Conditions: Secondary Progressive Multiple Sclerosis
Keywords: Multiple sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
Multiple sclerosis (MS) is a neurological condition which is a common cause of disability in young people. It is thought to be an autoimmune condition, where the body's immune system begins to attack itself. The cause of MS is unknown but is thought to be a mix of genetic and environmental factors. There are treatments available for early stages of MS, but the later stage known as Secondary Progressive MS (SPMS) has no current treatment.

Statins are a safe treatment traditionally used to reduce cholesterol levels. However, statins also have other effects which could reduce the progression of SPMS, such as effects on the immune system and circulation. A recent study (Chataway et al., 2014) showed that treatment with high-dose simvastatin, a type of statin, reduced the progression of SPMS but no effect on the immune system was seen. It is possible that simvastatin does not treat the immune system but improves how the blood and blood vessels in the brain work in this disease.

The purpose of the clinical trial is to test how Simvastatin (80mg/day) may slow down disease progression in people living with SPMS compared to placebo (dummy pill). Participants will receive either Simvastatin or placebo and will be asked to take 2 tablets daily, for up to 17 weeks.

Detailed description:
Approximately 60% of those affected with relapsing-remitting MS (RRMS) enter a SPMS stage after a median interval of 10 to 15 years, where disability accumulates gradually in the absence of relapses. A smaller proportion (15%), run a progressive course from onset (primary progressive (PP) MS). The progressive, "neurodegenerative" component of MS, rather than the clinical deficit resulting from incomplete recovery from each relapse in RRMS, is the dominant cause of long-term disability. Whilst over ten therapies are now licensed for RRMS, no treatment strategies, with the exception of a recent study by the investigators, have succeeded in slowing the progression of this later debilitating stage.

Optic neuritis, inflammation of the optic nerve, is a common event associated with MS resulting in 27% of subjects with residual visual impairment. The impact of damage arising from an inflammatory lesion in the optic nerve can be visualised using optical coherence tomography (OCT) as a reduction in both ganglion cell layer and retinal nerve fibre layer thickness. However it is increasingly being appreciated that a number of other inflammatory and neurodegenerative changes occur in the retina of MS patients. These retinal changes, reflecting both the disease and its level of activity, have highlighted its potential as a surrogate outcome measure to study preservation of neuronal and/or vascular structure/function after an inflammatory event or as the disease progresses.

During the last two decades there have been significant advances in the understanding of MS leading to treatment for the RRMS phase. Despite this, there has been a failure to find an effective treatment for progression and this remains a major unmet need, as highlighted by the International Progressive MS Alliance. The many challenges of progressive studies including optimal design, sensitive outcomes, suitable length and subject numbers are gradually being overcome by the MS community, but as yet extending the anti-inflammatory approach that has been effective in RRMS has not borne fruit in SPMS. Indeed the failure of the recent PPMS trial using fingolimod makes the success of simvastatin in the SPMS study all the more exciting, especially as the extensive systemic immunological assessment in this latter study revealed no impact on immune status. The real success of this simvastatin phase II study may be that it initiates novel avenues of investigation driven by the wide-ranging and well-characterised effects statins have on the body as well as a prelude to a definitive phase III trial. This premise underpins the research strategy.

Preclinical work has focused on the role played by the vascular barriers (the blood-brain and blood retinal barriers) in the inflammatory process and in particular how they support leukocyte traffic to the central nervous system (CNS). This research, along with that of others, led to the identification and characterisation of endothelial cell (EC) signalling processes that facilitate leukocyte diapedesis and activate pro-inflammatory responses. The investigators found that a key central regulator of the EC signalling pathway supporting leukocyte diapedesis was the small GTPase Rho, and this led to investigating whether small GTPases could be targeted pharmacologically to reduce aberrant leukocyte migration into the brain and retina. Since small GTPases require posttranslational lipid modification (prenylation) to become functional, the investigators tested whether inhibition of Rho prenylation with prenyl transferase inhibitors (PTIs) affects lymphocyte migration. Treatment of brain endothelial cell monolayers in vitro, or animals induced for experimental autoimmune encephalomyelitis (EAE, the animal model of MS), resulted in inhibition of lymphocyte migration and attenuation of the disease respectively.

Since the isoprenoids used for post-translational prenylation of small GTPases are derived from the cholesterol synthesis pathway, the investigators next investigated whether HMGCoA reductase inhibitors (statins) were also able to significantly inhibit Rho activity and reduce the severity of brain and retinal inflammatory disease. This research revealed that statins effectively reduced Rho prenylation and attenuated disease in experimentally induced models of MS and posterior uveitis. Whilst the investigators were able to demonstrate that one of the effects of statin treatment was to modify endothelia cell function and inhibit transendothelial migration of leukocytes, it is clear from many other experimental studies that efficacy may also be due to effects on other cell types such as immune cells.

Indeed, it is now widely recognised that statins have anti-inflammatory properties that operate independently of their cholesterol lowering effect. Accordingly, statins have been shown to inhibit MHC class II restricted Ag presentation, attenuate antigen-presenting cell maturation and down-regulate T cell activation and proliferation. Of those T cells that proliferate, statins induce a shift from a proinflammatory Th1 to a regulatory Th2 phenotype. In addition, statins block adhesion molecule expression and their interactions, inhibit the production of chemokines and their receptors, and reduce the secretion of matrix metalloproteinases. Activation of the transcription factor NFκB, an important activator of pro-inflammatory mediators, is also inhibited by statins, alongside a concomitant upregulation of endothelial cell protective genes. Finally, it has been shown that endothelial nitric oxide synthase (eNOS) activity is enhanced, whilst inducible NOS (iNOS) is inhibited.

This remarkable pleiotropic capacity for modulating the immune system and inflammation has prompted the clinical testing of statins for the treatment of RRMS and other inflammatory diseases. In one such study in 30 patients with RRMS, simvastatin (80mg) taken over 6 months reduced the number of brain lesions by 40%, although no change in disability scores was observed over this short study period. Other studies, however, have failed to demonstrate any significant clinical improvement in RRMS following statin treatment alone or in combination with other disease modifying drugs. Nevertheless, it should be noted that none of the studies so far have been sufficiently powered, rendering definitive conclusions impossible.

Whilst there is a clear-cut rationale for using statins for the treatment of RRMS, in SPMS there is less obvious justification, as disease progression in the absence of new plaque formation is thought to be due predominantly to neurodegeneration (or neuronal loss). This results from several mechanisms, including microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-related iron accumulation in the human brain. Whereas large scale inflammatory lesions rarely occur at this stage of the disease, inflammation is prominent in progressive MS, where it is found throughout the grey and white matter, and in the meninges, with its most severe form being represented by the ectopic follicles that contribute to grey matter damage. This suggested that given their Immunomodulatory / anti-inflammatory actions, statins might still provide some benefit in SPMS. Nonetheless, neuronal loss is regarded as the key pathological feature, which raised the question whether statins also possess neuroprotective properties. Several lines of evidence suggest this may be the case.

Firstly, statins are increasingly seen as vasculoprotective with a capacity to improve vascular perfusion and maintain/enhance blood vessel function thus protecting against long-term chronic hypoxic damage. This is germane given the growing evidence that dysfunctional/reduced blood flow in MS may predispose the tissue to damage resulting in neuronal cell dysfunction and ultimately cell death. Such beneficial effects on microvascular perfusion may be mediated through statins enhancing eNOS activation and inhibiting endothelin-1.

Secondly, there are reports that statins may also be neuroprotective through reducing free radical damage either by improving blood flow and reducing hypoxia-mediated reactive oxygen species (ROS) production, or through direct inhibition of cytotoxic pathways. In the latter case, statins may protect neuroparenchymal cells via inhibition of iNOS in activated microglia and astrocytes, resulting in attenuated cytotoxic damage to neurons and oligodendrocytes. Furthermore, statins may also exert a neuroprotective effect by preventing glutamate-mediated excitotoxicity.

Together these data provided a compelling rationale for testing the potential therapeutic effect of statins in SPMS. In 2008, the investigators therefore embarked on a two-year double-blind, controlled trial of 140 patients, randomising them to either 80mg of simvastatin or placebo. The recently published results of this trial showed that brain atrophy was reduced by over 40% alongside a similar favourable effect on two major disability outcome measures. This is the first evidence of a drug having a beneficial effect on SPMS disease progression. Surprisingly, however, and contrary to expectations, the investigators did not identify any modulation of the immune system, raising the critical question of the mechanism of statin action.

It is the hypothesis, therefore, that the neuroprotective effects of statins in SPMS are mediated by stimulating enhanced microvascular perfusion and/or by inhibition of oxidative damage/neurotoxicity. This study will test this hypothesis.

There are no current treatments for SPMS. Given the investigators demonstrated that simvastatin was beneficial in a phase II trial but were unable to elucidate any mechanism, it is important to try and understand the mechanism of action to develop further therapies.

The investigators will investigate the impact of high dose simvastatin (80mg/day) on cerebral and retinal blood perfusion and vascular structure/function, brain neuroaxonal density and glutamate excitotoxicity in SPMS. In addition, various systemic parameters will be evaluated to determine the effect of high dose statin treatment on immune function, oxidative damage and vascular barrier function.

Simvastatin is being used outside of its posology and method of administration. The previous phase two trial found simvastatin was safe up to the maximum dose of 80 mg/day given as a single dose in the evening. Based on the recommendations of the SPC and previous studies, the proposed use of 80mg of Simvastatin will, therefore, be used for this study.

Arms:
arm 1: Simvastatin is part of the pharmacotherapeutic group of HMG-CoA reductase inhibitors (ATC-Code: C10A A01). Simvastatin is licensed within the EU for hypercholesterolemia and cardiovascular prevention but for this trial its use will be outside its licensed indication. Oral Simvastatin will be taken 40mg daily (one tablet in the evening) for 4 weeks and then at week 4 up titrated to 80mg daily (two tablets in the evening. arm 2: Matched Placebo (one tablet in the evening) for 4 weeks and then at week 4 up titrated to two tablets daily in the evening.

Interventions: intervention 1: Simvastatin
Intervention descriptions: intervention 1: Simvastatin 40mg for first 4 weeks and 80mg (if tolerated) thereafter up to 17 weeks

Protocol document:
ICF_002.pdf: 
 
MS-OPT Informed Consent Form Version 1.3 dated 08/09/2020 
 
Page 1 of 2 
 
Consent Form for the Simvastatin in PMS Study (MS-OPT) 
Sponsor Reference number: 16/0730 
Version 1.3 dated 08/09/20 
 
Study title: A double-blind, randomised, placebo-controlled single site study of high dose 
simvastatin treatment for progressive multiple sclerosis: impact on vascular perfusion and 
oxidative damage. 
 
Name of Researcher (PI): 
 
Sponsor Study Number: 
16/0730  
Site: 
 
Participant Number: 
 
 
Please initial 
each box 
1. I have read and understood the patient information leaflet (version 1.4 
dated 08 Sept 2020) for the above study.  I have had the opportunity to 
consider the information, ask questions and have had these answered 
satisfactorily. 
 
2. I understand that my participation in this study is voluntary and that I am 
free to withdraw from the study at any time, without giving any reason, 
without my medical care or legal rights being affected. 
 
3. As described in the study information leaflet, I understand that sections of 
my medical notes may be looked at by responsible individuals from CCTU, 
institutions acting on their behalf or regulatory authorities where it is 
relevant to my taking part in research. I give permission for these 
individuals to have access to my records. 
 
4. As described in the study information leaflet, I understand that non 
identifiable data collected in the study may be sent to third parties (e.g. 
pharmaceutical companies or other academic institutions) for research, 
safety monitoring or licensing purposes and that this may involve some 
data being transferred within the European Union. 
 
5. As described in the study information leaflet, I agree to complete the study 
assessments including MRI and retinal imaging (scans of the eye). 
 
Queen Square MS Centre -  UCL Institute of 
Neurology 
 
 
 
Investigator: Professor Richard Nicholas 
Centre Number:  
Contact for Queries: 
If you have any questions about this study, you can contact: 
Daytime: 02031081955 
Out of hours (emergency): 07970479797 
 
The National Hospital for Neurology &  
Neurosurgery  
Queen Square  
London  
WC1N 3BG 
 


 
MS-OPT Informed Consent Form Version 1.3 dated 08/09/2020 
 
Page 2 of 2 
6. As described in the study information leaflet, I agree to my GP and/or 
consultant being informed about my participation in the study.   
 
7. As described in the study information leaflet, I agree to having my blood 
sample stored for the purpose of future research for up to 10 years from 
the date of my consent.  
 
8. If I or my partner becomes pregnant whilst I am on this study, I understand 
that my doctor will inform the treating obstetrician of my involvement in this 
study and that the obstetrician may be requested to provide relevant 
information regarding the pregnancy and or birth. I understand that this 
may involve requesting access to my medical records and that 
anonymised information relating to the pregnancy or birth may be reported 
to the sponsor, ethics committee or regulatory authorities.  I give 
permission for these individuals to have access to my medical records. 
 
9. I freely agree to take part in this study. 
 
 
 
Please print and sign your name below and add today’s date: 
 
 
 
__________________ 
 
 
 
___________________ 
 
 
 
____________ 
Name of patient 
Signature 
Date 
 
 
 
__________________ 
 
 
 
__________________ 
 
 
 
____________ 
Name of person taking consent  
Signature 
Date 
N.B. The patient must date his/her own signature 
 
1 original copy in study file; 1 copy for patient; 1 copy to be kept with hospital/clinic notes. 
 

Prot_000.pdf: 
Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 1 of 86 
  
 
 
 
 
 
 
 
 
 
Study Protocol 
 
Full title of trial: 
A 
double-blind, 
randomised, 
placebo-
controlled single-site study of high dose 
simvastatin treatment for progressive multiple 
sclerosis: impact on vascular perfusion and 
oxidative damage 
Short title: 
MS-OPT Study: Simvastatin in Progressive 
Multiple Sclerosis 
Version and date of protocol 
Version 1.7 dated 18/10/2022 
Sponsor: 
University College London (UCL) 
Sponsor protocol number: 
16/0730  
Funder:  
UK 
Multiple 
Sclerosis 
Society, 
Multiple 
Sclerosis Trials Collaboration (MSTC) 
EudraCT no: 
ClinicalTrials.gov Identifier: 
2017-003008-30 
NCT03896217 
Active imp: 
Simvastatin 
Placebo imp: 
Gelatine 
tablet 
with 
added 
cellulose 
microcrystalline. 
Phase of trial: 
Phase II 
Sites(s) 
 
 
 
 
 
Single-site 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 2 of 86 
Chief investigator: 
 
 
 
 
 
 
 
 
Sponsor Representative: 
Prof. Richard Nicholas 
UCL Institute of Neurology 
Queen Square MS Centre 
RSH, 1st floor 
London 
WC1B 5EH 
Email: richard.nicholas3@nhs.net 
 
Samim Patel 
Sponsor Regulatory Advisor 
Joint Research Office 
(part of the Research Support Centre) 
Postal Address: Joint Research Office, UCL, 
Gower Street, London WC1E 6BT 
Office Address: 
4th Floor, West  
250 Euston Road 
London NW1 2PG 
Telephone: 020 7679 9320 
Email: samim.patel@ucl.ac.uk 
 
 
 
 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 3 of 86 
Protocol Version History 
Version 
Number 
Date 
Protocol Update 
Finalised By (insert 
name of person):  
Reasons for Update 
1.0 
04/10/2017 
First final version 
Not applicable 
1.1 
14/12/2017 
Second Final Version 
MHRA prompted 
clarification of data 
monitoring 
1.2 
12/01/2018 
Third Final Version 
HRA prompted changes to 
protocol 
1.3 
23/05/2018 
Fourth Final Version 
Changes to retinal 
component 
1.4 
25/10/2018 
Fifth Final Version 
Update to sponsor 
representative and 
clarification on drug 
storage; PASAT instrument 
removed;  minor contact 
updates/grammar/spelling 
corrections to existing 
sections 
1.5 
10/04/2019 
Sixth Final Version 
Minor clarification on 
wording making clear the 
intention to split 
screening/baseline 
assessments across two 
days with randomisation 
occurring on day 1 of 2 after 
all eligibility assessments 
are complete. Subsequent 
visits may also take place 
over 1 or 2 days. 
1.6 
05/02/2020 
Seventh Final Version 
Revision of entry criteria: 
PPMS added and no upper 
age limit. 
Removal of fasting 
cholesterol/triglycerides 
Addition of ASL 
questionnaire at retinal 
visits. 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 4 of 86 
Binary disease type added 
to randomisation algorithm. 
1.7 
18/10/2022 
Eighth Final Version 
Revision of secondary 
objectives (Myelin changes 
instead of Glutamate 
concentration) in line with 
the MRI techniques used on 
the trial. 
MRI techniques updated in 
the MRI section. 
End of trial definition 
amended. 
IDMC removed 
 
 
 
 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 5 of 86 
 
Signatures 
The Chief Investigator and the JRO have discussed this protocol. The investigator agrees 
to perform the investigations and to abide by this protocol  
The investigator agrees to conduct the trial in compliance with the approved protocol, EU 
GCP and UK Regulations for CTIMPs (SI 2004/1031; as amended), the UK Data 
Protection Act (2018), the Trust Information Governance Policy (or other local equivalent), 
the current Research Governance Framework, the Sponsor’s SOPs, and other regulatory 
requirements as amended. 
 
