The UK MS Regsiter COVID-19 Substudy
Conditions: Multiple Sclerosis, COVID-19
Sponsor: Swansea University

 
 
 
UK MS Register substudy: 
the impact of COVID-19 in patients 
with multiple sclerosis 
 
 
 
STUDY PROTOCOL 
 
Ethics: South West Central Bristol: 16/SW/0194 
 
A study funded by the 
 
 
 

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Contents 
GLOSSARY OF TERMS: ABBREVIATIONS, ACRONYMS AND DEFINITIONS, ................. 4 
LAY SUMMARY OF THIS RESEARCH STUDY ............................................................................... 5 
BACKGROUND TO THIS RESEARCH STUDY ................................................................................ 6 
COVID-19 and multiple sclerosis ................................................................................................. 6 
STUDY AIM ................................................................................................................................................. 7 
Study objectives .................................................................................................................................. 7 
STUDY DESIGN AND RATIONALE .................................................................................................... 7 
DATA COLLECTION, MEASURES, AND ANALYSIS: .............................................................. 8 
ETHICAL ISSUES RELEVANT TO THIS STUDY ........................................................................... 9 
Coercion ................................................................................................................................................. 9 
Confidentiality ..................................................................................................................................... 9 
DISSEMINATION ...................................................................................................................................... 9 
Data transfer and storage ............................................................................................................... 9 
Record keeping and archiving ...................................................................................................... 9 
MANAGEMENT AND GOVERNANCE OF THIS STUDY ............................................................. 9 
REFERENCES…………………………………………………………………………………………………………………9 
 
Change Log 
Version 
Change 
Date 
Made By 
1.0 
Creation of document 
16/03/2020 
R Nicholas 
1.1 
Formatting 
and 
goal 
changes, 
added 
additional investigators 
24/03/2020 
R Nicholas 
1.2 
Formatting 
and 
structure 
Additional investigators 
Version of survey added 
26/03/2020 
R Middleton 
 
 
 

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Investigators 
Chief-Investigators: 
Richard Nicholas (r.nicholas@imperial.ac.uk) 1,2 
Nikos Evangelou (nikos.evangelou@nottingham.ac.uk) 3 
 
Co-Investigators: 
Katie Tuite Dalton (k.a.tuite-dalton@swansea.ac.uk ) 1 
Rachel Hunter (r.hunter@swansea.ac.uk.uk) 9 
Rod Middleton (r.m.middleton@swansea.ac.uk) 1 
Alasdair Coles (ajc1020@medschl.cam.ac.uk) 4 
Owen Pearson (owen.pearson@wales.nhs.uk) 5 
Martin Duddy (martin.duddy@nuth.nhs.uk) 6 
Ruth Dobson (ruth.dobson@qmul.ac.uk) 7 
Linda Middleton (linda.middleton@wales.nhs.uk 5  
Afagh Garjani (afagh.garjani@nottingham.ac.uk) 3 
Roshan das Nair (roshan.dasnair@nottingham.ac.uk) 3 
David Rog (David.Rog@srft.nhs.uk) 
Stella Hughes (Stella.Hughes@belfasttrust.hscni.net) 10 
 
Approached Investigators 
 
Emma Tallantyre 
Pete Connick 
 
Affiliations 
1 
UK MS Register, Swansea University Medical School 
2 
Department of Cellular & Molecular Neuroscience, Imperial College, Charing Cross Hospital 
3 
University of Nottingham and Nottingham University Hospitals NHS Trust   
4 
Department of Clinical Neuroscience, University of Cambridge 
5 
Neurology and Clinical Neurophysiology, Swansea Bay University Health board 
6 
Newcastle upon Tyne Hospitals NHS Trust 
7 
Preventive Neurology Unit, Queen Mary University London 
8 
Salford Royal NHS foundation Trust 
9 
Swansea University, College of Health and Human Science 
10 
Belfast Health and Social Care Trust, Belfast 

