAE form is filed in the Investigator Site File at each site. 
 
If necessary a verbal report can be given by contacting the PV Office on +44(0)141 330 4744. 
This must be followed up as soon as possible with an electronic or written report. 
 
8.9 
Responsibilities for Safety Reporting and Review 
 
This section details the responsibilities for reporting and reviewing safety information arising from the 
trial. 
8.10 
Data Centre  
The study Data Centre will: 
 Provide an eCRF for central data collection of AEs and SAEs; 
 Provide reports to the independent oversight committees identified for the trial 
(Independent Data Monitoring Committee (IDMC) and/or Trial Steering Committee (TSC)). 
8.11 
Principal Investigator (PI) 
 Checking for SAEs when participants attend for treatment / follow-up. 
 Ensuring that SAEs are recorded in line with the requirements of the protocol.  
 Ensuring that all SAEs are recorded in the eCRF within 24 hours of becoming aware of the 
event and provide further follow-up information as soon as available.  
 Using medical judgement in assigning seriousness, causality, severity and expectedness with 
reference to the trial protocol and Reference Safety Information. 
8.12 
Chief Investigator (CI)  
 Clinical oversight of the safety of patients participating in the trial, including an ongoing review 
of the risk / benefit. 
 Using medical judgement, confirm seriousness and causality and confirm expectedness of 
SAEs. 
 Immediate review of life-threatening SAEs  
8.13 
Sponsor  
 Verification of data collection, SAEs, according to the trial protocol  
 Reporting safety information to the CI or delegate for the ongoing assessment of the risk / 
benefit  

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 Preparing in collaboration with the CI the annual safety report to the Research Ethics 
Committee and until the End of the Study, at which time an End of Study form will be 
submitted. 
 
8.14 
Trial Steering Committee 
In accordance with the Charter for the TSC, periodically reviewing recruitment and the overall progress 
of the trial and liaising with the IDMC and sponsor regarding safety issues. 
 
8.15 
Independent Data Monitoring Committee 
The IDMC will develop and agree a charter in line with the DAMOCLES guidelines. In accordance with 
the Charter, periodically reviewing unblinded safety data in individual cases and to determine patterns 
and trends of events, or to identify safety issues, which would not be apparent on an individual case 
basis, reporting concerns to the TSC and sponsor. 
 
 
  
  
 
 

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9. 
Statistical Analysis 
  
9.1 
Statistical analysis plan 
This study will have a comprehensive Statistical Analysis Plan, which will govern all statistical aspects 
of the study, and will be authored by the Trial Statistician before unblinded data are seen. 
 
9.2 
General considerations 
The statistical Analysis Plan (SAP) will be based on intention to treat principles in line with CONSORT 
guidelines. The analysis will focus on estimation of treatment effect differences with 95% CIs and p-
values. All pre-specified secondary outcome analyses will be reported in study publications. 
 
9.3 
Primary efficacy analysis 
Alternative hypothesis: In patients with persisting symptoms during the convalescence phase after 
COVID-19, resistance exercise increases exercise capacity measured by the incremental shuttle walk 
test. The null hypothesis reflects no difference in exercise capacity between the groups. 
9.3.1 Primary outcome 
Incremental shuttle walk test at 3 months 
9.3.2 Primary analysis and sample size 
The minimum clinically important between-group difference in the ISWT at follow-up (3 months) = 
79 m, SD=105 [20], sample size for 80% power, 5% significance, no loss to follow-up (LTFU) = a 
minimum of 85 / group; allowing for LTFU and incomplete data, the sample size is n=110/group 
(n=220 total).  
After 50% of the patients have been recruited, if enrolment rates and the budget permit, we will 
seek approval from the trial committees and Sponsor to upscale to 90% power. For 90% power, 
n=318/group, or 398 patients would be needed, allowing for up to 20% attrition. If enrolment rates 
are sufficient we will seek IDMC approval to upscale to 90% power. 
 