Chief investigator 
Prof Richard Nicholas 
 
 
 
Signature 
Date 
 
Sponsor  
Dr Nick McNally 
Managing Director, 
Research UCL/UCLH 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 6 of 86 
Contents 
Signatures ..................................................................................................................................... 5 
Contents ........................................................................................................................................ 6 
GLOSSARY OF TERMS ........................................................................................................... 11 
1. Trial personnel ........................................................................................................................ 13 
2. Lay Summary ......................................................................................................................... 16 
2.1 Structured trial summary .................................................................................................. 17 
3. Background and Rationale ...................................................................................................... 21 
3.1   
Preclinical data ......................................................................................................... 22 
3.2 
Clinical data ................................................................................................................. 23 
3.3 
Rationale and risks/benefits ......................................................................................... 24 
4. 
Assessment and management of risk .................................................................................. 25 
5. 
Objectives ........................................................................................................................... 31 
5.1  
Summary ...................................................................................................................... 31 
5.2 
Hypothesis .................................................................................................................... 31 
5.3  
Aims ............................................................................................................................. 31 
5.4  
Primary objective ......................................................................................................... 31 
5.5  
Secondary objectives ................................................................................................... 31 
5.6 
Exploratory objectives ................................................................................................. 32 
6. 
Trial design ......................................................................................................................... 32 
6.1 
Overall design .............................................................................................................. 32 
7. Investigational Medicinal Products and Non-Investigational Medicinal Products ................ 34 
7.1 
Name and description of IMP(s) .................................................................................. 34 
7.2 
Source of IMP, Manufacture, Distribution and Storage .............................................. 35 
7.3 
Storage and handling of IMP(s) at site ........................................................................ 35 
7.4 
NAME AND DESCRIPTION OF EACH NIMP ........................................................ 35 
7.5 
Accountability of IMP(s) ............................................................................................. 36 
7.6 
Concomitant medication .............................................................................................. 37 
7.7 
Post-trial IMP arrangements ........................................................................................ 37 
8. 
Selection of Participants ..................................................................................................... 38 
8.1 
Eligibility of trial participants ...................................................................................... 38 
8.1.1 
Trial participant inclusion criteria ........................................................................ 38 
8.1.2 
Trial participant exclusion criteria ........................................................................ 39 
8.2 
Recruitment .................................................................................................................. 40 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 7 of 86 
8.2.1 
Patient Recruitment Flow Chart ........................................................................... 41 
8.2.2 
Retention ............................................................................................................... 42 
8.3 
Informed consent procedure ........................................................................................ 42 
9. 
Trial procedures .................................................................................................................. 43 
9.1 
Visit 0 Pre-Screening Assessments within 8 weeks prior to baseline visit (telephone)
 
43 
9.2 
Visit 1 Screening/Baseline combined assessment (Day 0) .......................................... 43 
9.3 
Follow-up assessments ................................................................................................. 44 
9.3.1 
Visit 2 (Week 4+1 week) ...................................................................................... 44 
9.3.2  
End of Study treatment visit (Week 16 +1 week) ................................................ 45 
9.3.3 
End of Study Follow-up (Week 20+2 weeks) ...................................................... 46 
9.3.4 
Unscheduled visits (Between V1-EOS Follow-up) .............................................. 46 
9.3.5 
Telephone Follow-up (As required) ..................................................................... 47 
9.3.6 Procedure for emergency telephone contact .............................................................. 47 
10. Randomisation Procedures ................................................................................................... 47 
10.1 
Treatment Schedule .................................................................................................. 48 
10.2  
Dose Modifications .................................................................................................. 48 
11 Laboratory Assessments and Procedures ........................................................................... 48 
11.1  
Local laboratories ..................................................................................................... 48 
12. 
Clinical Procedures and Data Collection ........................................................................ 50 
12.1 
Assessment of IMP/NIMP compliance .................................................................... 51 
13. 
Monitoring ...................................................................................................................... 52 
13.1    Study Monitoring ......................................................................................................... 52 
13.2 
Recording of subject compliance information ......................................................... 52 
14. Discontinuation/withdrawal of participants .......................................................................... 52 
14.1 
Protocol Treatment Discontinuation ........................................................................ 52 
14.2 
Discontinuation of Trial Treatment for clinical reasons .......................................... 52 
14.3 
Participant withdrawal from trial treatment ............................................................. 53 
14.4 
Withdrawal of Consent to Data Collection .............................................................. 53 
14.5 
Replacements ........................................................................................................... 53 
14.6 
Stopping rules ........................................................................................................... 53 
14.7 
Definition of End of Trial ......................................................................................... 54 
15. 
Recording and reporting of adverse events and reactions .............................................. 54 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 8 of 86 
15.1 
Definitions ................................................................................................................ 54 
15.3 
Assessment of Adverse Events ................................................................................ 56 
15.3.1 
Severity ..................................................................................................................... 56 
Severity or grading of AEs ......................................................................................................... 56 
15.3.2 
Causality ................................................................................................................... 56 
15.3.3 
Expectedness ............................................................................................................ 57 
15.3.4 
 Seriousness .............................................................................................................. 58 
All events are assessed for seriousness as defined for an SAE in section 15.1. ..................... 58 
15.4 
Procedures for recording and reporting Serious Adverse Events ............................ 58 
15.4.1 
 Flow Chart for SAE reporting ............................................................................... 59 
15.5 
Serious Adverse Events which do not require immediate reporting ........................ 60 
15.6 
Notification of Deaths .............................................................................................. 60 
15.7 
Reporting SUSARs .................................................................................................. 60 
15.8 
Unblinding ................................................................................................................ 60 
15.8.1 
Emergency Unblinding ............................................................................................ 61 
15.8.2 
Unblinding for the submission of SUSAR reports ................................................... 61 
16. 
Development Safety Update Reports ............................................................................. 62 
17. 
Pregnancy ....................................................................................................................... 62 
18. 
Overdose ......................................................................................................................... 63 
19 Reporting Urgent Safety Measures and other safety events ............................................... 63 
19.1 
Notification of Serious Breaches to GCP and/or the protocol (SPON/S15) ............ 63 
20. 
Data management and quality assurance ........................................................................ 64 
20.1 
Confidentiality .......................................................................................................... 64 
20.2 
Data collection tools and source document identification ....................................... 64 
20.3 
Completing Case Report Forms ............................................................................... 64 
20.4 
Data handling and analysis ....................................................................................... 65 
21. 
Statistical Considerations ............................................................................................... 65 
21.1 
Primary outcomes ..................................................................................................... 65 
21.2 
Secondary outcomes ................................................................................................. 65 
21.2.1 MRI parameters .................................................................................................... 65 
21.2.2 Retinal imaging parameters .................................................................................. 66 
21.2.2.1 Vascular imaging ....................................................................................... 66 
21.2.2.2 Neuronal imaging ....................................................................................... 66 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 9 of 86 
21.2.3 
 Lab Measurements .................................................................................................. 67 
21.2.3.1 Immune parameters .................................................................................................. 67 
21.2.3.2 Biomarkers ................................................................................................................ 67 
21.2.4 Other assessments ........................................................................................................ 68 
21.2.4.1 MRI parameters .................................................................................................... 68 
21.2.4.2 
Clinical measures .................................................................................................. 69 
21.2.4.3 Health Economic outcomes ...................................................................................... 69 
21.2.4.4 Retinal Imaging Metrics ........................................................................................... 69 
22. 
Sample size and recruitment ........................................................................................... 70 
22.1 
Sample size calculation ............................................................................................ 70 
22.2 
Planned recruitment rate ........................................................................................... 70 
22.3 
Randomisation methods ........................................................................................... 70 
23. 
Statistical analysis plan ................................................................................................ 71 
23.1 
Summary of baseline data and flow of participants ................................................. 71 
Recruitment ........................................................................................................................... 71 
Treatment Allocation ............................................................................................................. 72 
Follow-Up ............................................................................................................................... 72 
Data Analysed ........................................................................................................................ 72 
23.2 
Statistical Analysis Plan ........................................................................................... 72 
23.3 
Primary outcome analysis ........................................................................................ 72 
23.4 
Secondary outcome and other exploratory analyses ................................................ 73 
23.5 
Sensitivity and other planned analyses ..................................................................... 74 
23.6 
Interim analysis ........................................................................................................ 74 
23.7 Other Statistical Considerations ..................................................................................... 74 
24. 
Record keeping and archiving ........................................................................................ 74 
25. 
Oversight Committees ................................................................................................. 75 
25.1 
Trial Management Group (TMG) ............................................................................ 75 
26. 
Direct Access to Source Data/Documents ...................................................................... 75 
27. 
Ethics and regulatory requirements ................................................................................ 75 
28. Monitoring requirement for the trial ..................................................................................... 76 
29. 
Finance ............................................................................................................................ 76 
29.1 
Insurance .................................................................................................................. 76 
30. Publication policy ................................................................................................................. 77 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 10 of 86 
30.1 
Trial Results ............................................................................................................. 77 
30.2 
Authorship ................................................................................................................ 77 
30.3 
Reproducible Research ............................................................................................. 78 
31. 
References ...................................................................................................................... 78 
Appendix 1 - schedule of assessments ....................................................................................... 84 
 
 
 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 11 of 86 
GLOSSARY OF TERMS 
AE 
Adverse Event 
AOSLO 
Adaptive Optics and Scanning Light Ophthalmoscopy 
AR 
Adverse Reaction 
ASL 
Arterial Spin Labelling 
BAT 
Bolus Arrival Time 
BD 
Twice per day 
CA 
Competent Authority 
CBF 
Cerebral Blood Flow 
CCTU 
Comprehensive Clinical Trials Unit 
CI 
Chief Investigator 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
CTM 
Clinical Trials Manager 
DI 
Designated Individual 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EAE 
Experimental Autoimmune Encephalomyelitis 
EC 
Endothelial Cell 
EC 
European Commission 
EDSS 
Expanded Disability Status Score 
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE    European database for Pharmacovigilance 
FAB 
Frontal Assessment Battery 
GAfREC 
Governance Arrangements for NHS Research Ethics 


Short title: Simvastatin in Progressive MS   
 
 
Sponsor code: 16/0730   
UCL protocol  Version 1.7, dated 18/10/2022  
 
 
Page 12 of 86 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
HPS  
Heart Protection Study 
HRA 
Health Research Authority 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised   
MA 
Marketing Authorisation 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
Magnetic Resonance Imaging 
MS 
Multiple Sclerosis 
MS 
Member state 
MSFC 
Multiple Sclerosis Functional Composite 
MSIS-29v2 Multiple Sclerosis Impact Scale version 2 
MSWSv2 
Multiple Sclerosis Walking Score version 2 
Main REC Main Research Ethics Committee 
NHS R&D National Health Service Research & Development   
NODDI 
Neurite density and orientation dispersion imaging 
OCT 
Optical Coherence Tomography 
OD 
Once per day 
PASAT 
Paced Auditory Serial Addition Test 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PTI 
Prenyl Transferase Inhibitor 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person for release of trial drug 


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RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
RNFL 
Retinal Nerve Fibre Layer 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SDOCT 
Spectral-domain Optical Coherence Tomography 
SDV 
Source Document Verification 
SOP 
Standard Operating Procedure  
SmPC/SPC    Summary of Product Characteristics  
SPMS 
Secondary Progressive Multiple Sclerosis 
SSA 
Site Specific Assessment 
SSOCT 
Swept-source Optical Coherence  Tomography 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC  
Trial Steering Committee 
VBM 
Voxel-Based Morphometry 
 
 
1. Trial personnel 
See protocol cover page for Sponsor contact details. 
 
Chief Investigator 
Prof Richard Nicholas 
UCL Institute of Neurology 
Queen Square MS Centre 
RSH, 1st floor 
London 
WC1B5EH 
richard.nicholas3@nhs.net  


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Statistician 
Prof. Maria Pia Sormani 
Prof of Medical Statistics 
Department of Health Sciences 
University of Genoa 
Genoa, Italy 
mariapia.sormani@unige.it 
Local Laboratories 
Abraham Roodt 
UCL Laboratories 
Abraham.Roodt@tdlpathology.com  
Central Laboratories: 
Immune Parameters 
Dr Virginia Calder  
UCL Institute of Ophthalmology 
11/43 Bath Street 
London 
EC1V 9EL 
Tel: 020 7608 6848 
v.calder@ucl.ac.uk 
Central Laboratories: 
Biomarkers 
Prof John Greenwood  
UCL Institute of Ophthalmology 
11/43 Bath Street 
London 
EC1V 9EL 
Tel: 020 7608-6858 
j.greenwood@ucl.ac.uk 
Co-applicant 
Prof Jeremy Chataway 
Consultant Neurologist/Hon Senior Lecturer 
Dept. of Neuroinflammation 
UCL Institute of Neurology 
1st floor, Russell Square House 
10-12 Russell Square 
London WC1B 5EHTel: 020 3456 7890 
E-mail: j.chataway@ucl.ac.uk 
Co-applicant 
Prof Xavier Golay 
Professor of MR Neurophysics and Translational 
Neuroscience 
Vice-Dean for Enterprise, Faculty of Brain Sciences 
UCL Institute of Neurology 
National Hospital for Neurology & Neurosurgery 
Queen Square, London WC1N 3BG 
x.golay@ucl.ac.uk  
Tel: +44 (0)20 3448 3449 
Imaging (MRI) 
Prof Olga Ciccarelli 
Professor of Neurology 
Dept. of Neuroinflammation 
UCL Institute of Neurology 


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1st floor, Russell Square House 
10-12 Russell Square 
London WC1B 5EH 
o.ciccarelli@ucl.ac.uk 
Tel: +44 203 1087415 
 
Drug Preparation (Out-
sourced) 
Oliver Gupta 
Project Manager 
MODEPHARMA Ltd 
Phone: +44 207 0432 442 
Mobile: +44 774 070 1015 
E-mail: ogupta@modepharma.com  
Imaging (Retinal) 
Prof John Greenwood  
UCL Institute of Ophthalmology 
11/43 Bath Street 
London 
EC1V 9EL 
Tel: 020 7608-6858 
j.greenwood@ucl.ac.uk 
Dr Adam Dubis 
UCL Institute of Ophthalmology 
11-43 Bath Street 
Phone: +44 207608 4063 
E-mail: a.dubis@ucl.ac.uk 
 
Clinical Research Fellow 
(Neurologist) / Trial 
Manager 
Dr Alessia Bianchi 
Dept. of Neuroinflammation 
UCL Institute of Neurology 
1st floor, Russell Square House 
10-12 Russell Square 
London WC1B 5EH 
E-mail: a.bianchi@ucl.ac.uk  
Trial Finance Management Mrs Marie Braisher 
Dept. of Neuroinflammation 
UCL Institute of Neurology 
1st floor, Russell Square House 
10-12 Russell Square 
London WC1B 5EH 
E-mail: mariebraisher@nhs.net 
 
 
 


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2. Lay Summary 
Multiple sclerosis is a neurological condition which is a common cause of disability in 
young people. It is thought to be an autoimmune condition, where the body’s immune 
system begins to attack itself. The cause of MS is unknown but is thought to be a mix of 
genetic and environmental factors. There are treatments available for early stages of 
MS, but the later stage known as Secondary Progressive MS (SPMS) has no current 
treatment.  
 
Statins are a safe treatment traditionally used to reduce cholesterol levels. However, 
statins also have other effects which could reduce the progression of SPMS, such as 
effects on the immune system and circulation. A recent study (Chataway et al., 2014) 
showed that treatment with high-dose simvastatin, a type of statin, reduced the 
progression of SPMS but no effect on the immune system was seen. It is possible that 
simvastatin does not treat the immune system but improves how the blood and blood 
vessels in the brain work in this disease.  
The purpose of the clinical trial is to test how Simvastatin (80mg/day) may slow down 
disease progression in people living with Progressive Multiple Sclerosis (PMS) 
compared to placebo (dummy pill). Participants will receive either Simvastatin or 
placebo and will be asked to take 2 tablets daily, for up to 17 weeks.  
 
 
 
 
 
 
 
 


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2.1 Structured trial summary  
 
Public Title  
Simvastatin in Progressive Multiple Sclerosis  
 
Scientific Title  
 
A double-blind, randomised, placebo-controlled multi-
site study of high dose simvastatin treatment for 
progressive multiple sclerosis: impact on vascular 
perfusion and oxidative damage  
 
Countries of 
Recruitment  
 
United Kingdom  
 
Health Condition(s) 
or  
Problem(s) Studied  
Progressive Multiple Sclerosis  
 
Objectives: 
The primary outcome ASL measured CBF will be 
compared between patients on simvastatin or placebo 
using multiple linear regressions at 16 weeks. 
Secondary objectives include:  A. MRI: NODDI, myelin 
loss or changes, Grey matter atrophy and Number of 
new or enlarging T2 lesions. B. Clinical outcomes: 
EDSS, 25 foot timed walk, 9 hole peg test, MSIS-29v2, 
and MSWSv2. C. Retinal imaging parameters: vascular 
imaging, relative retinal vessel oxygen saturation and 
vessel width, non-invasive wide-field maps of both 
retinal (superficial and deep) and choroidal vascular 
plexuses, high-resolution retinal neuronal structure and 
SDOCT. D. Health Economic outcomes: EQ5D5L. E. 
Exploratory outcomes include immune parameters, and 
biomarkers. F. Frontal executive functioning will be 
assessed using the Frontal Assessment Battery (FAB) 
and other neuropsychological assessments (SDMT 
instrument). 
 