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GLOSSARY OF TERMS: ABBREVIATIONS, ACRONYMS AND DEFINITIONS,  
 
• 
Disease Modifying Drugs (DMDs): treatments for MS that aim to treat the underlying 
disease 
• 
Healthcare Providers (HCPs): are staff working in the healthcare sector who provide 
clinical care (interchangeable with healthcare workers) 
• 
National Health Service (NHS): UK wide public health system 
• 
Multiple Sclerosis (MS): autoimmune, inflammatory, demyelinating disorder of the 
central nervous system, with variable clinical presentation and illness trajectory (e.g. 
primary or secondary progressive, relapsing remitting), usually affecting young adults, 
associated with significant long-term disability 
• 
People with MS (PwMS) 
• 
Web EDSS (webEDSS): web-based assessment of extended disability status scale [1] 
• 
MS Impact Score-29 (MSIS-29): 29 question assessment of impact of MS on PwMS [2] 
• 
MS walking score-12 (MSWS-12): 12 question assessment of walking ability in 
PwMS[3] 
• 
Hospital Anxiety and Depression Score (HADS): standardised assessment of mood[4] 
• 
Fatigue Severity Score (FSS): assessment of fatigue [5] 
 
 
 
 

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LAY SUMMARY OF THIS RESEARCH STUDY 
 
The issue: 
COVID-19, the coronavirus infection that has recently emerged[6], has had a devastating 
impact on the health of affected populations. The disease is currently circulating in the 
UK[7], causing a major negative effect on the health of all. People with multiple sclerosis 
(PwMS) are a susceptible group both due to the impact of their disability but also as a 
result of taking immune modulating treatments. At this point, contradicting guidance is 
offered by different authorities, but without a solid evidence base of how COVID-19 
affects PwMS.  
 
Currently, we do not know how PwMS on immunomodulatory/immunosuppressive 
drugs are being affected as the authorities and clinicians are only aware of those 
presenting to secondary care services. Individuals with mild disease, staying at home, 
are not tested and not recorded anywhere.  
 
Aims: This study aims to collect information on how PwMS who are part of the UK MS 
Register are impacted by COVID-19 and other upper respiratory tract infections. 
 
What we will do:  
We will contact all PwMS on the UK MS Register and ask them to participate in this MS 
and COVID-19 study. They will be asked to complete a short questionnaire on their 
current clinical status and update their information stored on the UK MS Register, 
including details of the MS clinical team who normally coordinate their care. As some 
patients will fall ill with COVID-19 or other respiratory tract infections, we may contact 
them by phone to ask about their symptoms, if they had provided consent and their 
telephone number on the UK MS register or the questionnaire for us to do so. We will 
also collect current data regarding DMD use, suspension or cessation, switching or 
extending dosing interval as part of this, using a telephone interview questionnaire.  For 
those patients with a confirmed or suspected diagnosis of COVID-19, we will ask for their 
consent, over the phone, to contact their MS clinical team to gather more information 
about their health, using another brief questionnaire. Also, we are planning to call a 
random sample of PwMS, who have provided consent to be contacted, without 
symptoms suggestive of COVID-19 to record more detailed information about their MS 
and their response to the COVID-19 outbreak. 
We will generate timely rolling updates of the data collected to inform and support 
clinicians’ decision-making about the optimal treatment approaches in the context of 
COVID-19 pandemic and how it affects PwMS. 
 
The location for this study and who will be involved:  
The study will be conducted in the context of the UK MS Register, a UK MS Society-
funded study on PwMS in the UK. 
 
 
 

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BACKGROUND TO THIS RESEARCH STUDY  
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central 
nervous system that mainly affects people between the ages of 20 and 40 years. An 
estimated 2.5 million people have MS worldwide. Approximately 125,000 people and 
their families are affected by MS in the United Kingdom. People with MS represent a 
heterogeneous population, whilst some have little disability, MS can result in profound 
physical and psychological impacts as the disease progresses. Infection is a major issue 
for those who experience increasing disability - worsening MS symptoms, driving 
admission to hospital and ultimately causing death in a significant proportion. Disease 
modifying drugs (DMDs) are now widely used in relapsing MS, aiming to prevent 
subsequent disability. Recently, DMDs have also become available for the progressive 
stage of the disease, both primary progressive MS – ocrelizumab, and secondary 
progressive MS – Siponimod, where PwMS can have significant disability. All current 
DMDs target the immune system to a greater or lesser extent and this is believed to 
affect the risk of COVID-19 [8]. However, the extent of the impact each DMD has on 
susceptibility to COVID-19 and the severity of the illness, in the context of prior disability 
due to MS, is unknown. Furthermore, it appears that the pathogenesis of COVID-19 is 
partly through dysregulation of the immune response to the virus[9]Various 
immunomodulatory and immunosuppressive drugs are being tested as potential 
treatments for severe complications of this infection[10 ]including fingolimod which is a 
DMD 
used 
in 
MS[11]Therefore, 
studying 
the 
effects 
of 
these 
immunomodulatory/immunosuppressive DMDs used in MS on the natural course of the 
COVID-19 infection can be very informative. 
 