9.4 Software and statistical analysis 
Continuous outcomes will be analysed where data are approximately normally distributed and where 
baseline levels are available for adjustment. Where this is the case, two sample t-tests and 

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corresponding confidence intervals will be used. Where data are clearly not normally distributed (e.g. 
laboratory variables) standard transformations will be applied to achieve approximate normality prior 
to analysis.  
Clinical data will be made available to the data coordinating centre (the Robertson Centre for 
Biostatistics) through the web-based eCRF.  The RCB is UKCRC-registered Clinical Trials Unit (number 
16). The statistical software to be used will be SAS and/or R. 
All analyses will be governed by a Statistical Analysis plan, to be finalised prior to database lock, and 
prior to sharing of any summary results. This plan will summarise the types of methods to be used for 
each study hypothesis, allowing some flexibility in the precise methods to be used, given the 
exploratory nature of the study. 
 
 
 

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10. DATA HANDLING 
10.1 
Case Report Forms / Electronic Data Record 
An electronic case report form (eCRF) will be used to collect study data.  The eCRF will be developed 
by investigators in the University of Glasgow and access to the eCRF will be restricted, with only 
authorised site-specific personnel able to make entries or amendments to their patients’ data. It is the 
investigator's responsibility to ensure completion and to review and approve all data captured in the 
eCRF.  
All data handling procedures will be detailed in a Study Specific Data Management Plan.  Data will be 
validated at the point of entry into the eCRF and at regular intervals during the study.  Data 
discrepancies will be flagged to the study site and any data changes will be recorded in order to 
maintain a complete audit trail (reason for change, date change made, who made change).  
The data management plan will inform sharing and access to bone fide researchers and a standard 
research agreement. Individuals/centres will be recognised through publications (acknowledgement 
and named authors in line with their contributions). 
10.2 
Data Retention 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to keep 
records, including the identity of all participating subjects (sufficient information to link records), all 
original signed informed consent forms, serious adverse event forms, source documents, and detailed 
records of treatment disposition in accordance with EU GCP guidance, local regulations, or as specified 
in the Clinical Study Agreement, whichever is longer.  Data will be retained at the Data Centre for a 
minimum of 10 years after the end of the study. 
 
 
11. MONITORING, AUDIT & INSPECTION 
NHSGGC conducts monitoring and/or audit of studies on a risk basis and in accordance with local 
Standard Operating Procedures. The level, frequency and priorities of monitoring and/or audit will be 
agreed with the NHS Governance Manager. 
 
 
 
 

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12. ETHICAL AND REGULATORY CONSIDERATIONS 
12.1  Research Ethics Committee (REC) review & reports 
Before the start of the trial, approval will be sought from a REC for the trial protocol, informed consent 
forms and other relevant documents e.g. advertisements and GP information letters. 
Substantial amendments that require review by REC will not be implemented until the REC grants a 
favourable opinion (it is noted that amendments may also need to be reviewed and accepted by the 
NHS R&D departments before they can be implemented in practice at sites). 
All correspondence with the REC will be retained in the Trial Master File/Investigator Site File.  
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary date 
on which the favourable opinion was given, and annually until the trial is declared ended (this is the 
Chief Investigator’s responsibility). 
The Chief Investigator will notify the REC of the end of the study. 
If the study is ended prematurely, the Chief Investigator will notify the REC, including the reasons for 
the premature termination. 
Within 6 months after the end of the study, the Chief Investigator will submit a final report with the 
results, including any publications/abstracts, to the REC. 
12.2  Peer review 
The study design has benefitted from peer review through the Glasgow CTU, NHSGGC Patient and 
Public Involvement (PPI) group and the Chief Scientist Office of the Scottish Government (November 
– December 2020). 
12.3  Public and Patient Involvement 
Patient and public involvement (PPI) is led by Dr Tracy Ibbotson, of the Scottish Primary Care Research 
Network, who steers a patient group in NHS Glasgow. This group has been actively involved in the 
development of our proposal.  
We will establish a PPI group of patients who have had lived experience of COVID-19. They will 
participate in PPI activities including the design of patient packs, linking to appropriate patient groups, 
and co-producing written reports for patient websites and conferences. Given the level of public 
interest, we anticipate sharing information about our study through the media e.g. BBC, newspapers 
with coordination by NHS GGC and University communications teams. 
Our PPI group will meet every 3 months to oversee the study and funding is included in our budget. 
Constituting this group at the outset of the study will also be a deliverable and the reports (minutes) 
from each of the meetings (scheduled to correspond with the timelines/milestones).        
PPI in our research will include a patient representative on the TSC. 