Type of trial: 
Phase II, double-blind, randomised, parallel group, 
single-site trial in progressive multiple sclerosis. 
Trial 
design 
and 
methods: 
40 subjects will be randomised double blind 1:1 to 
simvastatin or placebo. Simvastatin will be started at 
40mg once daily for one month increasing to 80mg daily 
for a further three months with matching placebo based 


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on a satisfactory safety assessment at one month. The 
primary outcome ASL measured CBF and BAT will be 
compared between patients on simvastatin or placebo 
using multiple linear regressions with CBF or BAT at 16 
weeks as the dependent variable, and age, gender, CBT 
or BAT at baseline and treatment group entered as 
covariates. 
Trial 
duration 
per 
participant: 
Twenty-two weeks including follow-up (up to 17 weeks 
on treatment) 
Estimated total trial 
duration: 
Two years 
Planned trial sites: 
2 
Total number of 
participants 
planned: 
40 
Main 
inclusion/exclusion 
Criteria: 
Trial Participant inclusion criteria 
The following inclusion criteria must be met (answer 
yes) when assessing patient’s eligibility onto the trial: 
1. Patients must have a confirmed diagnosis of multiple 
sclerosis according to revised Mc Donald criteria 
and have entered the secondary progressive stage. 
(Polman et al., 2011, Lublin, 2014) or have been 
diagnosed with Primary Progressive MS. Steady 
progression rather than relapse must be the major 
cause of increasing disability in the preceding 2 
years. Progression can be evident from either an 
increase of at least one point on the EDSS or 
clinical documentation of increasing disability. 
2. EDSS 4.0 – 6.5 (inclusive). 
3.  Male and Females aged 18 with no upper age limit 
4. Females of childbearing potential and males with 
partners who are of childbearing age must be willing to 
use an effective method of contraception (Double 
barrier method of birth control or True abstinence) from 
the time consent is signed until 6 weeks after treatment 
discontinuation and inform the trial team if pregnancy 
occurs. For the purpose of clarity, True abstinence is 
when this is in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence, withdrawal, spermicides only 
or lactational amenorrhoea method for the duration of a 
trial, are not acceptable methods of contraception. 
5. Females of childbearing potential have a negative 
pregnancy test within 7 days prior to being 


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registered/randomised.  Participants are considered not 
of child bearing potential if they are surgically sterile 
(i.e. they have undergone a hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy) or they are 
postmenopausal. 
6. Willing and able to comply with the trial protocol (e.g. 
can tolerate MRI and fulfils the requirements for MRI, 
e.g. not fitted with pacemakers or permanent hearing 
aids) ability to understand and complete questionnaires 
7. Willing and able to provide written informed consent 
8. Willing to ingest gelatine (placebo will contain this). 
Participants must therefore be informed sensitive to 
personal beliefs.   
 
Trial participant exclusion criteria 
Patients presenting with any of the following exclusion 
criteria (i.e. answers yes) at screening will not be 
eligible to proceed with the trial: 
1. Unable to give informed consent. 
 
2. Those that have experienced a relapse or have 
been treated with steroids (both i.v. and oral) for 
multiple sclerosis relapse within 3 months of the 
screening visit. These patients may undergo a further 
screening visit once the 3 month window has expired 
and may be included if no steroid treatment has been 
administered in the intervening period. Patients on 
steroids for another medical condition may enter as 
long as the steroid prescription is not for multiple 
sclerosis (relapse/ progression). 
3. Patient is already taking or is anticipated to be 
taking  a statin or lomitapide for cholesterol control. 
4. Any medications that unfavourably interact with 
statins as per Spc recommendations e.g.: fibrates, 
nicotinic acid, cyclosporin, azole anti-fungal 
preparations, macrolideantibiotics, protease inhibitors, 
nefazodone, verapamil, amiodarone, large amounts of 
grapefruit juice or alcohol abuse within 6 months.  
5. The use of immunosuppressants (e.g. azathioprine, 
methotrexate, cyclosporin) or disease modifying 
treatments (avonex, rebif, betaferon, glatiramer, 
dimethyl fumerate, fingolimod) within the previous 6 
months. 
6. The use of mitoxantrone if treated within the last 12 
months. 
7. Patient has received treatment with alemtuzumab. 
8. Use of other experimental disease modifying 
treatment (including research in an investigational 
medicinal product) within 6 months of baseline visit  


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9. Active Hepatic disease or known severe renal 
failure (creatinine  clearance <30ml/min) 
10. Screening levels of alanine aminotransferase 
(ALT), aspartate aminotransferase (AST) or creatine 
kinase (CK) are three times the upper limit of normal 
patients. 
11. If the patient reports any ophthalmic conditions 
such as glaucoma, ocular trauma or degenerative eye 
disease. Cataracts are acceptable as long as they have 
not been advised to have surgery. No restrictions on 
post surgical care, unless the patient reports sight 
restricting capsule opacity.  
12. Patient unable to tolerate or unsuitable to have 
baseline MRI scan (e.g. metal implants, heart 
pacemaker) or MRI scan not of adequate quality for 
analysis (e.g. too much movement artefact).   
13. Females who are pregnant, planning pregnancy or 
breastfeeding. 
14. Allergies to IMP active substance or to any  
excipients of IMP and placebo or other conditions that 
contraindicate use of galactose (eg. Hereditary 
galactose intolerance, Lactase deficiency, glucose-
galactose malabsorption) 
 
Statistical 
methodology 
and 
analysis: 
Randomisation with a minimization algorithm will be 
used (up to a maximum of three binary variables). The 
study is exploratory and the number of subjects/arm is 
estimated based on established measures of within and 
between subject standard deviations using ASL, based 
on a large test-retest study (Petersen et al., 2010). The 
power calculation (N=20 subjects per arm) is based on 
the ability to detect a 30% change in perfusion induced 
by statins at 0.8 power and 5% significance level. An 
expected mean grey matter CBF of 40 mL/100g per min 
and a standard deviation per subject of 12 mL/100g per 
min were chosen leading to N=17 per group. Accounting 
for drop-outs and problems in imaging patients (e.g. 
motion artefacts (20%)) gives N=20 subjects per group. 
A hypothetical increase in CBF by 30% was estimated 
based on a previous paper comparing the effects of 
normal doses of statins on healthy volunteers (Xu et al., 
2008). Any potential regression to the mean, which was 
not accounted for above will lead to a lower number of 
subjects per arm being necessary. 


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3. Background and Rationale 
Multiple sclerosis (MS), an autoimmune condition affecting the central nervous system, 
is the most common cause of disability in young adults and affects over 2.3 million 
people worldwide. It is estimated that in the UK there are 150,000 people with MS, and 
about 75,000 people have secondary progressive MS (SPMS). It has an estimated 
global prevalence of 30 people per 100,000, although in the UK the incidence is 
considerably greater (Mackenzie et al., 2014). Apart from the enormous societal, 
psychological and emotional cost, it has been estimated that the total annual fiscal 
cost of MS to Europe is of the order of €14.6 billion, which increases with disability 
(Olesen et al., 2012). 
While the cause is unknown, it is thought to result from interplay of genetic and 
environmental factors. Initially, focal leukocyte infiltration leads to myelin damage and, 
in the majority of patients, this triggers a cascade of events that lead to neuro-
degeneration and long-term disability. MS presents most commonly as a relapsing and 
remitting (RR) disease, characterised by neurological deterioration followed by 
complete or incomplete recovery. Approximately 60% of those affected with RRMS 
enter a secondary progressive (SPMS) stage after a median interval of 10 to 15 years, 
where disability accumulates gradually in the absence of relapses. A smaller 
proportion (15%), run a progressive course from onset (primary progressive (PP) MS). 
The progressive, “neurodegenerative” component of MS, rather than the clinical deficit 
resulting from incomplete recovery from each relapse in RRMS, is the dominant cause 
of long-term disability. Whilst over ten therapies are now licensed for RRMS, no 
treatment strategies, with the exception of a recent study by our group (Chataway et 
al., 2014), have succeeded in slowing the progression of this later debilitating stage. 
Optic neuritis, inflammation of the optic nerve, is a common event associated with MS 
resulting in 27% of subjects with residual visual impairment. The impact of damage 
arising from an inflammatory lesion in the optic nerve can be visualised using optical 
coherence tomography (OCT) as a reduction in both ganglion cell layer and retinal 
nerve fibre layer thickness (Grecescu, 2014; Huang-Link et al., 2014; Bennett et al., 
2015). However it is increasingly being appreciated that a number of other 
inflammatory and neurodegenerative changes occur in the retina of MS patients. 
These retinal changes, reflecting both the disease and its level of activity, have 
highlighted its potential as a surrogate outcome measure to study preservation of 
neuronal and/or vascular structure/function after an inflammatory event or as the 
disease progresses (Grecescu, 2014; Huang-Link et al., 2014; Bennett et al., 2015). 
During the last two decades there have been significant advances in our 
understanding of MS leading to treatment for the RR phase. Despite this, there has 
been a failure to find an effective treatment for progression and this remains a major 
unmet need, as highlighted by the International Progressive MS Alliance (Fox et al., 


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2012). The many challenges of progressive studies including optimal design, sensitive 
outcomes, suitable length and subject numbers are gradually being overcome by the 
MS community, but as yet extending the anti-inflammatory approach that has been 
effective in RRMS has not borne fruit in SPMS. Indeed the failure of the recent PPMS 
trial using fingolimod (Lublin et al., 2016) makes the success of simvastatin in the 
SPMS study (Chataway et al., 2014) all the more exciting, especially as the extensive 
systemic immunological assessment in this latter study revealed no impact on immune 
status. The real success of this simvastatin phase II study may be that it initiates novel 
avenues of investigation driven by the wide-ranging and well-characterised effects 
statins have on the body as well as a prelude to a definitive phase III trial. This 
premise underpins our research strategy. 
3.1   Preclinical data 
Preclinical work has focused on the role played by the vascular barriers (the blood-
brain and blood retinal barriers) in the inflammatory process and in particular how they 
support leukocyte traffic to the central nervous system (CNS). This research, along 
with that of others, led to the identification and characterisation of endothelial cell (EC) 
signalling processes that facilitate leukocyte diapedesis and activate pro-inflammatory 
responses (for review see Greenwood et al., 2011). We found that a key central 
regulator of the EC signalling pathway supporting leukocyte diapedesis was the small 
GTPase Rho, and this led us to investigate whether small GTPases could be targeted 
pharmacologically to reduce aberrant leukocyte migration into the brain and retina. 
Since small GTPases require posttranslational lipid modification (prenylation) to 
become functional we tested whether inhibition of Rho prenylation with prenyl 
transferase inhibitors (PTIs) affects lymphocyte migration. Treatment of brain 
endothelial cell monolayers in vitro, or animals induced for experimental autoimmune 
encephalomyelitis (EAE, the animal model of MS), resulted in inhibition of lymphocyte 
migration and attenuation of the disease respectively (Walters et al., 2002). 
Since the isoprenoids used for post-translational prenylation of small GTPases are 
derived from the cholesterol synthesis pathway, we next investigated whether 
HMGCoA reductase inhibitors (statins) were also able to significantly inhibit Rho 
activity and reduce the severity of brain and retinal inflammatory disease. This 
research revealed that statins effectively reduced Rho prenylation and attenuated 
disease in experimentally induced models of MS and posterior uveitis (Greenwood et 
al., 2003; Gegg et al., 2005). Whilst we were able to demonstrate that one of the 
effects of statin treatment was to modify endothelia cell function and inhibit 
transendothelial migration of leukocytes, it is clear from many other experimental 
studies that efficacy may also be due to effects on other cell types such as immune 
cells (Greenwood et al., 2006; Weber et al., 2006; Greenwood and Mason, 2007).  
Indeed, it is now widely recognised that statins have anti-inflammatory properties that 
operate independently of their cholesterol lowering effect. Accordingly, statins have 


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been shown to inhibit MHC class II restricted Ag presentation, attenuate antigen-
presenting cell maturation and down-regulate T cell activation and proliferation. Of 
those T cells that proliferate, statins induce a shift from a proinflammatory Th1 to a 
regulatory Th2 phenotype. In addition, statins block adhesion molecule expression and 
their interactions, inhibit the production of chemokines and their receptors, and reduce 
the secretion of matrix metalloproteinases. Activation of the transcription factor NFκB, 
an important activator of pro-inflammatory mediators, is also inhibited by statins, 
alongside a concomitant upregulation of endothelial cell protective genes (Greenwood 
and Mason, 2007). Finally, it has been shown that endothelial nitric oxide synthase 
(eNOS) activity is enhanced, whilst inducible NOS (iNOS) is inhibited. 
3.2  Clinical data 
This remarkable pleiotropic capacity for modulating the immune system and 
inflammation has prompted the clinical testing of statins for the treatment of RRMS 
and other inflammatory diseases (Vollmer et al., 2004; Neuhaus and Hartung, 2007; 
Paraskevas, 2008; Yuan et al., 2012; Young and Hopkins, 2013). In one such study in 
30 patients with RRMS, simvastatin (80mg) taken over 6 months reduced the number 
of brain lesions by 40%, although no change in disability scores was observed over 
this short study period (Vollmer et al., 2004). Other studies, however, have failed to 
demonstrate any significant clinical improvement in RRMS following statin treatment 
alone or in combination with other disease modifying drugs. Nevertheless, it should be 
noted that none of the studies so far have been sufficiently powered, rendering 
definitive conclusions impossible. 
Whilst there is a clear-cut rationale for using statins for the treatment of RRMS, in 
SPMS/PPMS there is less obvious justification, as disease progression in the absence 
of new plaque formation is thought to be due predominantly to neurodegeneration (or 
neuronal loss). This results from several mechanisms, including microglia activation, 
chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-
related iron accumulation in the human brain (Mahad et al., 2015). Whereas large 
scale inflammatory lesions rarely occur at this stage of the disease, inflammation is 
prominent in progressive MS, where it is found throughout the grey and white matter, 
and in the meninges, with its most severe form being represented by the ectopic 
follicles that contribute to grey matter damage (Kutzelnigg et al., 2005; Magliozzi et al., 
2007). This suggested that given their Immunomodulatory / anti-inflammatory actions, 
statins might still provide some benefit in SPMS/PPMS. Nonetheless, neuronal loss is 
regarded as the key pathological feature, which raised the question whether statins 
also possess neuroprotective properties. Several lines of evidence suggest this may 
be the case.  
Firstly, statins are increasingly seen as vasculoprotective (Greenwood and Mason, 
2007; Liao, 2002; Mason, 2003; Haendeler et al., 2004; Antonopoulos et al., 2012) 
with a capacity to improve vascular perfusion (Endres et al., 1998; Giannopoulos et al., 


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2012) and maintain/enhance blood vessel function (Xu et al., 2008) thus protecting 
against long-term chronic hypoxic damage. This is germane given the growing 
evidence that dysfunctional/reduced blood flow in MS (De Keyser et al., 2008; 
D’Haeseleer et al., 2013; Paling et al., 2014) may predispose the tissue to damage 
resulting in neuronal cell dysfunction and ultimately cell death. Such beneficial effects 
on microvascular perfusion may be mediated through statins enhancing eNOS 
activation (Laufs et al., 1998) and inhibiting endothelin-1 (Mraiche et al., 2005).  
Secondly, there are reports that statins may also be neuroprotective through reducing 
free radical damage either by improving blood flow and reducing hypoxia-mediated 
reactive oxygen species (ROS) production, or through direct inhibition of cytotoxic 
pathways. In the latter case, statins may protect neuroparenchymal cells via inhibition 
of iNOS in activated microglia and astrocytes (Pahan et al., 1997; van der Most et al., 
2009), resulting in attenuated cytotoxic damage to neurons and oligodendrocytes. 
Furthermore, statins may also exert a neuroprotective effect by preventing glutamate-
mediated excitotoxicity (Schmeer et al., 2006). 
Together these data provided a compelling rationale for testing the potential 
therapeutic effect of statins in SPMS. In 2008 we therefore embarked on a two-year 
double-blind, controlled trial of 140 patients, randomising them to either 80mg of 
simvastatin or placebo. The recently published results of this trial showed that brain 
atrophy was reduced by over 40% alongside a similar favourable effect on two major 
disability outcome measures (Chataway et al., 2014). This is the first evidence of a 
drug having a beneficial effect on SPMS disease progression. Surprisingly, however, 
and contrary to expectations, we did not identify any modulation of the immune 
system, raising the critical question of the mechanism of statin action. 
3.3  Rationale and risks/benefits 
It is our hypothesis, therefore, that the neuroprotective effects of statins in SPMS are 
mediated by stimulating enhanced microvascular perfusion and/or by inhibition of 
oxidative damage/neurotoxicity. This study will test this hypothesis. 
There are no current treatments for SPMS/PPMS. Given we demonstrated that 
simvastatin was beneficial in a phase II trial but were unable to elucidate any 
mechanism, it is important to try and understand the mechanism of action to develop 
further therapies. 
We will investigate the impact of high dose simvastatin (80mg/day) on cerebral and 
retinal blood perfusion and vascular structure/function, brain neuroaxonal density and 
myelin loss or changes in PMS. In addition, various systemic parameters will be 
evaluated to determine the effect of high dose statin treatment on immune function, 
oxidative damage and vascular barrier function.  
Simvastatin is being used outside of its posology and method of administration. The 
previous phase two trial found simvastatin was safe up to the maximum dose of 80 


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mg/day given as a single dose in the evening.  Based on the recommendations of the 
SPC and previous studies, the proposed use of 80mg of Simvastatin will, therefore, be 
used for this study (Chataway et al, 2014). 
 