COVID-19 and multiple sclerosis 
COVID-19 is a coronavirus infection that is currently affecting multiple countries 
throughout the world with a major impact on the health of all within the population. It 
has, however, been more severe in those with multiple comorbidities, physical 
limitations, and most significantly increasing age, resulting in death in 0.6-3.5% of the 
population. In the absence of widespread testing for the virus[12], it is essential to 
understand how many people are infected, which can include asymptomatic or 
minimally symptomatic patients. 
 
In this prospective study, we aim to understand the true impact of COVID-19 on patients 
with MS. Initially, PwMS on the UK MS Register will be contacted by email to confirm 
their agreement to take part in the study by answering an online survey. Through this 
approach, we will identify the MS patients who have not been affected by COVID-19 yet, 
in addition to those who have symptoms suggestive of COVID-19 or have been given a 
diagnosis of COVID-19. We will then capture their ongoing health status through regular 
follow up online surveys.  
 
 

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STUDY AIM 
The aim of the study is to understand the impact of COVID-19 on PwMS in the UK. 
 
Study objectives  
1. To identify the incidence of upper respiratory tract symptoms: fever, cough and 
breathing difficulties, other symptoms suggestive of COVID-19 infection, 
respiratory tract infections suggestive of COVID-19, and COVID-19 confirmed by 
laboratory testing among the UK MS population 
 
2. To establish if some DMDs increase the risk of COVID-19 infection 
 
3. To determine the incidence and effectiveness of self-isolation in the MS 
population. To examine the impact self-isolation has on mood, fatigue, and other 
routinely collected patient reported outcome measures from the MS Register. 
 
4. To determine the clinical outcome of respiratory tract infections, including 
confirmed and suspected cases of COVID-19, in terms of symptoms, time to 
recovery, hospital admission, requirement for ventilation, and death.  
 
5. To determine the longer-term impact of COVID-19 on MS, using routinely 
collected MS outcomes in the MS register, including impact on disability, 
relapses and changes in DMDs as assessed at 3 monthly intervals. 
 
6. To determine where people are obtaining their health information during the 
COVID-19 outbreak.   
 
7. To establish changes in DMDs prior to and as a result of symptoms related and 
unrelated to COVID-19 
 
STUDY DESIGN AND RATIONALE 
To realise our study aims, we will run this as a sub-study for those who have consented 
to be part of the UK MS Register. Therefore, all questionnaires and procedures will be 
conducted in accordance with the ethical approval covered under the umbrella of the 
current ethical approval for the UK MS Register (16/SW/0194 South West Central 
Bristol). Contacting all members of the UK MS Register and confirming if a person wishes 
to offer data will enable us to get a clear baseline of an unaffected MS population. We 
will then be able to follow-up this group regularly via email contact. In addition, we will 
inform PwMS who are not members of the MS Register about the Register and this study 
and request them to join, so they can participate in the study, if they wish to do so. The 
recruitment campaign will happen through social media and NHS MS clinics 
communications. 
 
Inclusion criteria for PwMS completing the questionnaires  
1. Being part of the UK MS Register 
2. Adults aged 18+yrs with a confirmed diagnosis of multiple sclerosis 
3. Consent to take part in the questionnaire sub-study 

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Inclusion criteria for PwMS completing the interviews  
1. Having completed the COVID-19 questionnaire  
2. Consent to take part in the interview sub-study 
 
 
Recruitment process for PwMS for the questionnaire sub-study 
PwMS will be part of the UK MS Register and will have given permission to be contacted 
by email or telephone call about studies that the UK MS Register hosts.  
 
PwMS will be provided with a brief introduction about the sub-study and will be able to 
complete a brief online consent form and then a short survey about their current clinical 
status. They will also be asked to update their MS Register details with emphasis on 
DMD use. If not already registered, they will need to join the UK MS Register before 
being able to take part in this sub-study. 
 
If patients report that they have been tested positive for COVID-19, we will also ask their 
consent to contact their clinical team to ascertain clinical details about their MS and the 
details of their COVID-19 treatment and outcome. 
 
Recruitment process for PwMS for the interview sub-study 
 
PwMS who have completed the COVID-19 questionnaire and who have consented to be 
contacted for a follow-up interview will be approached by a healthcare professional 
member of the MS Register team through a telephone call. We will sample all those who 
have been diagnosed as having COVID-19 Coronavirus, 20% of those who have reported 
symptoms compatible with COVID-19 but with no formal diagnosis of the infection, and 
10% of those who do not report any symptoms in a random fashion. 
 