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12.4  Regulatory Compliance  
The trial will not commence until full approval has been granted by the Research Ethics Committee, 
the R&D Management Office and Sponsor. 
For any amendment that will potentially affect a site’s NHS permission, the Chief Investigator/ 
Principal Investigator or designee will confirm with that site’s R&D department that NHS permission 
is ongoing (note that both substantial amendments, and amendments considered to be non-
substantial for the purposes of REC may still need to be notified to NHS R&D). 
12.5 
Protocol compliance  
Prospective, planned deviations or waivers to the protocol are not allowed under the UK regulations 
on Clinical Trials and must not be used e.g. it is not acceptable to enrol a participant if they do not 
meet the eligibility criteria or restrictions specified in the trial protocol.  Accidental protocol deviations 
can happen at any time. They must be adequately documented on the relevant forms and reported 
to the Chief Investigator, Sponsor and GCTU immediately. Deviations from the protocol which are 
found to frequently recur are not acceptable, will require immediate action and could potentially be 
classified as a serious breach. 
12.6  Notification of Serious Breaches to GCP and/or the protocol  
A “serious breach” is a breach which is likely to affect to a significant degree – 
 
the safety or physical or mental integrity of the subjects of the trial; or 
 
the scientific value of the trial 
If any of the above occurs, then the CI and Sponsor will be notified. The sponsor will notify the 
appropriate authorities in writing of any serious breach in accordance with their standard operating 
procedures. 
12.7  Data protection and patient confidentiality  
All investigators and trial site staff must comply with the requirements of applicable data protection 
legislation with regards to the collection, storage, processing and disclosure of personal information 
and will uphold the core principles of such legislation.  
Personal information will be collected via the eCRF to enable record linkage to be carried out and to 
provide electronic access to study monitors to a copy of the signed informed consent document. These 
data items will be encrypted and only those individuals who require to see these data i.e. the person 
performing the record linkage and site research team staff or the study monitor, as appropriate, will 
be able to view them.  All electronic data will be held securely in accordance with ISO 27001:2013 at 
the Robertson Centre for Biostatistics, part of the Glasgow Clinical Trials Unit. All Centre staff are 
required to sign confidentiality agreements and to follow Standard Operating Procedures in 
accordance with Good Clinical Practice and ISO certification. 
The trial data managers, statisticians, or any other staff who will perform data related tasks will only 
be able to access depersonalised data where the participant’s identifying information is replaced by a 
unique study identifier.  

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Only those that have been trained and approved will be able to enter or view any data via the web 
portal.  Each site can only see their own patients’ data. Patient consent forms will be stored at the 
study site in a secure location accessible only to study teams. 
12.8  Financial and other competing interests for the chief investigator, PIs at each site 
and committee members for the overall trial management  
A log of financial or other competing interests for the CI, PIs and committee members will be held 
centrally by the Trial Coordinator throughout the trial. The Trial Coordinator will request this 
information at the site initiation visit and at regular intervals during study conduct, and it will be made 
available to the Sponsor. 
12.9  Indemnity 
The NHS Indemnity Scheme will apply to this study to meet the potential legal liability of the sponsor 
for harm to participants arising from the management of the research.   
The University of Glasgow Clinical Trials Insurance will apply to this study to meet the potential legal 
liability for harm to participants arising from the design of the research.   
The sponsor has not made any arrangements for payment of compensation in the event of harm to 
the research participants where no legal liability arises.  University of Glasgow insurance is also 
relevant. 
12.10  Amendments  
Any change in the study protocol will require an amendment. Any proposed substantial protocol 
amendments will be initiated by the CI following discussion with the Sponsor and TSC and any required 
amendment forms will be submitted to the, ethics committee and Sponsor. The Sponsor will 
determine whether an amendment is non-substantial or substantial. All amended versions of the 
protocol will be signed by the CI and Sponsor representative.  Following a substantial amendment, 
favourable opinion/approval must be sought from the original reviewing REC, and Research and 
Development (R&D) office prior to implementation. The Chief Investigator will be responsible for 
informing the Trial Management Group of all protocol amendments. 
12.11  Post-trial care 
At the end of the trial, participants will be returned to usual care as defined by local and national 
guidelines at that time.  
12.13  Access to the final trial dataset 
During the trial and in the period prior to publication of the main study results as described in the 
protocol, only the Glasgow CTU will have access to the full dataset. After that period, the Trial Steering 
Committee will conduct further data analyses for a period of three years. After that time the Trial 
Steering Committee will consider requests from external parties for further analyses of the study data. 
The TSC will review the proposals and provide a view on scientific merit to the Sponsor and CI. 
Proposals that are scientifically well founded and have an academic basis and where relevant data 