4. Assessment and management of risk  
Risk minimisation:. All symptoms will be monitored as per routine best medical 
practice. 
 
The table below summarises the risks, frequencies and mitigations of the IMP. 
Name of IMP  Potential risk 
 
Risk 
Frequency 
Risk Management 
 
Simvastatin 
Hypersensitivity 
Rare 
Patients with known hypersensitivity to 
the active substance or any of the 
excipients will be excluded from the 
trial. Patients on trial treatment phase 
who have an allergic reaction will, at the 
discretion of the treating clinician, 
simvastatin be discontinued. 
Simvastatin 
Hepatitis or 
Jaundice 
Rare  
Patient will have liver function tests 
performed prior to study entry and 
whilst on study to monitor their Hepatic 
function.  Patients with known Hepatic 
failure, who consume substantial 
quantities of alcohol and / or have 
screening Liver function test > 3XULN 
will be excluded from the study. If 
patients whilst on study have LFTs > 
3XULN or present with clinical 
symptoms of liver injury, then, at the 
discretion of the treating clinician, 
simvastatin will be discontinued (see 
section 14.2 for discontinuation).  
Simvastatin 
fatal and non fatal 
hepatic failure) 
Very rare 
Patient will have liver function tests 
performed prior to study entry and 
whilst on study to monitor their Hepatic 
function.  Patients with known Hepatic 
failure, who consume substantial 
quantities of alcohol and/or have 
screening Liver function test > 3XULN 
will be excluded from the study. If 


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patients whilst on study have LFTs > 
3XULN or present with clinical 
symptoms of liver injury, then, at the 
discretion of the treating clinician, 
simvastatin will be discontinued.  
Simvastatin 
Myopathy/ 
Rhabdomyolysis 
Rare 
Simvastatin occasionally causes 
myopathy manifested as muscle pain, 
tenderness or weakness with creatine 
kinase (CK) above ten times the upper 
limit of normal (ULN). The risk of 
myopathy is greater in patients on 
simvastatin 80 mg.  The risk of 
myopathy and rhabdomyolysis is also 
significantly increased by concomitant 
use of simvastatin with certain 
medications and supplements such as 
potent inhibitors of CYP3A4, Fibrates, 
grapefruit juice, Calcium Channel 
Blockers (see section 7.5 for full list of 
medications). Myopathy sometimes 
takes the form of rhabdomyolysis with 
or without acute renal failure secondary 
to myoglobinuria, and very rare fatalities 
have occurred.  
Patient’s plasma renal function will be 
tested at screening and monitored 
whilst on study. Patients with known 
renal failure and or plasma potassium 
exceeds 5.5mmol/l or plasma sodium 
<125mmol/l or creatinine>130mmol/l, 
will be excluded. If these parameters 
are breached during the trial, patient will 
be monitored as per routine best 
medical practice and at the discretion of 
the treating clinician, simvastatin dose 
may be reduced or discontinued. 
Potassium conserving drugs and 
potassium supplements are also 
prohibited (see section 7.5). 
Patients who are on medications that 
interact with Simvastatin and increases 
the risk of myopathy (see list in section 


Short title: Simvastatin in Progressive MS   
 
 
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7.5) will be excluded from the study. 
The patient information sheet will 
explain the risk of myopathy, explain to 
patients the need to inform doctors of 
the medications they take and advise 
patients on medications/supplements 
they need to avoid whilst on the study. 
As a higher rate of myopathy has been 
observed in patients titrated to the 80 
mg dose, Creatine Kinase (CK) will be 
tested at screening and monitored 
whilst on study. Patients who have a 
screening CK of > 3xULN will be 
excluded. If patients whilst on study 
have CK > 3XULN or present with 
clinical symptoms of myopathy, then, at 
the discretion of the treating clinician, 
simvastatin will be discontinued. 
Simvastatin 
Hyperglycaemia 
Rare 
Some evidence suggests that statins as 
a class raises blood glucose and in 
some patients at risk of future diabetes. 
Patients who have or are at risk of 
Diabetes Mellitus will be monitored both 
clinically and biochemically according to 
national guidelines for Diabetes. 
Simvastatin 
Interstitial lung 
disease 
(dyspnoea, non 
productive cough) 
Not Known 
If Interstitial lung disease is suspected 
whilst on the study, at the discretion of 
the treating clinician, simvastatin will be 
discontinued. 
Simvastatin 
Gastro-intesitinal 
disorders 
(diarrhoea, 
nausea, vomiting, 
pancreatitis) 
Rare 
Vital signs will be observed prior to 
study enrolment and at treatment visits 
to ensure significant hypotension or 
hypovolaemia does not occur during the 
trial. Patients will be advised to avoid 
dehydration and the volume status will 
be carefully monitored of the patients. 
The Patient information sheet will 
explain this risk and advise patients on 
avoiding dehydration. 


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Simvastatin 
Anaemia 
Rare 
Full blood Count will be tested at 
screening and monitored whilst on 
study. Patients whose results show 
clinical significant levels will be 
monitored and treated at the discretion 
of the treating clinician as per routine 
best medical practice. 
Simvastatin 
Elevated 
International 
Normalized Ratio 
(INR) 
Very Rare 
Very rare cases of elevated INR have 
been reported in patients taking oral 
coumarin anticoagulants. Patients who 
are on these anticoagulants will be 
monitored and treated at the discretion 
of the treating clinician as per routine 
best medical practice. 
Recommendations outlined in the SPC 
will also be considered. 
Simvastatin 
Insomnia 
Very Rare 
Symptoms will be monitored and 
treated at the discretion of the treating 
clinician as per routine best medical 
practice.  
 
Cognitive /  
memory 
impairment  
Very rare 
There have been rare post-marketing 
reports of cognitive impairment (e.g. 
memory loss, forgetfulness, amnesia, 
memory impairment, confusion) 
associated with statin use. The reports 
are generally nonserious, and reversible 
upon statin discontinuation, with 
variable times to symptom onset (1 day 
to years) and symptom resolution 
(median of 3 weeks). Symptoms will be 
monitored and treated at the discretion 
of the treating clinician as per routine 
best medical practice. 
Simvastatin 
Headache, 
paresthsia, 
dizziness or 
peripheral 
neuropathy. 
Rare 
Symptoms will be monitored and 
treated at the discretion of the treating 
clinician as per routine best medical 
practice. Simvastatin has no or 
negligible influence on the ability to 
drive and use machines. However, 
when driving vehicles or operating 
machines, it should be taken into 


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account that dizziness has been 
reported rarely in post-marketing 
experiences and the patient information 
sheet will explain this rare risk and 
caution. 
Simvastatin 
Skin and 
Subcutaneous 
disorders ( e.g. 
rash, pruritus, 
alopecia) 
Rare 
Symptoms will be monitored and 
treated at the discretion of the treating 
clinician as per routine best medical 
practice.  
Simvastatin 
Pregnancy 
Not Known 
Safety in pregnant women has not been 
established and it is not known whether 
simvastatin or its metabolites are 
excreted in human milk. Women who 
are pregnant or breast feeding will be 
excluded. Women of Child bearing 
potential will need to agree to use 
adequate contraception and  will have a 
urine pregnancy test to confirm they are 
not pregnant prior to being enrolled.  
 
 
The table below summarise the risks and mitigations of all tests above standard care 
that are being performed: 
Intervention  
Potential risk 
Risk Management 
Venepuncture for 
Blood Tests 
Risk of discomfort, bruising, 
excessive bleeding, fainting or 
feeling lightheaded, 
hematoma & infection 
Venepuncture risks will be 
managed using standard clinical 
care precautions which include 
wearing protective clothing, hand 
and surface hygiene. Risks to 
participants from venepuncture 
will be managed using standard 
clinical care. Non clinical staff 
performing venepuncture will 
receive appropriate training. Every 
effort will be made to make 
participants feel comfortable 
before, during and after 
venepuncture by encouraging 
participants to relax and talking 


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through any concerns they have 
about the procedure. 
Trust incident reporting will apply 
and be followed in the event of 
patient/staff needle stick injury. 
MRI 
MRI is generally well 
tolerated. There can 
occasionally be some 
discomfort and/ or 
claustrophobia. It is however 
unsafe in patients who have 
metal inplants or heart 
pacemaker. Also not 
recommended in patients who 
are pregnant. 
Trial participants will have had 
MRI as part of the diagnostic 
pathway and will be familiar with 
it. During the scan they have real-
time contact with the radiographer 
with any concerns and can halt 
the scan if needed. Patients fitted 
with pacemakers or permanent 
hearing aids are excluded 
because these are metal 
containing products and highly 
unsafe for MRI. Protocol excludes 
patients who are unable to 
tolerate scans.  Pregnant 
participants will be excluded from 
the study and women of child 
bearing potential will need to have 
a negative urine pregnancy test. 
Advanced retinal 
imaging inc. OCT 
Patients may have some 
discomfort from glare induced 
by having their eyes 
dilated.  There is also a small 
risk of eye irritation from 
application of the drops. 
 
Light levels are well below 
recommended levels and are 
electronically controlled to 
prevent accidental over exposure 
Patient will be advised to bring 
sunglasses to protect against 
glare.  Lights within the building 
are designed to account for 
increased light 
sensitivity.  Irritation from the 
drops is mitigated by use of a 
sterile single use applicators. 
 
 
In accordance with the MRC/DH/MHRA Joint Project Risk-adapted Approaches to the 
Management of Clinical Trials of Investigational Medicinal Products, this trial is 
categorised as:  
 
Type B = somewhat higher than the risk of standard medical care  
 


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5. Objectives 
5.1  
Summary 
The general aim of the study is to determine the effect high-dose Simvastatin 
treatment has on vascular perfusion and oxidative damage in progressive multiple 
sclerosis. 
5.2 
Hypothesis 
Simvastatin reduces the progression of progressive MS by increasing vascular 
perfusion and reducing oxidative damage as demonstrated by measuring cerebral 
blood flow in people with SPMS/PPMS. 
5.3  
Aims  
Primary: To test against placebo the efficacy and mechanism of simvastatin in 
progressive MS. 
Secondary: To advance our understanding of the mechanisms of efficacy, and how 
vascular perfusion and oxidative damage is affected in progressive MS both in the 
presence and absence of simvastatin. 
5.4  
Primary objective  
To establish whether simvastatin has an effect on cerebral blood flow in progressive 
MS over 20 weeks using arterial spin labelling MRI. 
5.5  
Secondary objectives 
• To establish whether ASL and AOSLO measurements of blood flow are useful 
correlates for cerebral blood flow measurement on and off treatment.  This will 
be supported by a questionnaire investigating factors that influence brain 
perfusion. 
• To explore whether statin reduce the rate of brain atrophy on MRI (excluding 
the effect of pseudo-atrophy, which is a temporary response to the drug rather 
than an actual loss of tissue). 
• To detect subtle changes in both normal-appearing white matter and normal-
appearing grey matter using DWI and tract-based analyses. 
• To determine the role of myelin loss or changes in PMS using MTV imaging as 
a surrogate marker of brain myelin volume. 


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• To examine the clinical effect of simvastatin treatment as reported by the 
clinician (EDSS, SDMT, MSFC inc. 9HPT and 25FTW) and patient reported 
outcome measures (MSIS-29v2, and MSWSv2). 
• Frontal executive functioning will be assessed using the Frontal Assessment 
Battery (FAB). 
• To collect health economic data (EQ5D5L) to inform future phase III trials  
• Investigate the effect statins may have on retinal parameters such as blood 
flow, oxygen saturation, structure of vascular plexuses, neuronal structure and 
retinal layer thicknesses. 
5.6      Exploratory objectives 
• To investigate phenotypic immune markers in whole blood to determine effect 
simvastatin has on immune function 
• To measure biomarkers of blood brain barrier dysfunction, vascular leakage 
and oxidative damage in participants treated with statins and placebo 
• To investigate levels of circulating cholesterol   
 
 
6. Trial design 
6.1 Overall design 
This is a non-commercial short duration (up to 17 weeks on treatment), double-blind 
placebo-controlled randomised trial of high dose simvastatin versus placebo to 
determine the impact of simvastatin on the MS population described. 
 
The 17 week duration is based on the tolerability of previous studies which 
demonstrated that this length of treatment at the given dose of 80mg Simvastatin was 
well tolerated. Given simvastatin has a well-established safety profile and the half-life 
of the simvastatin is short, patients will be followed-up until 4 weeks post-IMP 
administration.  
 
The trial design will be double blinded so as to reduce any bias from the power of 
suggestion of which treatment the patient is receiving by both the researchers and the 
patient.   
 
 
 


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 Figure 1: Schematic of overall trial design from recruitment to end of follow up 
 
 


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7. Investigational Medicinal Products and Non-Investigational 
Medicinal Products 
7.1 Name and description of IMP(s) 
Simvastatin is part of the pharmacotherapeutic group of HMG-CoA reductase 
inhibitors (ATC-Code: C10A A01).Simvastatin is licensed within the EU for 
hypercholesterolemia and cardiovascular prevention but for this trial its use will be 
outside its licensed indication. 
 
After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver 
to the corresponding active beta-hydroxyacid form which has a potent activity in 
inhibiting HMG-CoA reductase (3 hydroxy – 3 methylglutaryl CoA reductase). This 
enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-
limiting step in the biosynthesis of cholesterol.  
 
Simvastatin has been shown to reduce both normal and elevated LDL-C 
concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised 
predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering 
effect of simvastatin may involve both reduction of VLDL-cholesterol (VLDL-C) 
concentration and induction of the LDL receptor, leading to reduced production and 
increased catabolism of LDL-C. Apolipoprotein B also falls substantially during 
treatment with simvastatin. In addition, simvastatin moderately increases HDL-C and 
reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and 
LDL- to HDL-C are reduced. 
Following randomisation study drug will be dispensed by the site pharmacy.  
Patients will be randomised to one of the following treatment arms: 
• Oral Simvastatin 40mg daily (one tablet in the evening) for 4 weeks and then at 
week 4 up titrated to 80mg daily (two tablets in the evening) 
or 
• Matched Placebo (one tablet in the evening) for 4 weeks and then at week 4 up 
titrated to two tablets daily in the evening. 
 
For dose modification, please see section 10.2. 
For treatment stopping rules, please see section 14.2. 
The blinding will be achieved by over-encapsulation of Simvastatin and producing an 
matched placebo. Commercial simvastatin will be used which have marketing 
authorisations within the EU, encompassing a variety of brands that can be used. 
Further details on the sourcing and manufacturing arrangements is given in section 7.2. 


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7.2 
Source of IMP, Manufacture, Distribution and Storage 
The over-encapsulation of Simvastatin, manufacture of the placebo and QP release of 
both will be done by a third party manufacturer holding a MIA IMP in conformance with 
EU GMP. Mode Pharma will source Simvastatin and ingredients for placebo and will 
over encapsulate the Simvastatin and matching placebo.   
 
ModePharma will issue the Simvastatin and placebo tablets in child-resistant tamper-
evident containers of 220 tablets per container. Each will be labelled in a blinded 
fashion labelled “Simvastatin or Placebo” along with a unique randomisation number.  
ModePharma will conduct the final QP release and ship supplies to the site pharmacy 
using temperature loggers to monitor temperature during transfer.  
 
As each participant in the trial attends their visit for issue of their medication, the site 
pharmacist will issue the total amount of tablets to end of study of the trial medication 
according to the patients’ clinical trial randomisation number . The participant will be 
advised to uptitrate at Visit 2 to 80mg from 40mg (issued at baseline). 
Sourcing of the IMP(s) is also discussed in the Summary of Drug Arrangements/IMP 
management plan. 
7.3 
Storage and handling of IMP(s) at site 
All IMP aspects of the trial at participating sites are the responsibility of the PI, who may 
delegate this duty to the local pharmacist or other appropriately trained personnel.  The 
delegation of duties must be recorded on the Staff Signature and Delegation of Tasks. 
Storage and handling of the IMP will be completed in accordance with the relevant IMPD 
or Investigator Brochure and summary of drug arrangements.  
Do not store the trial drug above 30°C. Store in the original container, in order to protect 
from light. All active and placebo drugs will be packaged and QP released by the third 
party manufacturer in High-density polyethylene (HDPE) Bottles containing an identical 
allocation of tablets.  
Labelling will be blinded and carried out in accordance with EU GMP.  In order to 
maintain blinding, bottles will be labelled with numbers predetermined by a code list 
supplied by Sealed Envelope which will correspond to the treatment allocation.  Shelf-
life and storage conditions will be monitored. 
7.4  NAME AND DESCRIPTION OF EACH NIMP 
Patients will have their pupils dilated using one drop each of phenylephrine (2.5%) and 
tropicamide (1%) before imaging. This is done for each patient in clinic and Moorfields 
tracks uses.  
 