In addition to patients' surveys, we will run a MS healthcare professional survey 
requesting clinicians to report, anonymously, clinical details of patients with MS and 
confirmed COVID-19 infection.  
 
 
DATA COLLECTION, MEASURES, AND ANALYSIS:  
Data are collected within the UK MS Register as per standard procedures[13]. Scales that 
are routinely used on the MS Register assess mood using the Hospital Anxiety and 
Depression Scale (HADS), and fatigue using the Fatigue Severity Scale (FSS). Disability is 
assessed using the web version of the Expanded Disability Status Scale (webEDSS), 
Multiple Sclerosis Impact Scale (MSIS-29), and Multiple Sclerosis Walking Scale (MSWS-
12). 
 
Data that will be collected over the telephone will seek to clarify and collect more details 
about participants’ response to the questionnaires. We will be using a semi-structured 
interview schedule to collect these data. PwMS will be told the purpose of the interview 

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on the phone, and verbal consent will be taken and noted in our records. Interviews will 
be conducted by a clinician who is part of the MS Register team. The research team will 
not provide clinical care but will signpost patients, if asked, to current national clinical 
advice regarding COVID-19.  
 
Participants’ personal details will only be known to those who currently have access to 
the UK MS Register under its protocols. All data will be anonymised for use outside of 
the MS Register team (for example, for dissemination purposes).  
 
Analysis: Data will be analysed by the UK MS Register team on a 2 weekly basis to 
provide updates for PwMS on the website and Healthcare Professionals (HCPs) involved 
in the care and management of PwMS.  
 
ETHICAL ISSUES RELEVANT TO THIS STUDY  
Coercion 
PwMS will be free not to respond to our contact email regarding this sub-study. They 
will be free to leave this sub-study at any time by choosing not to respond to the 
questionnaires and shutting the web-browser, or by emailing the MS Register team. This 
will not affect their rights to remain within the UK MS Register. 
 
Identification of potentially unwell PwMS 
The MS Register will provide all current information regarding current national advice if 
a participant reports symptoms suggestive of COVID-19.  
 
Confidentiality 
All data will be stored in accordance with the EU General Data Protection Regulation 
(GDPR), the Data Protection Act and existing MS Register data management protocol 
(3.1[14])   
 
DISSEMINATION  
We will ensure local, national and international dissemination channels to stakeholders, 
including public and professional.  This will take place via the UK MS Register and UK MS 
Society websites, as well as via publications in scientific journals and presentations at 
conferences nationally and internationally. 
 
Data transfer and storage 
All data will be stored by Swansea University Medical School as the operators of the UK 
MS Register as per standard protocols. 
 
Record keeping and archiving  
All data will be archived within the UK MS Register as per standard protocols. 
 
MANAGEMENT AND GOVERNANCE OF THIS STUDY  
The Steering Committee will be the primary scientific governing body for the study 
responsible for designing the protocol, overseeing the administrative progress of the 
ongoing study, analyzing the study data, and interpreting the results. The Steering 

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Committee prepared the study protocol and once the study is initiated, will meet at least 
once every 6 weeks to monitor participant accrual, participant retention, and study 
conduct. The Steering Committee will determine whether the study should be stopped, 
or the protocol amended. 
  
The study Steering Committee will be co-chaired by the two co-PIs (Prof R. Nicholas and 
Dr N. Evangelou) and will also have PPI member, key investigators (R. Middleton, K. 
Tuite-Dalton, Dr E. Gray, Prof D. Ford, Prof R. Das Nair, Dr O. Pearson, Dr M. Duddy, Dr 
R. Dobson, Dr L. Middleton, Dr D. Rog, Prof J. Chataway, Dr Rachel Hunter, Dr Stella 
Hughes and Prof A. Coles), and study statisticians. The co-PIs will hold calls every two 
weeks with Rod Middleton, Katie Tuite-Dalton, Prof R. Das Nair and Dr A. Garjani in 
addition to Steering Committee meetings.  
Currently investigating adding this study to clinicaltrials.gov or other registration body. 
UK MS Register is already an NIHR portfolio study. Other investigators have been invited 
to be part of the study as we aim to be as inclusive as country wide as possible. 
 