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extractions and analyses are appropriately funded will not be refused. These will be considered as 
collaborative exercises where the contributions related to study design, conduct, database creation 
and maintenance and data analysis will be recognised in authorship of any scientific publication. The 
approach we will take will be to minimise any possibility of breach of participant confidentiality. 
Normally this will be achieved by minimising data travel. However, for the purposes of individual 
patient meta-analysis and other reasons, data may be transferred to other sites. Such transfer will 
require assurances on information security systems at the sites that data are to be transferred to and 
will involve a legal data transfer agreement. A log of all data requests and subsequent data transfers 
will be held at the Glasgow CTU. 
 
 

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13.  DISSEMINATION POLICY  
  
13.1  Dissemination policy  
The data arising from this study will be owned by the University of Glasgow and NHS Greater Glasgow 
and Clyde.   
Once the study has been completed, a final report will be prepared for publishing purposes, and to 
feedback research results to both sponsor and REC. This will be provided to sponsor/REC via email and 
will be made accessible to the wider research community on international study registry websites such 
as clinicaltrials.gov. The CI will have the right to publish the study data. There are no plans to notify 
participants of the outcome of the study. Participants will be provided with CI/PI contact details in the 
Patient Information Sheet. Participants will be advised upon requesting results that these will be made 
available once data analysis has been completed and/or the final study report has been compiled.   
The main study documentation - study protocol and full study report – will be made accessible to the 
wider research community on international study registry websites such as clinicaltrials.gov within 1 
year of study opening.   
  
13.2  Authorship eligibility guidelines and any intended use of professional writers  
 Key contributors to the protocol and final report will be noted as authors, as will study clinicians who 
contribute significantly to the running/management of the study at site. All will be provided with a 
draft copy of the final report for review prior to publication. Criteria for individually named authors or 
group authorship will adhere to that of The International Committee of Medical Journal Editors.  
 
 

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14.  
REFERENCES  
 
1. 
Coronavirus 
(COVID-19): 
daily 
data 
for 
Scotland. 
Scottish 
Government. 
https://www.gov.scot/publications/coronavirus-covid-19-daily-data-for-scotland/ 
2. 
Ball S, Banerjee A, Berry C, et al; CVD-COVID-UK Consortium. Monitoring indirect impact of 
COVID-19 pandemic on services for CV diseases in the UK. Heart. 2020 Oct 5:heartjnl-2020-317870. 
3. 
Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with 
covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort 
study. BMJ British Medical Journal Publishing Group; 2020;369. 
4. 
Mangion K, Morrow A, Bagot C, …Berry C. The Chief Scientist Office Cardiovascular and 
Pulmonary Imaging in SARS Coronavirus disease-19 (CISCO-19) study. Cardiovasc Res. 2020 Jul 
23:cvaa209. doi: 10.1093/cvr/cvaa209. Epub ahead of print. PMID: 32702087; PMCID: PMC7454350.  
5. 
Sattar N, Ho FK, Gill JM, .., Berry C, Pell JP, McMurray JJ, Welsh P. BMI and future risk for 
COVID-19 infection and death across sex, age and ethnicity: Preliminary findings from UK biobank. 
Diabetes Metab Syndr. 2020 Sep-Oct;14(5):1149-1151. 
6. 
Guzik TJ, .. Berry C, Touyz RM, Kreutz R, Wang DW, Bhella D, Sagliocco O, Crea F, Thomson EC, 
McInnes IB. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and 
treatment options. Cardiovasc Res. 2020 Aug 1;116(10):1666-1687.  
7. 
Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 2020 Sep 
1;41(32):3038-3044. doi: 10.1093/eurheartj/ehaa623. PMID: 32882706; PMCID: PMC7470753. 
8. 
Dweck MR, Bularga A, Hahn RT, et al. Global evaluation of echocardiography in patients with 
COVID-19. Eur Heart J Cardiovasc Imaging Oxford Academic; 2020;21:949–958.  
9. 
Gualtieri P, Falcone C, Romano L, Macheda S, Correale P, Arciello P, Polimeni N, Lorenzo A. 
Body Composition Findings by Computed Tomography in SARS-CoV-2 Patients: Increased Risk of 
Muscle Wasting in Obesity. Int J Mol Sci. 2020 Jun 30;21(13):4670.  
10. 
Morley JE, Kalantar-Zadeh K, Anker SD. COVID-19: a major cause of cachexia and sarcopenia? 
J Cachexia Sarcopenia Muscle. 2020 Aug;11(4):863-865.  
11. 
Berry C, Clark AL. Catabolism in chronic heart failure. Eur Heart J. 2000 Apr;21(7):521-32. 12.
 