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The host site are responsible for maintaining a system which allows adequate 
reconstruction of NIMP movements; there should be a procedure that permits 
recording which participants received which NIMPs during the trial with an evaluation 
of the compliance. 
 
These drugs are considered to be non-investigational medicinal products (NIMPs) in 
this Trial.  Drops usage is always noted in Moorfields patient notes (each research 
patient has their own) by the person instilling the drops, and the type of drops and time 
of day is noted. Giving patients drops in Moorfields requires full training. 
7.5 Accountability of IMP(s)  
IMP shipping arrangement instructions for site will be described in the Summary of 
Drug Arrangements.  
Usual procedures for monitoring of temperature and transport conditions of the IMP 
will apply and will be documented on the IMP shipping form. Upon receipt of the IMP, 
the site pharmacy will confirm receipt of the IMPs by posting/faxing back the 
accompanying shipping form to the supplier and copies retained at trial sites file. In 
cases where the IMP was damaged or not stored correctly this will warrant an urgent 
notification to the manufacturer, ModePharma, and a replacement will be arranged. 
ModePharma will be responsible for dispatching replacement IMPs to sites.  Site 
pharmacy will be responsible for logging receipt of the IMPs on the site accountability 
log within the site pharmacy file. Site pharmacy will be responsible for storing the IMP 
in line with storage requirements as set out in this protocol. Site pharmacy will monitor 
temperature of IMP storage and report to the sponsor any temperature excursions that 
have occurred. Details of reporting temperature excursion are in the Summary of drug 
arrangements and in the SOP for IMP Management. Full IMP accountability will be 
conducted during the trial. All IMP dispensed by pharmacy will be logged on the site 
accountability log within the site pharmacy file. 
Once the IMP is dispensed, the IMP will be administered to participants initially 40 mg 
per day, escalating after one month to 80 mg per day. Participants will be advised on 
how to take their medication at their study visit and thereafter at home. For this 
purpose, all participants will be given a drug diary which will document their drug 
compliance.  This information will also be provided in the patient information leaflet. 
Patients will be instructed to bring the bottles, drug diary, and unused IMP back at the 
next visit so that the research staff can conduct a pill count.   The administration of the 
IMP will be documented in the source data and CRF. 
All used/unused IMPs will be returned to site pharmacy, to be then updated in the drug 
accountability log in the pharmacy site file. Drug destruction will be conducted, once 
authorised by the sponsor and in accordance with local practice, and this will be 
documented in the drug destruction log in the hospital pharmacy file. 
Detailed instructions are contained in the summary of drug arrangements  


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7.6  Concomitant medication 
All medications are permitted, apart from those outlined below. Concomitant 
medications will be recorded in the participant’s medical records/CRF/eCRF. 
The following medications have known interactions with Simvastatin and increases the 
risk of Myopathy and are therefore, contra-indicated: 
• Potent inhibitors of cytochrome P450 3A4 (e.g. Itraconazole, Ketoconazole, 
Posaconazole, Erythromycin, Clarithromycin, Telithromycin, HIV protease 
inhibitors (e.g. nelfinavir), Nefazodone, Ciclosporin, Danazol, Gemfibrozil 
• Fibrates 
• Cyclosporin 
• Fluconazole 
• Danazol 
• Gemfibrozil 
• Amiodarone 
• Calcium Channel Blockers(e.g. Verapamil, Diltiazem and Amlodipine) 
• Niacin 
• Grapefruit Juice 
The following medication have known interactions with Simvastatin and caution and 
careful monitoring is required: 
• Colchicine 
• Fusidic acid (Temporary suspension of simvastatin treatment may be 
considered. If it proves necessary, patients on fusidic acid and simvastatin 
should be closely monitored). 
• Moderate inhibitors of CYP3A4 
• Rifampicin (patients on long term therapy may experience loss of efficacy) 
• Lomitapide (patients with homozygous familial hypercholesterolemia and 
treated with Lomitapide, the dose of simvastatin must not exceed 40mg) 
 
7.7 
Post-trial IMP arrangements 
The IMP will not be provided to trial participants post-trial participation in any 
circumstance. 
 
 
 
 


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8. Selection of Participants 
8.1 Eligibility of trial participants 
All potential participants must meet all the inclusion and exclusion criteria as set out in 
sections 8.1.1 and 8.1.2. No eligibility waivers or deviations will be permitted.  
8.1.1 Trial participant inclusion criteria 
The following inclusion criteria must be met (answer yes) when assessing patient’s 
eligibility onto the trial. 
1. Patients must have a confirmed diagnosis of multiple sclerosis according to revised 
Mc Donald criteria  and have entered the secondary progressive stage or a diagnosis 
of Primary Progressive MS.(Polman et al., 2011, Lublin, 2014)  
Steady progression rather than relapse must be the major cause of increasing 
disability in the preceding 2 years. Progression can be evident from either an 
increase of at least one point on the EDSS or clinical documentation of increasing 
disability. 
 
2. EDSS 4.0 – 6.5 (inclusive). 
 
3. Male and Females aged 18 with no upper age limit 
 
4. Females of childbearing potential and males with partners who are of childbearing 
age must be willing to use an effective method of contraception (Double barrier 
method of birth control or True abstinence) from the time consent is signed until 6 
weeks after treatment discontinuation and inform the trial team if pregnancy occurs. 
For the purpose of clarity, True abstinence is when this is in line with the preferred 
and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence, withdrawal, 
spermicides only or lactational amenorrhoea method for the duration of a trial, are 
not acceptable methods of contraception. 
 
5. Females of childbearing potential have a negative pregnancy test within 7 days prior 
to being registered/randomised.  Participants are considered not of child bearing 
potential if they are surgically sterile (i.e. they have undergone a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal. 
 
6. Willing and able to comply with the trial protocol (e.g. can tolerate MRI and fulfils the 
requirements for MRI, e.g. not fitted with pacemakers or permanent hearing aids) 
ability to understand and complete questionnaires. 
 
7. Willing and able to provide written informed consent. 
 
8. Willing to ingest gelatine (placebo will contain this). Participants must therefore be 
informed sensitive to personal beliefs e.g. faith, diet.  


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8.1.2 Trial participant exclusion criteria 
Patients presenting with any of the following exclusion criteria (i.e. answers yes) at 
screening will not be eligible to proceed with the trial: 
1. Unable to give informed consent. 
 
 
2. Those that have experienced a relapse or have been treated with steroids (both 
i.v. and oral) for multiple sclerosis relapse within 3 months of the screening visit. 
These patients may undergo a further screening visit once the 3 month window 
has expired and may be included if no steroid treatment has been administered 
in the intervening period. Patients on steroids for another medical condition may 
enter as long as the steroid prescription is not for multiple sclerosis (relapse/ 
progression). 
 
3. Patient is already taking or is anticipated to be taking a statin or lomitapide for 
cholesterol control. 
 
4. Any medications that unfavourably interact with statins as per Spc 
recommendations e.g.: fibrates, nicotinic acid, cyclosporin, azole anti-fungal 
preparations, macrolideantibiotics, protease inhibitors, nefazodone, verapamil, 
amiodarone, large amounts of grapefruit juice or alcohol abuse within 6 months. 
 
5. The use of immunosuppressants (e.g. azathioprine, methotrexate, cyclosporin) 
or disease modifying treatments (avonex, rebif, betaferon, glatiramer, dimethyl 
fumerate, fingolimod) within the previous 6 months. 
 
6. The use of mitoxantrone if treated within the last 12 months. 
 
7. Patient has received treatment with alemtuzumab. 
 
8. Use of other experimental disease modifying treatment (including research in an 
investigational medicinal product) within 6 months of baseline visit. 
 
9.  Active Hepatic disease or known severe renal failure (creatinine clearance 
<30ml/min). 
 
10.  Screening levels of alanine aminotransferase (ALT), aspartate aminotransferase 
(AST) or creatine kinase (CK) are three times the upper limit of normal patients. 
 
11.  If the patient reports any ophthalmic conditions such as glaucoma, ocular trauma 
or degenerative eye disease.  . Cataracts are acceptable as long as they have 
not been advised to have surgery. No restrictions on post surgical care, unless 
the patient reports sight restricting capsule opacity. 
 


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12.  Patient unable to tolerate or unsuitable to have baseline MRI scan (e.g. metal 
implants, heart pacemaker)  or MRI scan not of adequate quality for analysis (e.g. 
too much movement artefact). 
 
13. Females who are pregnant, planning pregnancy or breastfeeding. 
 
14. Allergies to IMP active substance or to any excipients of IMP and placebo or other 
conditions that contraindicate use of galactose (eg. Hereditary galactose 
intolerance, Lactase deficiency, glucose-galactose malabsorption) 
 
 
8.2 
Recruitment 
Participant recruitment at the site will only commence when the trial has  
1. Been initiated by the Sponsor and  
2. Issued with the ‘Open to Recruitment’ letter. 
 
There are several routes of referral which are shown in the flowchart in section 8.2.1: 
Neurologist/GP referral from routine NHS clinics, self-referral and referral from known 
interested subjects. Patients who are happy to be contacted i.e. pre-screen consented, 
or have been acknowledged as happy to be contacted in a referral letter, will have a 
patient information sheet (PIS) mailed to them following an explanation of the trial by a 
member of the study team. A request to organise a telephone pre-screening visit to 
explain the trial and ensure the patient is likely to fulfil the criteria to enter the trial will 
also be arranged as per flowchart 8.2.1. Subsequently if the patient is interested in 
joining the trial and they appear to meet all entry criteria, a combined 
screening/baseline visit will be arranged. If the patient is eligible and wishes to enter 
the trial, they sign appropriate consent both to enter the trial, for contact to be made 
with their GP/consultant, and for medical information to be released about their 
condition.  Letters are to be written both to the patient’s GP and neurologist explaining 
the trial. 
All procedures on human subjects will be performed following approval from the 
MHRA, REC and Health Research Authority (HRA) to allow trial activity at Moorfields 
Eye Hospital and The National Hospital for Neurology and Neurosurgery. Procedures 
will be performed as per protocol and Good Clinical Practice (GCP) guidelines.  
 
 
 
 


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8.2.1 Patient Recruitment Flow Chart 
Patient Recruitment Flow Chart 
Neurologist/GP referral  
Self-referral  
Patient database/clinics 
 
                          
 
 
 
 
 
Invitation letter sent 
Refers patient 
 
Patient signs  
 
 
 
 
pre-screening consent via 
 
 
 
 
study website & downloads 
 
 
 
 
invitation letter 
 
 
 
Invitation letter sent 
 
 
Pre-screening consent received  
(patient agrees to be contacted) 
 
 
 
 
 
 
 
 
Contact participant by phone 
Explanation of the trial by member of the trial team 
 
 
If interested and likely to be suitable, send patient information sheet 
 
 
Subsequently, if would like to be considered for the trial contacts trial team to 
have pre-screening assessment over telephone. 
 
 
If eligible, participant will attend in-person a screening/baseline visit and sign  
consent to be reviewed. If not, they will be informed that they have not met the 
eligibility criteria and they will be recorded as a screen failure and a copy of 
their consent form will be kept in the trial master file (TMF)/Investigator site file 
(ISF). An ISF will be kept at all participating sites.  However, a participant may 
be re-screened if eligibility criteria is later met. 
 
 
Letters written to patient’s GP/neurologist explaining the trial 


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8.2.2 Retention 
Every effort will be made to retain patients in-trial.  Drug compliance and commitment 
to study visits will be monitored by the research team through the use of drug diaries 
completed by the trial participants in addition to a pill count at the relevant visits. The 
short duration of the study (four months on treatment) should increase the probability 
of a high patient retention versus a longer duration study.  For those participants who 
are unable to tolerate the Simvastatin dose at 40 mg or 80 mg see section 10.2.  
8.3 
Informed consent procedure 
It is the responsibility of the Investigator, or a person delegated by the Investigator to 
obtain written informed consent from each participant prior to participation in the trial, 
following adequate explanation of the aims, methods, anticipated benefits and potential 
hazards of the trial.  
The person taking consent will be GCP trained, suitably qualified and experienced, and 
will have been delegated this duty by the CI/ PI on the Staff Signature and Delegation 
of Tasks. 
“Adequate time” must be given for consideration by the participant before taking part. 
Consent will be sought at least 24 hours after being given the study documentation. It 
must be recorded in the medical notes when the participant information sheet (PIS) has 
been given to the participant.  
The Investigator or designee will explain that participants are under no obligation to 
enter the trial and that they can withdraw at any time during the trial, without having to 
give a reason. 
No clinical trial procedures will be conducted prior to the participant giving consent by 
signing the Consent form. Consent will not denote enrolment into trial.  
A copy of the signed informed consent form will be given to the participant.  The original 
signed form will be retained in the trial file at site and a copy placed in the medical notes. 
The PIS and consent form will be reviewed and updated if necessary throughout the trial 
(e.g. where new safety information becomes available) and participants will be re-
consented as appropriate. 
 
 
 
 
  


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9. Trial procedures  
All procedures will be carried out as specified in this section and the schedule of 
assessments (appendix 1). 
9.1 Visit 0 Pre-Screening Assessments within 8 weeks prior to baseline visit 
(telephone) 
The pre-screening visit will occur within 8 weeks prior to the baseline visit.   
At this visit, the trial will be explained to participant and eligibility for the trial will be 
assessed using the pre-screening questionnaire.  
If the patient is eligible as per pre-screen entry criteria, they will be asked to return for 
baseline (Visit 1) assessments. 
9.2 
Visit 1 Screening/Baseline combined assessment (Day 0) 
At this visit (which may be conducted over two days), the following will be assessed:  
• Informed consent  
• Medical History & Contraindications 
• Physical examination & Medical review** 
• Vital signs inc. pulse, blood pressure, temperature  
• Concomitant medications 
• EDSS disability assessment 
• MSFC inc. 25FTW, 9HPT 
• SDMT 
• FAB 
• Questionnaires (MSIS-29v2, MSWsv2, EQ5D5L) 
• Safety Bloods (see section 11.1 for list of laboratory tests) 
• Bloods for Immunology and biomarkers 
• Urine pregnancy test for females of child bearing potential 
• MRI inc. ASL / Questionnaire 
• Modified Vascular Function Retinal Imaging Questionnaire 
• Visual assessment (likely to take place on day 2 of this visit) 
• Retinal Imaging (Advanced retinal imaging, OCT – likely to take place on 
day 2 of this visit) 
• Full eligibility assessment 


Short title: Simvastatin in Progressive MS   
 
 
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• Randomisation  (see section 10) 
• Drug dispensation at 40mg dose (see section 10.1) * .   
• Drug diary issued 
• Emergency telephone contact given 
Participants will be advised on the administration of the medication and will be given a 
study specific patient card which will have study title, IMP details, patient ID and 
contact details of the out of hours contact in cases of emergency (see section 9.3.6).  
A drug diary will also be issued for participants to document compliance to IMP.  
Participants will be reminded to bring the drug diary to the next visit. 
This visit will take place across two sites. Visit 1 assessments will take place over two 
days, one for each site with the option to complete all assessments on one day if 
feasible. Randomisation and drug dispensation will take place on day 1 of visit 1. 
* Study medication must only be dispensed after randomisation i.e. once all day 1 of 
visit 1 assessments (with the exception of visual assessment and advanced retinal 
imaging) have been completed and the relevant safety reports have been obtained.  
All eligibility criteria has to be fulfilled and no exclusion criteria must be identified. As 
the study medication is best taken in the evening and due to the volume of 
assessments required, it will be advisable for the patient to take study medication on 
the evening of day 2 of visit 1 (if visit 1 takes place over two days). For the purpose of 
safety, the study participant will be advised to contact the study team if a complication 
as a result of taking the study medication arises.  Possible adverse events and side 
effects will be included in the PIS.  
** Medical review will encompass any medical or MS-related symptoms that have 
arisen. 
9.3  Follow-up assessments 
9.3.1 Visit 2 (Week 4+1 week) 
 
• Recording of AEs and concomitant medications 
• Physical Examination & Medical Review** 
• Vital signs inc. pulse, blood pressure, temperature  
• Safety bloods (see section 11.1 for list of laboratory tests) 
• Bloods for Immunology and biomarkers 
• Drug compliance (pill count and drug diary review)  
• Uptitration of drug at 80mg dose.   
• MRI appointment for next visit booked/date confirmed with patient 


Short title: Simvastatin in Progressive MS   
 
 
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• Retinal imaging appointment for next visit booked/date confirmed with patient 
• Patient reminded to bring diary card, trial medication bottles with unused trial 
medication back for the next visit. 
** Medical review will encompass any medical or MS-related symptoms that have 
arisen. 
If a patient is unable to attend the clinic at week 4 or within the visit window, a TC will 
be arranged to check for AEs and acceptability to uptitrate and an appointment 
nearest to the timeframe will be scheduled. 
9.3.2  End of Study treatment visit (Week 16 +1 week) 
At this visit, any remaining study medication will be returned to site pharmacy. 
• Recording of AEs and concomitant medications 
• Physical Examination & Medical Review** 
• Vital signs inc. pulse, blood pressure, temperature  
• EDSS disability assessment 
• MSFC inc. 25FTW, 9HPT 
• SDMT 
• Questionnaires (MSIS-29v2, MSWsv2, EQ5D5L) 
• Safety Bloods (see section 11.1 for list of laboratory tests) 
• Bloods for Immunology and biomarkers 
• Urine pregnancy test for females of child bearing potential 
• MRI inc. ASL questionnaire follow-up 
• Retinal Imaging Vascular Function Questionnaire 
• Retinal Imaging (Advanced retinal imaging, OCT) 
• Drug compliance (pill count and drug diary review)  
• MRI appointment booked/date confirmed with patient 
• Retinal imaging booked/date confirmed with patient 
As at screening/baseline (visit 1), the assessment will take place across two sites. All 
assessments will take place over two days, one for each site with the option to 
complete all assessments on one day if feasible. 
** Medical review will encompass any medical or MS-related symptoms that have 
arisen. 
If a patient is unable to attend the clinic within the visit window, a TC will be arranged 
to check for AEs and an appointment nearest to the timeframe will be scheduled. 