 
 

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REFERENCES 
 
 
1.  Leddy S, Hadavi S, McCarren A, Giovannoni G, Dobson R. Validating a novel 
web-based method to capture disease progression outcomes in multiple 
sclerosis. J Neurol. 2013;260:2505–2510.  
2.  Hobart J. The Multiple Sclerosis Impact Scale (MSIS-29): A new patient-based 
outcome measure. Brain. 2001;124:962–973.  
3.  Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ. Measuring the 
impact of MS on walking ability: The 12-Item MS Walking Scale (MSWS-12). 
Neurology. 2003;60:31–36.  
4.  Zigmond, A, Snaith, R.P. The Hospital Anxiety and Depression Scale. Acta 
Psychiatr Scaninavica. 1983;67:361–370.  
5.  Krupp LB. The Fatigue Severity Scale: Application to Patients With Multiple 
Sclerosis and Systemic Lupus Erythematosus. Arch Neurol. 1989;46:1121.  
6.  Wu Z, McGoogan JM. Characteristics of and Important Lessons From the 
Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a 
Report of 72 314 Cases From the Chinese Center for Disease Control and 
Prevention. JAMA [online serial]. Epub 2020 Feb 24. Accessed at: 
https://jamanetwork.com/journals/jama/fullarticle/2762130. Accessed 
March 16, 2020. 
7.  Public Health England. Coronavirus (COVID-19): guidance [online]. 2020. 
Accessed at: https://www.gov.uk/government/collections/coronavirus-covid-
19-list-of-guidance. 
8.  Coles A. ABN GUIDANCE ON THE USE OF DISEASE-MODIFYING THERAPIES IN 
MULTIPLE SCLEROSIS IN RESPONSE TO THE THREAT OF ACORONAVIRUS 
EPIDEMIC [online]. Accessed at: 
https://cdn.ymaws.com/www.theabn.org/resource/collection/6750BAE6-
4CBC-4DDB-A684-
116E03BFE634/ABN_Guidance_on_DMTs_for_MS_and_COVID19.pdf. Accessed 
March 16, 2020. 
9.  Qin C, Zhou L, Hu Z, et al. Dysregulation of Immune Response in Patients with 
COVID-19 in Wuhan, China. SSRN Electron J [online serial]. Epub 2020. 
Accessed at: https://www.ssrn.com/abstract=3541136. Accessed March 26, 
2020. 
10.  Zhang L, Liu Y. Potential interventions for novel coronavirus in China: A 
systematic review. J Med Virol. 2020;92:479–490.  
11.  Ning W. Fingolimod in COVID-19 [online]. Accessed at: 
https://clinicaltrials.gov/ct2/show/NCT04280588. Accessed February 26, 
2020. 

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12.  Department of Health and Social Care. Coronavirus action plan: a guide to what 
you can expect across the UK [online]. 2020. Accessed at: 
https://www.gov.uk/government/publications/coronavirus-action-
plan/coronavirus-action-plan-a-guide-to-what-you-can-expect-across-the-uk. 
Accessed March 16, 2020. 
13.  Middleton RM, Rodgers WJ, Chataway J, et al. Validating the portal population 
of the United Kingdom Multiple Sclerosis Register. Mult Scler Relat Disord. 
2018;24:3–10.  
14.  Middleton R. UK MS Register Data Management Protocol [online]. 2016. 
Accessed at: https://swanseauniversity-
my.sharepoint.com/:w:/g/personal/r_m_middleton_swansea_ac_uk/EQvk6Ez
HqHNOubVVFTj6JBcBs3dAuH04sdSjwix5GRpmdg?e=ORZCdy. Accessed March 
17, 2020. 

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Appendix 1 
Launch PwMS Questionnaire 
First Page 
 

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The follow up questionnaire will be appended once compete 
 

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Appendix 2 Clinical Questionnaire 
COVID-19 and MS Case Report Form (CRF) for Clinicians 
This secure, anonymised CRF has been created in response to the global COVID-19 
coronavirus pandemic. It is intended for healthcare professionals caring for patients 
with MS and documented coronavirus (COVID-19). 
 
We hope that this CRF will aid MS clinicians and researchers in assessing and treating 
patients with MS and the coronavirus and in assessing the risk of the virus on patients 
on DMTs 
ONLY ENTER PATIENTS THAT HAVE LAB CONFIRMED COVID-19 
 
This form: 
Is for clinicians to use to report any cases of COVID-19 in MS patients. 
• Should be completed after the patient has had COVID19 confirmed.  
• The form asks for reporter contact details, but other than that, there is no patient 
identifiable information collected.  
• Follow up details will be sought to the reporter seeking further (minimal data) 
outcomes. 
• Takes around 5-10 minutes to complete.  
• This information will be shared securely on request, to any sites contributing data. 

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• 
 

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