Breen L, Stokes KA, Churchward-Venne TA, et al. Two weeks of reduced activity decreases leg 
lean mass and induces "anabolic resistance" of myofibrillar protein synthesis in healthy elderly. J Clin 
Endocrinol Metab. 2013 Jun;98(6):2604-12.  
13. 
Krogh-Madsen R, Thyfault JP, Broholm C, et al. A 2-wk reduction of ambulatory activity 
attenuates peripheral insulin sensitivity. J Appl Physiol (1985). 2010 May;108(5):1034-40. 14.
 
Rooney S, Webster A, Paul L. Systematic Review of Changes and Recovery in Physical Function 
and Fitness After Severe Acute Respiratory Syndrome-Related Coronavirus Infection: Implications for 
COVID-19 Rehabilitation. Phys Ther. 2020 Sep 28;100(10):1717-1729.  
15. 
Al Ozairi E, Alsaeed D, Taliping D, .. Sattar N, Gray C, Welsh P, Gray SR. Protocol for a 
randomised controlled trial to investigate the effect of home- and gym-based resistance exercise 
training on glycaemic control, body composition and muscle strength. Trials. 2020 Jul 15;21(1):650.  
16. 
Long 
Covid: 
https://www.bhf.org.uk/informationsupport/heart-matters-
magazine/news/coronavirus-and-your-health/long-covid-the-long-term-symptoms-of-coronavirus 
(21 October 2020)  
17. 
Sudre CH, Murray B, Varsavsky T et al. Attributes and predictors of Long-COVID: analysis of 
COVID 
cases 
and 
their 
symptoms 
collected 
by 
the 
Covid 
Symptoms 
Study 
App.  
https://www.medrxiv.org/content/10.1101/2020.10.19.20214494v1  
18. 
Hart PD, Buck DJ. The effect of resistance training on health-related quality of life in older 
adults: Systematic review and meta-analysis. Health Promot Perspect. 2019 Jan 23;9(1):1-12.  

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19. 
Singh SJ, Morgan MD, Scott S, Walters D, Hardman AE. Development of a shuttle walking test 
of disability in patients with chronic airways obstruction. Thorax. 1992 Dec;47(12):1019-24.  
20. 
Puente-Maestu L, et al. Use of exercise testing in the evaluation of interventional efficacy: an 
official ERS statement. Eur Respir J. 2016 Feb;47(2):429-60.   
21. Ayoubkhani D et al. Epidemiology of post-COVID syndrome following hospitalisation with 
coronavirus: a retrospective cohort study. https://doi.org/10.1101/2021.01.15.21249885 
22. The OpenSAFELY Collaborative; John Tazare et al. Rates of serious clinical outcomes in survivors of 
hospitalisation with COVID-19: a descriptive cohort study within the OpenSAFELY platform. 
https://doi.org/10.1101/2021.01.22.21250304 
  
  
  
 
 

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15.   APPENDICES 
15.1 Appendix 1 – Amendment history   
 
Amendment  
No.  
Protocol 
version no.  
Date issued  
Author(s) of 
changes  
Details of changes made  
 
 
 
 
 
 
 
 
 
 
  
List details of all protocol amendments here whenever a new version of the protocol is produced.  
Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC 
committee.  
 