Short title: Simvastatin in Progressive MS   
 
 
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9.3.3 End of Study Follow-up (Week 20+2 weeks) 
The following assessments will be covered: 
• Recording of AEs and concomitant medications 
• Physical Examination & Medical Review** 
• Vital signs inc. pulse, blood pressure, temperature  
• EDSS disability assessment 
• MSFC inc. 25FTW, 9HPT 
• SDMT 
• FAB 
• Questionnaires (MSIS-29v2, MSWsv2, EQ5D5L) 
• Safety Bloods(see section 11.1 for list of laboratory tests) 
• Bloods for Immunology and biomarkers 
• Urine pregnancy test for females of child bearing potential 
• MRI inc. ASL questionnaire follow-up 
• Retinal Imaging Vascular Function Questionnaire 
• Retinal Imaging(Advanced retinal imaging, OCT) 
As at screening/ baseline (visit 1) and end of study treatment visit, the assessment 
will take place across two sites. All assessments will take place over two days, one 
for each site with the option to complete all assessments on one day if feasible. 
** Medical review will encompass any medical or MS-related symptoms that have 
arisen. 
 
9.3.4 Unscheduled visits (Between V1-EOS Follow-up) 
Participants will be instructed to contact the local study team between scheduled visits 
should they suspect a relapse or any adverse events that are deemed serious or 
require further examination. An unscheduled visit (either for or not for a relapse) can 
occur at the local study team’s discretion and the following will be assessed and 
recorded:  
• Recording of AEs and concomitant medications 
• Physical Examination & Medical Review** 
• Vital signs inc. pulse, blood pressure, temperature  
• EDSS disability assessment 
• Safety Bloods(see section 11.1 for list of laboratory tests) 


Short title: Simvastatin in Progressive MS   
 
 
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** Medical review will encompass any medical or MS-related symptoms that have 
arisen. 
9.3.5 Telephone Follow-up (As required) 
Participants may be contacted by a member of the trial team if there are safety 
concerns or updates to the trial.  As stated in appendix 1, the participant as standard 
will be asked if they have any side effects (as listed in section 4), concomitant 
medications and adverse events will also be checked. Medical review and drug 
compliance will be dependent on the circumstances of the participant and the 
timepoint in the study. 
9.3.6 Procedure for emergency telephone contact 
An emergency phone will be kept by a medically qualified member of the study team 
on rotation.  They will then advise the patient as per seriousness of the medical 
emergency as to how they should proceed e.g. A&E admission.   
10. Randomisation Procedures  
Randomisation will take place at Visit 1. Participants are considered to be enrolled into 
the trial following consent and the completion of all entry-criteria assessments (carried 
out on day 1 of visit 1). It may not be possible to complete all visit 1 assessments in 
one day so visit 1 may occur over 2 days. Randomisation will take place on day 1 of 
visit 1. The entry-criteria assessments at visit 1 will be prioritised for the purpose of 
randomisation on day 1 of visit 1, with the advanced retinal imaging and visual 
assessments (not required to confirm eligibility for the study) carried out on day 2 of 
visit 1 after randomisation (when visit is across 2 days). The patient will be instructed 
not to take the study medication until all study assessments are completed on day 2 of 
visit 1. If visit 1 is completed over 1 day, the patient can take study medication on the 
evening when all visit assessments are complete. 
Screening/baseline visit and eligibility criteria form and randomisation will be 
performed via an on line system hosted by a specialist company 
(www.sealedenevelope.com) who will hold the randomisation list (to conceal actual 
treatment allocation to the research team) and provide 24/7 randomisation services. 
Detailed instruction on logging in and randomising participants on this system is in the 
randomisation SOP.   After randomisation, the site research team will be given a 
unique trial randomisation number via email from sealedenvelope.com. Randomisation 
details of patients will be entered on a trial subject enrolment log and the participant 
will be given a study specific patient card which will have study title, IMP details, 
patient ID and contact details of the out of hours contact in cases of emergency. 
Section 21.3 describes how assignment to treatment groups will be done and the 
statistical methods used to generate randomisation. 


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10.1 Treatment Schedule 
The starting dose at baseline will be 40mg of Simvastatin or placebo (one tablet) to be 
taken orally in the evening.  This will be up-titrated at Visit 2 (week 4) to 80mg (two 
tablets) if all safety parameters have been met at visit 2. 
Participants will be allocated one bottle each containing 220 tablets for the duration of 
the study. There will therefore be one drug dispensation at baseline and the patient will 
be reminded to up titrate after one month at Visit 2.   
10.2  Dose Modifications 
If the participant is able to tolerate the 40 mg dose, after 4 weeks they will be uptitrated 
to 80 mg. If the participant is unable to tolerate the 40 mg dose at 4 weeks or at any 
point during the study, the medication will be withdrawn (e.g. any significant side effect 
as listed in section 4). If the participant is able to tolerate the 40 mg but not the 80 mg 
dose, then the participant will continue on this dose until the end of the study.  They will 
then be re-approached at week 12 to uptitrate to 80mg if tolerated.  If this is not tolerated, 
they will remain on 40 mg until the end of study.  
Participants who were unable to tolerate the 40 mg dose at 4 weeks, and were 
withdrawn at this stage, will be re-approached to re-start the drug at 40 mg at week 12.  
Those participants who were unable to tolerate 40 mg beyond 4 weeks will have their 
study medication withdrawn and not re-approached at week 12.  
This assessment will be made by the treating physician. The final decision will be 
made by the CI. The uptitration is to ensure that the end of study MRI is conducted on 
treatment.  
See section 14.2 for treatment stopping rules. 
 
11 Laboratory Assessments and Procedures 
11.1  Local laboratories  
The following tests will be carried out at Central Laboratories (Institute of 
Ophthalmology).  
Blood samples from these patients will be taken at baseline and at weeks 4, 16 and 20 
to investigate the effect of statins on vascular leakage and free radical damage. 
Biomarkers will be determined as follows: (i) For RNA/DNA oxidative damage serum 
levels of 8-hydroxyguanosine (8-OHG)/8-hydroxydeoxyguanosine (8-OHdG); (ii) 
Protein oxidative damage will be determined by assaying plasma proteins for 
nitrotyrosine and carbonyl content; and (iii) Detection of lipid oxidative damage by 
assaying for the advanced lipid peroxidation end products 4-hydroxynonenal (4-HNE 


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or HNE), malondialdehyde (MDA), 8-iso-prostaglandin F2α and thiobarbituric acid 
reactive substances (TBARS) (Miller et al., 2012).  
 
All assays will be conducted using standard commercial kits (Cell Biolabs). To 
determine dysfunction of the blood-brain barrier (BBB) circulating levels of S100B and 
ubiquitin C-terminal hydrolase 1 (UCHL1) will be measured. Detection will be through 
the use of commercially available ELISA kits. In addition circulating cholesterol levels 
will be determined. 
 
Details on handling, processing, storage and shipment of these samples are in the 
laboratory SOP. 
 
The following safety blood tests will be carried out at Local Laboratories (Queens 
Square):  
BLOOD: 
Analyte 
Units 
SODIUM 
mmol/L 
POTASSIUM 
mmol/L 
CHLORIDE 
mmol/L 
UREA 
mmol/L 
CREATININE 
umol/L 
BILIRUBIN 
Umol/L 
ALKALINE PHOSPHATASE 
IU/L 
ALANINE TRANSFERASE 
IU/L 
CK 
IU/L 
TOTAL PROTEIN 
g/L 
ALBUMIN 
g/L 
GLOBULIN 
g/L 
TRIGLYCERIDES 
mmol/L 
CHOLESTEROL 
mmol/L 
HDL CHOLESTEROL 
mmol/L 
LDL CHOLESTEROL 
mmol/L 
ESTIMATED GFR 
mL/min/1.73sqm 
THYROID STIMULATING HORMONE 
mIU/L 
HAEMOGLOBIN 
g/L 
HCT 
% 
RED CELL COUNT 
x10^12/L 
MCV 
fL 
MCHC 
g/L 
RDW 
 


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Analyte 
Units 
PLATELET COUNT 
x10^9/L 
MPV 
fL 
WHITE CELL COUNT 
x10^9/L 
NEUTROPHILIS 
x10^9/L 
LYMPHOCYTES 
x10^9/L 
MONOCYTES 
x10^9/L 
EOSINOPHILIS 
x10^9/L 
BASOPHILIS 
x10^9/L 
 
URINE: 
Urine analysis: Pregnancy test (dipstick) 
12. Clinical Procedures and Data Collection 
Clinical examination will include:  
 
Clinician observed expanded disability status score (EDSS) is a method of quantifying 
disability in MS and records changes in disability over time. The EDSS scale ranges 
from 0 (no disability) to 10 (death due to MS) in 0.5 unit increments that represent 
higher levels of disability. Scoring is based on an examination by a neurologist and 
encompasses pyramidal, cerebellar, brainstem, sensory, bowel/bladder function in 
addition to visual, cerebral and other functions. 
 
MSFC inc. 9HPT, 25TFW, PASAT comprises quantitative functional measures of three 
key clinical aspects of MS: leg function/ambulation (25TFW), arm/hand function 
(9HPT), and cognitive function/working memory (PASAT). However, PASAT will not be 
performed in this study as the SDMT is able to measure this component. 
 
Frontal Assessment Battery (FAB) is a concise cognitive test in neurodegenerative 
disease with frontal involvement.  
 
Symbol Digit Modalities Test (SDMT) is measure of cognitive impairment. The subject 
is asked to match single digits to symbols using a key as a guide that pairs the 
numbers to the symbols. They are presented with a page headed by a key that pairs 
the single digits 1–9 with nine symbols and they then write or orally report their 
responses in a scoring form. It can be administered in oral and written form and is 
timed and guided by a trained examiner ie. suitably qualified member of the research 
team.  
 
Patient reported multiple sclerosis impact scale version 2 (MSIS-29v2) is a self-
administered questionnaire that asks to what degree the impact of MS has on a 
person’s day-to-day life during the past two weeks.  


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Patient reported Multiple Sclerosis Walking Score version 2 (MSWSv2) is a self-
administered questionnaire that measures walking performance. 
 
Concomitant medication: all over-the counter or prescription medication, vitamins, 
and/or herbal supplements will be recorded. 
 
MRI is a non-invasive test that produces detailed images of the brain utilising magnetic 
field and radio waves, without radiation.  
In this study we will use ASL, a sophisticated MRI technique that measures brain 
cerebral blood flow, which is a process of delivering blood and nutrients to the capillary 
beds of the brain and the time taken by blood to reach the capillary bed.  
We will also measure brain tissue loss and quantify lesion load.  
 
All will be measured over time to determine any changes. 
 
MRI ASL questionnaire: Brain perfusion is affected by numerous factors related to 
demographics, physiology, lifestyle, diet and medication use which in turn can affect 
the MRI analysis. This questionnaire will measure the impact of these factors on MRI. 
Retinal Imaging Vascular Function Questionnaire: This is an abbreviated version of the 
ASL questionnaire to be provided on the day of retinal imaging. This questionnaire 
accounts for caffeine, tobacco, alcohol and sleep effect. 
Advanced retinal imaging including OCT and AOSLO. The light sensitive layer of the 
back of the eye, the retina, can be affected in MS and we can image this layer in a 
number of non-invasive ways. OCT is a method of imaging the retina using light. 
Similar to ultrasound, an OCT device shines light into the eye and detects the light 
which is returned, allowing us to “see” the retinal layers of the back of the eye in cross 
section. The same technique can be used to see the blood vessels of the retina and 
form a map of their locations, known as OCT Angiography. The quality of our images 
using these techniques is impeded by small optical changes which occur in everyone’s 
eyes. These small changes can be adjusted for using an “adaptive optics” imaging 
device, which allows us to look at the smallest blood vessels and cells in the retina in 
real time. We can also use standard colour photography techniques to take photos of 
the retinal vessels at different light wavelengths, which allows us to visualise oxygen 
levels within these blood vessels. 
12.1 Assessment of IMP/NIMP compliance 
Noncompliance to the Protocol study procedures will be documented by the 
investigator and reported to the Sponsor as agreed. Persistent noncompliance may 
lead the patient to be withdrawn from the study.  If a participant is 80% non-compliant 
as measured by the drug diary, then they will be withdrawn from treatment. 
 


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13. Monitoring 
13.1    Study Monitoring 
The sponsor will determine the appropriate level and nature of monitoring required for 
the trial.  Risk will be assessed on an ongoing basis and adjustments made accordingly. 
The degree of monitoring will be proportionate to the objective, purpose, phase, design, 
size, complexity, blinding, endpoints and risks associated with the trial. A trial specific 
oversight and monitoring plan will be established for studies. The trial will be monitored 
in accordance with the agreed plan. 
13.2 Recording of subject compliance information 
A drug diary will be kept by the participant and completed on a daily basis for the 
duration of the study. 
 
14. Discontinuation/withdrawal of participants 
14.1 Protocol Treatment Discontinuation 
In consenting to participate in the trial, participants are consenting to trial treatment, 
assessments, follow-up and data collection.  
14.2 Discontinuation of Trial Treatment for clinical reasons 
A participant may be withdrawn from trial treatment whenever continued participation is 
no longer in the participant’s best interests, but the reasons for doing so must be 
recorded.  Reasons for discontinuing treatment may include: 
1 
disease progression whilst on therapy 
2 
unacceptable toxicity (e.g. toxicity as listed in section 4 e.g. LFT >3x ULN) 
3 
intercurrent illness which prevents further treatment 
4 
patients withdrawing consent to further trial treatment (see section 14.3) 
5            Any alterations in the participant’s condition which justifies the 
           discontinuation of treatment in the site investigator’s opinion 
6 
Persistent non-compliance to protocol requirements 
7 
Patient unable to tolerate 40 mg Simvastatin 
The decision to withdraw a participant from treatment must be recorded in the CRF and 
medical notes, and the sponsor when required should be notified in writing. 


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In these cases participants remain within the trial for the purposes of follow-up for safety 
and or data analysis according to the treatment option to which they have been 
allocated. 
14.3 Participant withdrawal from trial treatment 
In consenting to the trial, participants are consenting to trial treatments, trial follow-up 
and data collection.  If a participant expresses their wish to withdraw from trial 
treatment, sites should explain the importance of remaining on trial follow-up and seek 
permission to allow use of routine follow-up data to be used for trial purposes. The 
importance of safety follow-up is explained in the participant in the Participant 
Information Sheet.  
As participation in the trial is entirely voluntary, the participant may choose to 
discontinue trial treatment at any time without penalty or loss of benefits to which they 
would otherwise be entitled. Although not obliged to give a reason for discontinuing 
their trial treatment, a reasonable effort should be made to establish this reason, whilst 
remaining fully respectful of the participant’s rights. If the participant gives a reason for 
their withdrawal, this should be recorded in the CRF and medical notes. 
 
Participants who discontinue protocol treatment, for any of the above reasons, should 
remain in the trial for the purpose of follow-up and analysis. 
If a participant is lost to follow-up at a site every effort should be made to contact the 
participant’s GP to obtain information on the participant’s status 
14.4 Withdrawal of Consent to Data Collection  
If a participant explicitly states they do not wish to contribute further data to the trial 
their decision must be respected and recorded in the CRF and medical notes. 
14.5 Replacements 
Participants who stop trial follow-up early will not be replaced. 
14.6 Stopping rules  
The trial may be stopped before completion for the following reasons: 
 
On the recommendation of the Independent Data Monitoring Committee (IDMC)  
 
On the recommendation of the sponsor and CI 
 
If a participant is unable to tolerate Simvastatin at 40mg or 80mg dosage (see 
section 10.2).  


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14.7 Definition of End of Trial 
• The expected duration of the trial is 2 years from recruitment of the first 
participant. 
• The end of trial is defined as the date when sample analysis for Immune 
Parameters and Biomarkers has been completed. 
 
15. Recording and reporting of adverse events and reactions 
Collection, recording and reporting of adverse events (including serious and non-serious 
events and reactions) to the sponsor will be completed according to the sponsor’s SOP 
(INV/S05). 
15.1 Definitions 
Table 1: Adverse Event Definitions 
Adverse Event 
(AE) 
Any untoward medical occurrence in a patient or 
clinical trial participant administered a medicinal 
product and which does not necessarily have a 
causal relationship with this treatment. Therefore an 
AE can be any unfavourable or unintended change 
in the structure (signs), function (symptoms) or 
chemistry (laboratory data) in a participant to who an 
IMP or procedural intervention has been 
administered, including occurrences which are not 
necessarily caused by or related to that product. 
Adverse Reaction 
(AR) 
Any untoward and unintended response in a 
participant to an investigational medicinal product 
which is related to any dose administered to that 
participant.  
This includes medication errors, uses outside of 
protocol (including misuse and abuse of product 
Serious Adverse 
Event (SAE), 
Serious Adverse 
Reaction (SAR) or 
Unexpected 
Serious Adverse 
Reaction 
Any adverse event, adverse reaction or unexpected 
adverse reaction, respectively, that: 
• 
results in death, 
• 
is life-threatening*, 
• 
requires hospitalisation or prolongation of 
existing hospitalisation**, 


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• 
results in persistent or significant disability or 
incapacity, or 
• 
consists of a congenital anomaly or birth defect 
*A life- threatening event, this refers to an event in 
which the participant was at risk of death at the time 
of the event; it does not refer to an event which 
hypothetically might have caused death if it were 
more severe. 
** Hospitalisation is defined as an in-patient 
admission, regardless of length of stay. 
Hospitalisation for pre-existing conditions, including 
elective procedures do not constitute an SAE.” 
*A life- threatening event, this refers to an event in which the participant was at risk 
of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
** Hospitalisation is defined as an in-patient admission, regardless of length of 
stay. Hospitalisation for pre-existing conditions, including elective procedures do 
not constitute an SAE. 
Unexpected 
Adverse Reaction 
(UAR) 
An adverse reaction the nature and severity of which is 
not consistent with the information about the medicinal 
product in question set out: 
(a) in the case of a product with a marketing 
authorization, in the summary of product 
characteristics for that product,  
(b) in the case of any other investigational 
medicinal product, in the investigator's 
brochure relating to the trial in question. 
Suspected 
Unexpected 
Serious Adverse 
Reaction (SUSAR) 
• An unexpected adverse reaction which is also 
categorised as serious. 
Important Medical 
Event 
These events may jeopardise the participant or may 
require an intervention to prevent one of the above 
characteristics/consequences. Such events should 
also be considered ‘serious’. 
 
15.2 
Recording adverse events 


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All adverse events following IMP administration will be recorded in the medical records 
in the first instance. As simvastatin is a licensed product with a well-established safety 
profile, AEs that are non–serious or MS related (see section 15.5 for MS expected 
adverse events) will be recorded in the source data (Medical records and Participant 
diary cards) only.  
All adverse events will be recorded with clinical symptoms and accompanied with a 
simple, brief description of the event, including dates as appropriate.  
Clinically significant abnormalities in the results of objective tests (e.g. laboratory 
variables) will also be recorded as adverse events in the medical notes and if are 
assessed as serious they will also be recorded on the SAE log and in the CRF.  If these 
events are not expected as part of disease or IMP, these will be recorded as unexpected. 
All adverse events will be recorded until 6 weeks after the participant’s final  clinical visit 
(EOS). 
15.3 Assessment of Adverse Events 
Each adverse event will be assessed for severity, causality, seriousness and 
expectedness as described below. 
15.3.1 Severity 
Severity or grading of AEs 
Grade 
Degree of Severity 
1 
Mild, with mild or no symptoms; no 
interventions required 
2 
Moderate; minimal intervention indicated; 
some limitation of activities 
3 
Severe but not life threatening; hospitalisation 
required; limitation of patient’s ability to care 
for him/herself 
4 
Life threatening; urgent intervention required 
5 
Death related to adverse event 
 
15.3.2 Causality 
The assessment of relationship of adverse events to the administration of IMP is a 
clinical decision based on all available information at the time of the completion of the 
case report form.   


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The following categories will be used to define the causality of the adverse event: 
Category 
Definition 
Definitely: 
There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. 
Probably: 
There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the 
event occurred within a reasonable time after administration of the 
trial medication). However, the influence of other factors may have 
contributed to the event (e.g. the participant’s clinical condition, 
other concomitant events). 
Unlikely 
There is little evidence to suggest there is a causal relationship 
(e.g. the event did not occur within a reasonable time after 
administration of the trial medication). There is another reasonable 
explanation for the event (e.g. the participant’s clinical condition, 
other concomitant treatments). 
Not related 
There is no evidence of any causal relationship. 
Not 
Assessable 
Unable to assess on information available. 
 15.3.3 
Expectedness 
Category 
Definition 
Expected 
An adverse event which is consistent with the information about 
the IMP listed in the Investigator Brochure (or SPC if Licensed 
IMP) or clearly defined in this protocol. 
Unexpected An adverse event which is not consistent with the information 
about the IMP listed in the SPC * or clearly defined in this 
protocol. 
* this includes listed events that are more frequently reported or more severe than 
previously reported 
 
The reference document to be used to assess expectedness against the IMP is the 
SPC for Simvastatin 40mg film coated tablets (Sandoz Limited) 
The following events listed below describe expected procedural related AEs:  


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• MRI is generally well tolerated. There can occasionally be some discomfort 
and/or claustrophobia.   
 
• Discomfort from glare with optical imaging. 
15.3.4  Seriousness 
All events are assessed for seriousness as defined for an SAE in section 15.1.  
15.4 Procedures for recording and reporting Serious Adverse Events 
All serious adverse events (SAEs/SARs/SUSARs) will be recorded in the medical 
records and the CRF, and the sponsor’s SAE log.  The SAE log of SAEs will be reported 
to the sponsor at least once or twice per year in liaison with JRO Pharmacovigilance 
Manager. 
All SAEs will be recorded from the time of the first enrolled participant’s drug release (at 
Visit 2) until 6 weeks post-treatment (defined as six weeks beyond end of treatment). 
All SAEs (except those specified in section 15.5 as not requiring reporting to the 
Sponsor), must be recorded on a serious adverse event (SAE) form. The CI/PI or 
designated individual will complete the sponsor’s SAE form and email the form to the 
Sponsor at SAE@ucl.ac.uk within 24 hours of his / her becoming aware of the event. 
The Chief or Principal Investigator will respond to any SAE queries raised by the sponsor 
as soon as possible. 
 
 
 
 
 
 
Reporting to the sponsor will be completed as per the sponsor’s SOP and using the UCL 
SAE form (INV/S05) as amended for the trial.   
SAE’s will be reported to the sponsor until the end of the trial. SAR and SUSAR will need 
to be reported to the Sponsor irrespective of how long after IMP administration the 
reaction has occurred. 
Participants must be followed up until clinical recovery is complete and laboratory results 
have returned to normal or baseline values, or until the event has stabilised. Follow-up 
should continue after completion of protocol treatment and/or trial follow-up if necessary.  
Follow-up SAE forms (clearly marked as follow-up) should be completed and emailed 
to the JRO as further information becomes available. 
Completed SAE forms must be sent within 24 hours of becoming 
aware of the event to the Sponsor  
Email forms to SAE@ucl.ac.uk  


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15.4.1  
Flow Chart for SAE reporting  
 
 
No 
Yes
Is the event specified as an adverse event which does not require immediate reporting as an SAE?  
No 
Was the event an Other 
Notifiable event?  
 
See section 15.3 for notifiable 
events which should also be 
reported as serious 
Assign Severity Grade 
AE occurs 
Record in medical records, CRF (and AE Log if required)  
Complete an SAE report form 
Record in medical records,  
And CRF in accordance with the protocol  
Record in medical records and 
CRF (if applicable) 
 
Was the event Serious? 
Criteria: 
Results in death 
Is life threatening  
Results in persistent significant disability/incapacity 
Results in a congenital anomaly or birth defect 
Requires in-patient hospitalisation or prolongs existing 
hospitalisation  
Is otherwise medically significant  
Submit SAE form to Sponsor within 24 hours 
Email forms to SAE@ucl.ac.uk  
No 
Yes 
Completed Pregnancy Reporting Forms must be sent within 24 hours of becoming aware 
of the event to the Sponsor (Email forms to SAE@ucl.ac.uk) 
Yes 


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15.5 Serious Adverse Events which do not require immediate reporting 
SPMS and PPMS are progressive neurological conditions and as such deterioration in 
neurological symptoms is expected. Symptoms of MS disease progression will be 
RECORDED in the participants’ medical notes and in the CRF. However, SAE forms 
will not be completed and sent to the sponsor.  The following SAEs are deemed as 
symptoms of MS disease progression and do not require immediate reporting:  
• natural changes in motor, sensory, balance, sphincter (including urinary tract 
infections), visual, cognitive and fatigue levels 
Symptoms of disease progression will be graded as follows: 
Grade 1 relapse: relapse not treated with corticosteroids 
Grade 2 relapse: relapse treated with corticosteroids, but not requiring hospitalisation 
Grade 3 relapse: relapse treated with corticosteroids and requiring in-patient 
hospitalisation; or relapse not treated with corticosteroids but requiring in-patient 
hospitalisation 
If the participant feels they are experiencing a relapse, they should contact their local 
MS team (nurse/consultant) or General Practitioner as per routine practice, so that 
appropriate management can occur. They should also inform the study team at their 
next scheduled visit, so that the relapse can be documented. At the 
Investigator’s/nurse’s discretion the patient can attend for an unscheduled visit, see 
section 9.3.4. 
If the frequency or severity of these symptoms is not consistent with the SPC or disease 
the event must be reported to the sponsor as an SAE in the normal way 
15.6 Notification of Deaths 
All deaths will be reported to the sponsor.  This report will be immediate. 
15.7 Reporting SUSARs 
The sponsor will notify the main REC and MHRA of all SUSARs.  SUSARs that are fatal 
or life-threatening must be notified to the MHRA and REC within 7 days after the sponsor 
has learned of them.  Other SUSARs must be reported to the REC and MHRA within 15 
days after the sponsor has learned of them.   
15.8 Unblinding  
As this is a double-blind trial, the option to unblind treatment is essential. This will only 
occur for a participant when it is felt necessary to do so on clinical grounds. Only 
authorised users, eg. An unblinded pharmacist, will be issued with an unblinding 
account via ‘Sealed Envelope’. Other access will be at the discretion of the chief 
investigator. 
 


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In the event of an emergency, the unblinding service will be available 24 hours a day, 7 
days a week and will be appropriately backed up.  
15.8.1 Emergency Unblinding  
The trial code will only be broken for valid medical or safety reasons e.g. in the case of a 
severe adverse event where it is necessary for the investigator or treating health care 
professional to know which treatment the participant is receiving before the participant 
can be treated. Subject always to clinical need, where possible, members of the research 
team should remain blinded. 
 
The code breaks for the trial are held at www.sealedenevelope.com  
In the event that unblinding is required a formal request will be made by the 
Investigator/treating health care professional to an individual authorised and delegated to 
perform code break. 
 
If the person requiring the unblinded information is a member of the Investigating team 
then a request to the authorised individual to unblind will be made and the treatment 
allocation information obtained.  
 
If the person requiring the unblinded information is not the CI/PI then that healthcare 
professional will contact the Investigating team to request the code break. Unblinding will 
take place if in the opinion of a treating physician a patient’s health is compromised.  The 
authorised individual will break the code and immediately inform the treating healthcare 
professional of the participant’s treatment allocation. The treating physician has the 
ultimate decision and right to unblind the patient. 
 
On receipt of the treatment allocation details the CI/PI or treating health care professional 
will treat the participant’s medical emergency as appropriate.  
 
The CI/PI will document the breaking of the code and the reasons for doing so on the 
CRF and unblinding log and will file this, in the site file and medical notes. It will also be 
documented at the end of the trial in any final trial report and/or statistical report. 
 
The CI/Investigating team will notify the JRO in writing as soon as possible following the 
code break detailing the necessity of the code break.  
 
The written information will be disseminated to the Trial Management Group. 
 
For detail instructions on unblinding, please refer to ‘Unblinding SOP’ for further details.   
15.8.2 Unblinding for the submission of SUSAR reports  
The following procedure will be used to unblind for the submission of a SUSAR report to 
the regulatory agencies. 
1. A representative of the Sponsor will be authorised to access the code break 
system [setup through specialist ‘Sealed Envelope’] for the purposes of unbinding 
for the submission of a SUSAR. 
2. The Sponsor will follow the SOP on unblinding. 


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3. On receipt of the treatment allocation, the Sponsor will provide the unblinded 
information on the e-SUSAR website form.  
4. Unblinded information in the SUSAR reports will not be forwarded to the trial 
team and kept in the JRO sponsor file. 
5. SUSAR reports will be disseminated to Investigators at site(s) but will remain 
blinded. 
6. The unblinded information will not be forwarded to the trial team and will be kept 
in the JRO sponsor file. 
Sealed Envelope provides a comprehensive randomisation system via secure SSL 
connections and the randomisation application conforms to the requirements of FDA 21 
CFR part 11, Electronic Records; Electronic Signatures and ICH GCP. User accounts are 
by invitation only and are created and managed by a designated administrator. In 
addition, no one can delete records from the randomisation database, so all 
randomisations have to be accounted for and audit log files detailing all activity on the 
randomisation system are available to the trial manager. 
16. Development Safety Update Reports 
The sponsor will provide the main REC and the MHRA with Development Safety Update 
Reports (DSUR) which will be written in conjunction with the trial team and the Sponsor’s 
office. The report will be submitted within 60 days of the Developmental International Birth 
Date (DIBD) of the trial each year until the trial is declared ended. 
17. Pregnancy 
If a female participant or the female partner of a male participant becomes pregnant at 
any point during the trial, a completed trial specific Pregnancy Reporting Form will be 
emailed to the Sponsor at SAE@ucl.ac.uk within 24 hours of his / her becoming aware of 
the event in line with the Sponsors SOP (JRO/INV/S05). The Chief or Principal 
Investigator will respond to any queries raised by the sponsor as soon as possible.   
 
The Sponsor must be kept informed of any new developments involving the pregnancy 
through the completion of a follow-up Pregnancy Reporting Form. Any pregnancy that 
occurs in a female trial subject during a clinical trial should be followed to termination or 
to term. 
 
Consent to report information regarding the pregnancy and follow up of a child born must 
be obtained from the pregnant participant or pregnant partner of a participant.  A trial-
specific pregnancy monitoring information sheet and informed consent form for trial 
participants and partners of trial participants must be used for this purpose.   
With consent additional information regarding the pregnancy will be collected and 
reported to the Sponsor, the Sponsor will advise on the length of follow up of the 
pregnancy/ child on a case by case basis. 


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18. Overdose  
The research team will record details of reported overdoses on the deviation log and 
inform UCL as soon as possible after being made aware of the information. Sources of 
information can include patient-reported, pill counts, diary cards and drug charts.  
 
In the event that an SAE is associated with the overdose, the SAE reporting procedure 
should be followed (section 15.3). Details of the overdose will documented in the SAE 
form.  
 
An overdose is defined as taking double the normal medication/day for 1 day or more. If 
an overdose has taken place, the patient will suspend medication for at least 48 hours, 
and resume the previous dose as soon as possible afterwards, at the discretion of the 
PI. The patient will continue in trial.  
To date, a few cases of overdosage have been reported; the maximum dose taken was 
3.6 g. All patients recovered without sequelae. There is no specific treatment in the 
event of overdose. In this case, symptomatic and supportive measures should be 
adopted. Source: 
https://www.medicines.org.uk/emc/product/4555/smpc#OVERDOSE 
 
19 
Reporting Urgent Safety Measures and other safety events 
If any urgent safety measures are taken the CI/ PI shall immediately and in any event no 
later than 3 days from the date the measures are taken, give written notice to the MHRA, 
the relevant REC and Sponsor of the measures taken and the circumstances giving rise 
to those measures. 
19.1 Notification of Serious Breaches to GCP and/or the protocol (SPON/S15)  
 A “serious breach” is a breach which is likely to effect to a significant degree – 
(a) the safety or physical or mental integrity of the participants of the 
trial; or 
(b) the scientific value of the trial. 
The sponsor of a clinical trial shall notify the licensing authority in writing of any serious 
breach of – 
(a) the conditions and principles of GCP in connection with that trial; or (b) 
the protocol relating to that trial, as amended from time to time, within 7 
days of becoming aware of that breach. 
The sponsor will be notified immediately of any case where the above definition applies 
during the trial conduct phase.  The sponsor’s SOP on the ‘Notification of violations, 
urgent safety measures and serious breaches’ will be followed.  
 