 

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15.2    Appendix 2. Demographic, medical and COVID-19 history  
Participant details   
CHI – Place Label  
Age …… Years            Sex: Male / Female  
Height _________    Weight _________  
Ethnicity   
 
White  
Date of admission  
….. / …../   
COVID-19 symptom 
onset date  
… /…/ 
Date of COVID-19 
diagnosis  
… /…/  
Blood pressure at 
presentation  
Systolic / Diastolic (mmHg)  
Heart rate at 
presentation  
bpm  
Initial troponin, ng/L  
  
Peak Troponin I, ng/L  
  
Date of peak troponin I  ….. / …../    
Initial point of care  
A&E / AMRU / CCU / Medicine / Care of Elderly / Surgery / ICU  
Second point of care  
AMRU / CCU / Cardiology / Medicine / Care of Elderly / Surgery / ICU  
Third point of care  
AMRU / Cardiology / Medicine / Care of Elderly / Surgery / ICU  
Date of discharge  
….. / ….. /    
Co-morbidity   
Charlson Comorbidity Index (CCI) 
Predicts 10-year survival in patients with multiple comorbidities. 
Age 
<50 years 
0 
50–59 years 
+1 
60–69 years 

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+2 
70–79 years 
+3 
≥80 years 
+4 
Myocardial infarction 
History of definite or probable MI (ECG changes and/or enzyme changes) 
No 
0 
Yes 
+1 
CHF 
Exertional or paroxysmal nocturnal dyspnoea and has responded to digitalis, diuretics, or afterload 
reducing agents 
No 
0 
Yes 
+1 
Peripheral vascular disease 
Intermittent claudication or past bypass for chronic arterial insufficiency, history of gangrene or acute 
arterial insufficiency, or untreated thoracic or abdominal aneurysm (≥6 cm) 
No 
0 
Yes 
+1 
CVA or TIA 
History of a cerebrovascular accident with minor or no residual and transient ischemic attacks 
No 
0 
Yes 
+1 
Dementia 
Chronic cognitive deficit 
No 
0 
Yes 
+1 
COPD 
No 
0 
Yes 
+1 
Connective tissue disease 
No 
0 
Yes 
+1 
Peptic ulcer disease 
Any history of treatment for ulcer disease or history of ulcer bleeding 
No 
0 

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Yes 
+1 
Liver disease 
Severe = cirrhosis and portal hypertension with variceal bleeding history, moderate = cirrhosis and portal 
hypertension but no variceal bleeding history, mild = chronic hepatitis (or cirrhosis without portal 
hypertension) 
None 
0 
Mild 
+1 
Moderate to severe 
+3 
Diabetes mellitus 
None or diet-controlled 
0 
Uncomplicated 
+1 
End-organ damage 
+2 
Hemiplegia 
No 
0 
Yes 
+2 
Moderate to severe CKD 
Severe = on dialysis, status post kidney transplant, uraemia, moderate = creatinine >3 mg/dL (0.27 mmol/L) 
No 
0 
Yes 
+2 
Solid tumour 
None 
0 
Localized 
+2 
Metastatic 
+6 
Leukaemia 
No 
0 
Yes 
+2 
Lymphoma 
No 
0 
Yes 
+2 
AIDS 
No 
0 
Yes 

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+6 
 
Is this a COVID-19 patient? 
For research purposes only; answer does NOT impact results. 
Confirmed positive 
Suspected 
Unlikely 
Confirmed negative 
 
Outcome 
= CCI index (points) 
= % estimated 10-year survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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COVID Risk score  
 
ISARIC-4  
WHO 
  
Cardiovascular symptoms  
 
Angina  
Canadian Cardiovascular Society angina class: 1 / 2 / 3 / 4  
 
If angina is reported, then subject to complete angina diary  
Function 
s 
New York Heart Association Functional Class 1 / 2 / 3 / 4  
 
 
CV Risk scores  
  
Heart age score  
https://www.bhf.org.uk/informationsupport/risk-factors/check-your-heart-
age  
  
QRisk3 Risk score  
 https://www.qrisk.org/three/index.php 
  
Smoking  
status,  defined  
as  
per  
the  
internationally  established 
 definitions https://www.cdc.gov/nchs/nhis/tobacco/tobacco_glossary.htm   
Current 
smoker:  
An adult who has smoked 100 cigarettes in his or her lifetime and who currently 
smokes cigarettes.  Beginning in 1991 this group was divided into “every day” 
smokers or “some days” smokers.  
Never smoker:  An adult who has never smoked, or who has smoked less than 100 cigarettes in 
his or her lifetime.  
Former 
smoker:  
An adult who has smoked at least 100 cigarettes in his or her lifetime but who 
had quit smoking at the time of interview  
Some days 
smoker:  
An adult who has smoked at least 100 cigarettes in his or her lifetime, who 
smokes now, but does not smoke every day.  Previously called an “occasional 
smoker”.  

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Every day 
smoker:  
An adult who has smoked at least 100 cigarettes in his or her lifetime, and who 
now smokes every day.  Previously called a “regular smoker”.  
Pre-existing preventive cardiovascular therapy (medication prescribed prior to initial admission)  
Aspirin / Clopidogrel / Ticagrelor  
ACE-I or ARB  
Statin  
Mineralocorticoid (spironolactone or 
eplerenone)  
Beta-blocker  
  
Anticoagulation = warfarin or NOAC (circle)  
  
Discharge preventive therapy (final discharge medication)  
Aspirin / Clopidogrel / Ticagrelor  
ACE-I or ARB  
Statin  
Mineralocorticoid (spironolactone or 
eplerenone)  
Beta-blocker  
  
Anticoagulation = warfarin or NOAC (circle)  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19  
COVID-19 diagnosis  
  
  
Clinical diagnosis  
Yes  
No  
Laboratory test - positive PCR test  
Yes  
No  
Laboratory test – antibody test  
Yes  
No  
Radiology diagnosis - CXR  
Yes  
No  
CXR findings 
 
 
Radiology diagnosis – CT scan  
Yes  
No  

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CT findings 
 
 
C-19 = main/primary cause of admission to hospital i.e. suspected/known on 
admission  
(community acquired)  
Yes  
No  
C-19 = developed in hospital (nosocomial)  
  
  
Admission diagnosis = non-COVID; i.e. COVID-19 diagnosed occurred in-hospital  
Yes  
No  
Healthcare worker   
Yes  
No  
ICU  
Yes  
No  
COVID-19 treatment  
  
  
Supplemental oxygen  
  
  
Non-invasive respiratory support e.g. BIPAP, CPAP  
  
  
Invasive ventilation   
  
  
Extracorporeal membrane oxygenation  
  
  
Inotropes  
  
  
Haemodialysis  
  
  
COVID-19 Research Study: TITLE = …………………………………………………..  
  
  
Control – no treatment or placebo  
  
  
Antiviral – e.g. Remdesivir  
  
  
Antiviral (other) Lopinavir 400mg-Ritonavir 100mg or  
  
  
Immune regulator e.g. tocilizumab, sarilumab 
  
  
Steroid e.g. Dexamethasone  
  
  
Colchicine  
  
  
Aspirin  
  
  
Plasma 
 
 
Blinded study drug  
  
  
Other – please specify ............................................................................................  
  
  
  
   
  
Myocarditis Diagnostic Criteria  
Caforio et al. Position statement of the ESC Working Group on Myocardial and Pericardial Diseases, 
European Heart Journal (2013) 34, 2636–2648 [68].  

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Clinical presentations (A) (TICK if present)  
  
Acute chest pain,   
If yes circle / mark - pericarditic / pseudo-ischaemic (myocarditis) / ischaemic / dyspepsia / 
pleuritic.  
  
New-onset (days up to 3 months) or worsening of: dyspnoea at rest or exercise, and/or 
fatigue, with or without left and/or right heart failure signs  
  
Subacute/chronic (.3 months) or worsening of: dyspnoea at rest or exercise, and/or 
fatigue, with or without left and/or right heart failure signs  
  
Palpitation, and/or unexplained arrhythmia symptoms and/or syncope, and/or aborted 
sudden cardiac death  
Unexplained cardiogenic shock  
  
  
= TOTAL NUMBER PRESENT  
  
Diagnostic criteria (TICK if present)  
  
I. ECG/Holter/stress test features - Newly abnormal 12 lead ECG and/or Holter and/or 
stress testing, any of the following: I to III degree atrioventricular block, or bundle 
branch block, ST/T wave change (ST elevation or non ST elevation, T wave 
inversion), sinus arrest, ventricular tachycardia or fibrillation and asystole, atrial 
fibrillation, reduced R wave height, intraventricular conduction delay (widened QRS 
complex), abnormal Q waves, low voltage, frequent premature beats, 
supraventricular tachycardia  
  
 II.  
Myocardiocytolysis markers – elevated troponin  
  
III. Functional and structural abnormalities on cardiac imaging (echo/angio/CMR) - New, 
otherwise unexplained LV and/or RV structure and function abnormality (including 
incidental finding in apparently asymptomatic subjects): regional wall motion or 
global systolic or diastolic function abnormality, with or without ventricular 
dilatation, with or without increased wall thickness, with or without pericardial 
effusion, with or without endocavity thrombi  
  
IV.  Tissue characterization by CMR – Modified Lake Louise Criteria (T2 map abnormality +/-  
T1 abnormality (native T1 map, late gadolinium enhancement, extracellular volume (ECV)  
 
  
  
= TOTAL NUMBER PRESENT  
  
Diagnostic criteria  
Clinically suspected myocarditis if ≥1 clinical presentation and ≥1 diagnostic criteria from different 
categories, in the absence of: (1) angiographically detectable coronary artery disease (coronary 
stenosis ≥ 50%), if known; (2) known pre-existing cardiovascular disease or extra-cardiac causes that 
could explain the syndrome (e.g. valve disease, congenital heart disease, hyperthyroidism, etc.) 
Suspicion is higher with higher number of fulfilled criteria.  

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A - If the patient is asymptomatic ≥2 diagnostic criteria should be met.  
 
Myocarditis should be suspected in the presence of:  
1 or more of the clinical presentations, with or without ancillary features (see below), 
and  
1 or more of the diagnostic criteria from different categories (I to IV) in Table 4 or when 
the patient is asymptomatic, 2 or more diagnostic criteria from different categories (I to 
IV).  
  
To completed by clinician:  
ACS (at any time)  
Myocardial injury is defined as a high sensitivity troponin I > upper reference limit (99th centile).  
Myocardial injury  
Yes / No  
Myocardial injury  
Acute / chronic  
ACS  
Yes / No  
Initial primary diagnosis  
Type 1 MI / Type 2 MI / Type 3 MI / Myocardial Injury (Cardiac / 
Non-cardiac)*   
Initial secondary diagnosis  
Type 1 MI / Type 2 MI / Type 3 MI / Myocardial Injury (Cardiac / 
Non-cardiac)   
Final primary diagnosis  
Type 1 MI / Type 2 MI / Type 3 MI / Myocardial Injury (Cardiac / 
Non-cardiac)   
Final secondary diagnosis  
Type 1 MI / Type 2 MI / Type 3 MI / Myocardial Injury (Cardiac / 
Non-cardiac)   
*For T2MI / myocardial injury, circle either cardiac or non-cardiac   
T2MI / Myocardial Injury - Inciting cause or associated (tick all/multiple)  
CARDIAC  
NON-CARDIAC  
Tachyarrhythmia  
Anaemia  
Bradyarrhythmia  
Hypoxia  
Coronary embolus/spasm/dissection/microvascular  
Renal disease  
Heart failure / cardiomyopathy  
Surgery (recent)  
Hypotension  
Pulmonary embolism  
Hypertension  
Infection – COVID-19  
Structural heart disease e.g. valve  
Infection – non-COVID: - Chest, 
Abdomen,  

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UTI, Cellulitis, CNS, other - specify  
Infection – endocarditis, myocarditis, pericarditis  
COPD  
Stress  
  
Other – specify