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20. Data management and quality assurance 
20.1 Confidentiality 
All data will be handled in accordance with the UK Data Protection Act 1998. 
The Case Report Forms (CRFs) and drug diaries will not bear the participant’s name or 
other personal identifiable data.  The participant’s initials, date of birth and trial 
identification number, will be used for identification and this will be clearly explained to 
the patient in the Patient information sheet.  Patient consent for this will be sought. 
20.2 Data collection tools and source document identification 
Data will be collected from sites on Trial specific paper case report forms (CRFs) will be 
provided for source documentation and an electronic excel database will act as the 
electronic CRF. 
Source data are contained in source documents and must be accurately transcribed on 
to the CRF. Examples of source documents are medical records which include laboratory 
and other clinical reports etc. 
A source document list will be implemented prior to the start of the trial to identify: 
- 
which data is to be recorded directly onto the CRF;  
- 
which data is recorded firstly into source documents, such as medical 
notes, and then transcribed into the CRF; and   
- 
which data is not to be recorded in the CRF but only recorded in source 
documents, e.g., participant questionnaires and diary cards.  
It is the responsibility of the investigator to ensure the accuracy of all data entered in the 
CRFs. The delegation log will identify all those personnel with responsibilities for data 
collection and handling, including those who have access to the trial database. 
All CRFs will be paper-based and used as source documentation.  Additional clinical 
information will be documented in the patient’s hospital notes. 
The paper CRFs will be stored at Queen Square Multiple Sclerosis Centre, Floor 1 of 
UCL Institute of Neurology.  This is a secure area only accessible by designated 
employees via an entry card system with additional security present at street access. 
All efforts will be made to provide complete data (eg. telephoning patients with missing 
data or attempts to obtain clarification on data at follow-up visits).   
20.3 Completing Case Report Forms  
All CRFs must be completed and signed by staff that are listed on the site staff delegation 
log and authorised by the CI to perform this duty.  The CI is responsible for the accuracy 
of all data reported in the CRF.  A PDF file will be periodically obtained and filed from the 
excel database that act as eCRF to record any changes to the data.  


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20.4 Data handling and analysis 
A trial specific data management SOP will be in place for the trial. This will contain more 
details of the database software, the process of database design, data entry, data 
quality checks, data queries, data security, database lock and any data transfer if 
applicable 
 
This will be in accordance with the UK Data Protection Act 2018 as well as UCL 
Information Security Policy and Trust Information Governance Policy.  There will be a 
documented record of data transfer and measures in place for the recovery of original 
information after transfer. 
 
21. Statistical Considerations  
21.1 Primary outcomes 
A sophisticated magnetic resonance imaging (MRI) technique, called arterial spin 
labelling (ASL), will be employed to evaluate the effect of high dose statin on brain 
haemodynamics. Specifically, patients on statin or placebo will be subjected to multiple 
delay time ASL to quantify arterial hemodynamic parameter bolus arrival time (BAT) and 
cerebral blood flow (CBF) in normal-appearing white matter (NAWM) and deep gray 
matter as previously described (Paling et al., 2014). ASL is an MRI method that allows 
non-invasive measurement of CBF using inversion of arterial water spins as a tracer. In 
a recent study (Paling et al., 2014) the Golay team has demonstrated alteration in cerebral 
arterial hemodynamics in MS, in particular an increase in cerebral blood flow (CBF) in 
NAWM (14.4±4.4 versus 10.1±2.1 mL/100 g per min, P<0.001), and a decrease in CBF 
in the deep gray matter (40.3±12.0 versus 46.0±5.7 mL/100 g/min, P<0.005) in patients 
with MS compared with controls. As such, we expect ASL to be able to detect subtle 
changes in CBF between baseline, 16 and 20 weeks between placebo and simvastatin 
treated patients in the current study, including potential waning of the effects of the drug 
over time.  
21.2 Secondary outcomes 
21.2.1 MRI parameters 
Total and regional grey matter volumes, including thalamic volumes, will be calculated, 
and changes in volumes over time using longitudinal VBM will be investigated.  


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21.2.2  Retinal imaging parameters 
21.2.2.1 
Vascular imaging 
As microvascular perfusion cannot be measured directly in most of the brain we will use 
the retina, as this is an accessible extension of the brain that lies outside the skull and 
thus lends itself to non-invasive imaging. Applicants Dr Adam Dubis and Professor John 
Greenwood (UCL Institute of Ophthalmology and Moorfields Eye Hospital) will lead this 
aspect of the study. We will use a purpose built microscope that enables us to focus on, 
and image in real time, retinal photoreceptors, retinal capillary microvessels and 
measure capillary flow dynamics at rest and under retinal stimulation (Chui et al, 2012; 
Dubra and Sulai, 2011; Sulai et al. 2014, Scoles et al, 2014, Zhong et al, 2008). 
Until recently the non-invasive visualisation of the smallest capillaries, blood cells and 
measurements of microvascular retinal blood flow in the CNS has not been possible. 
This is now achievable through coupling adaptive optics (AO) technology to current 
scanning light ophthalmoscopy (SLO) imaging capabilities. This results in an imaging 
system that overcomes the optical imperfections of the eye, providing near diffraction 
limited (2μm lateral resolution) viewing of the living human retina. These new confocal 
and non-confocal (split detection) imaging techniques now allow visualisation of the 
smallest capillaries and individual blood cells, including erythrocytes, moving through 
the vascular lumen. 
This ground-breaking development allows for more accurate calculations of retinal 
perfusion and blood flow levels at the capillary bed and this will be used to gain 
unprecedented insight into microvascular perfusion of the living human eye in healthy, 
diseased and treated patients. In conjunction with the imaging described above, we will 
determine relative retinal vessel oxygen saturation and vessel width with the Oxymap 
T1 installed on a conventional Topcon fundus camera, and obtain non-invasive wide-
field maps of both retinal (superficial and deep) and choroidal vascular plexuses using 
the optical coherence tomography angiography (OCTA). 
21.2.2.2 Neuronal imaging 
In addition to using the AOSLO to measure the vascular parameters described above, it 
will also be employed to obtain high-resolution retinal neuronal structural data including 
the retinal nerve fibre layer (RNFL), and rod and cone photoreceptor mosaics. We will 
also use spectral-domain OCT (SDOCT) to evaluate retinal lamination, total retinal 
thickness and inner retinal thickness (including RNFL thickness). 
This advanced retinal imaging approach will allow us to evaluate changes in both retinal 
microvasculature and neuronal integrity, determine any relationships, and compare this 
to other brain perfusion or structural measures. All measurements will require correction 
for retinal magnification, so axial length and corneal curvatures measures will be taken 
with Zeiss IOLmaster. 


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21.2.3  Lab Measurements 
21.2.3.1 Immune parameters 
In our previous study we determined multiple immune parameters in patients following 
6, 12, and 24 months of treatment and contrary to expectations found no change in 
those patients on 80mg/kg simvastatin. One reason for this may be that immune 
modulation by statins is temporary due to the induction of compensatory mechanisms. 
To test this, phenotypic markers will be investigated in whole blood specimens collected 
from placebo and statin treated patients at baseline and 1 month. This will investigate 
CD4+T cells intracellular cytokine expression (IFN-γ and IL-17) as markers of Th1 and 
Th17 T cell populations, respectively on unstimulated T cells and cells stimulated with 
phorbol 12-myristate 13-acetate (PMA) and ionomycin. The co-expression of CD4+ and 
intracellular expression of FoxP3 and IL-10 will be examined as markers of regulatory T 
cells.  
 
This component of the work will be led by Dr Virginia Calder (UCL Institute of 
Ophthalmology). 
21.2.3.2 Biomarkers 
Blood samples from these patients will be taken at baseline and at 16 weeks to 
investigate the effect of statins on vascular leakage and free radical damage. For 
determining the impact of statins on oxidative damage we will measure the following 
biomarkers: (i) For RNA/DNA oxidative damage we will determine serum levels of 8-
hydroxyguanosine (8-OHG)/8 hydroxydeoxyguanosine (8-OHdG); (ii) Protein oxidative 
damage will be determined by assaying plasma proteins for nitrotyrosine and carbonyl 
content; and (iii) Detection of lipid oxidative damage by assaying for the advanced lipid 
peroxidation end products 4-hydroxynonenal (4-HNE or HNE), malondialdehyde (MDA), 
8-isoprostaglandin F2α and thiobarbituric acid reactive substances (TBARS) (Miller et 
al., 2012).  
All assays will be conducted using standard commercial kits (Cell Biolabs). To establish 
whether there is dysfunction of the blood-brain barrier (BBB) and if so whether statins 
improve barrier function, we will measure circulating levels of S100B and ubiquitin C-
terminal hydrolase 1 (UCHL1). These biomarkers have been reported to increase in the 
serum following disruption of the BBB (Marchi et al., 2003; Blyth et al., 2011) and will be 
detected by commercially available ELISA kits. In addition we will measure changes in 
circulating cholesterol.  
This part of the study will be overseen by Professor John Greenwood of the UCL 
(Institute of Ophthalmology).  


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21.2.4 Other assessments 
21.2.4.1 MRI parameters 
In addition to ASL, we propose to explore the changes in the behaviour over time of 
conventional and advanced imaging measures, which may be influenced by the effects 
of simvastatin.  
 
We will combine the well-established imaging measures that reflect both 
neurodegeneration, such as brain grey matter atrophy, and neuro-inflammation, such as 
the number of new or enlarging T2 lesions, with novel measures (i.e., NODDI-derived 
measures and myelin maps), that have potential to detect more specific neuro-axonal 
abnormalities and metabolic changes, and any effects of simvastatin. 
 
These novel markers may provide complementary information to that given by the 
retinal microvascular study, ASL and clinical measures (see statistical paragraph below 
for a comment on the role of these measures). 
 
(1) Diffusion weighted imaging (DWI) is an MR imaging technique based upon the 
measurement of the random Brownian motion of water within a voxel of tissue. This 
technique has been used to analyse the microstructure of neuronal tissue in particular 
myelin and axonal integrity. Multi-shell DWI acquisition allows the use of several multi-
fibres and multi-shell modelling approaches, such as Diffusion Kurtosis Imaging (DKI) 
and Neurite Orientation Dispersion and Density imaging (NODDI), which have been 
successfully used to study patients with MS. It has been demonstrated that NODDI has 
higher sensitivity and specificity than standard Diffusion Tensor Imaging (DTI).  
 
(2) Macromolecular tissue volume (MTV) is a method of myelin mapping to determine 
the role of myelin loss or changes in progressive MS. With the macromolecular volume 
being made up of 50% myelin, we are able to use an in-house analysis pipeline to 
calculate the MTV - a surrogate marker of brain myelin volume. This metric, alongside 
diffusion weighted imaging will provide micro-structural detail into the cross-sectional 
and longitudinal changes occurring in the brain parenchyma of people with progressive 
MS. 
 
(3) Grey matter atrophy, which is significantly associated with long-term disability in 
SPMS (Fisniku et al., 2008) and correlates with physical disability better than white 
matter atrophy (Roosendaal et al.,2011). Our previous simvastatin trial demonstrated a 
reduction of 43% in the annualized rate of whole brain atrophy associated with the drug 
(Chataway et al., 2014), but the rate of grey matter atrophy was not assessed. The 
recent Lamotrigine trial in patients with SPMS demonstrated that the grey matter 
atrophy was greater than white matter atrophy (-1.18% per year vs. 0.12% per year), 
and was the only atrophy measure that correlated with clinical changes; in addition, no 
pseudo-atrophy was seen in the grey matter (Kapoor et al., 2010). Total and regional 
grey matter volumes, including thalamic volumes, will be calculated, and changes in 


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volumes over time using longitudinal VBM will be investigated. 
 
Atrophy measures will be performed at baseline 16 and 20 weeks to assess the rate of 
atrophy; the extra time point added after the end of the study (20 weeks) when patients 
are off treatment will allow us to take into account a possible reduced volume in patients 
on treatment which results from pseudo-atrophy, rather than lack of neuroprotective 
effects of simvastatin. With regard to the atrophy calculation, T2 and T1 weighted 
conventional scans will be also acquired to perform the lesion-filling technique that 
reduces the impact of white matter lesions on grey matter volume (Chard et al., 2010). 
 
(4) Number of new or enlarging T2 lesions, as surrogate markers for the inflammatory 
process, and number of new hypo-intense lesions seen on T1 weighted spin-echo, as a 
marker of tissue destruction. 
 
This part of the study will be led by Professor Olga Ciccarelli, NMR Unit, UCL Institute of 
Neurology. 
 
21.2.4.2 
Clinical measures 
 
(1) Clinician observed expanded disability status score (EDSS) 
 
(2) Clinician observed 25 foot timed walk and 9HPT as part of the MSFC 
assessment. 
 
(3) Patient reported multiple sclerosis impact scale version 2 (MSIS-29v2) 
 
(4) Patient reported Multiple Sclerosis Walking Score version 2 (MSWSv2). 
 
(5) Frontal Assessment Battery (FAB) and Single Digit Modality Test (SDMT). 
 
21.2.4.3 Health Economic outcomes 
A standard health economic measure will be applied, the EQ5D5L questionnaire. 
 
21.2.4.4 Retinal Imaging Metrics 
(1) Vascular imaging: adaptive optics and scanning light ophthalmoscopy (AOSLO) of 
retinal capillary microvessels (Dubra and Sulai, 2011; Sulai et al. 2014). This enables us 
to calculate retinal perfusion and measure blood flow dynamics at the capillary level. We 
will measure vein and arteriole wall thicknesses and erythrocyte occupancy in the 
capillaries. We will also look at how flow changes between resting and retinal stimulation 
(Zhong et al, 2008).  Briefly, this will be accomplished by flashing a dim light and looking 


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at how blood cell movements change and vessel walls expand.  Metrics will be occupancy 
before and after stimulation and vessel width before and after flashing. 
  
(2) Relative retinal vessel oxygen saturation and vessel width: using the Oxymap T1 
installed on a conventional Topcon fundus camera we will be able to measure relative 
venous and artery blood pO2 levels near the optic nerve (central 3 disk diameters).   
 
(3) Non-invasive wide-field maps of both retinal (superficial and deep) and 
choroidal vascular plexuses: using optical coherence tomography angiography 
(OCTA) vessel density and organisation (fractal dimension) will be assessed. 
 
(4) Spectral-domain OCT (SDOCT): to evaluate retinal lamination, total retinal 
thickness, inner retinal thickness (including RNFL thickness), outer retinal thickness and 
the inner and outer segment lengths. 
22. 
Sample size and recruitment 
22.1 Sample size calculation 
The power calculation (N=20 subjects per arm) is based on the ability to detect 
a 30% change in perfusion induced by statins at 0.8 power and 5% significance level. An 
expected mean grey matter CBF of 40 mL/100g per min and a standard deviation per 
subject of 12 mL/100g per min were chosen leading to N=17 per group. Accounting for 
drop-outs and problems in imaging patients (e.g. motion artefacts (20%) gives N=20 
subjects per group. A hypothetical increase in CBF by 30% was estimated based on a 
previous paper comparing the effects of normal doses of statins on healthy volunteers 
(Xu et al., 2008). Any potential regression to the mean, which was not accounted for 
above will lead to a lower number of subjects per arm being necessary.  
22.2 Planned recruitment rate 
Patients will be recruited over one year. Based upon a projected recruitment figure of 3-
4 patients per month, the target recruitment number (n=40) is expected to be achievable.  
This is supported by the large size of the MS patient population in the London area and 
the multi-site nature of the referral system working out of two MS specialist centres 
(Imperial College Healthcare NHS Trust & UCLH).  In addition, there is no licensed 
treatment currently available for the SPMS population.   
22.3 Randomisation methods 
This study will have a participant randomised design with equal allocation between 
treatment arms. Randomisation with a minimization algorithm will be used, using up to a 
maximum of four binary variables:  
• 
gender  


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• 
binary age (≤55/>55 years old) 
• 
binary disability (EDSS ≤ 5.0/>5.0) 
• 
binary progressive clinical phenotype (SPMS/PPMS) 
The cut-offs have been decided based on the literature: an age ≤ 55 years old was part 
of the inclusion criteria for the ORATORIO trial (ref: Montalban et al., NEJM 2016); in 
the same trial an EDSS score of 5.0 or lower was considered as ‘less disabled’, for 
which shorter disease durations were assumed/required to enter the trial (ref: 
Montalban et al., NEJM 2016). The study is exploratory and the number of subjects/arm 
is estimated based on established measures of within and between subject standard 
deviations using ASL, based on a large test-retest study (Petersen et al., 2010). 
Randomisation will be performed by the PI or delegated member of the clinical 
investigating team at local sites using the web-based randomisation service, Sealed 
Envelope. A random sequence for study arm allocation will be computer generated by 
Sealed Envelope providing a unique trial identification code for each recruited 
participant.  
Eligibility and consent will be verified before each patient is randomised. Study arm 
allocation into two treatment arms (1:1) will take into consideration these minimisation 
factors: 
Randomisation with minimisation will ensure comparability of the two study arms, and 
prevent selection bias. 
Sealed Envelope will generate unique identifiers for every active/placebo drug kit. The 
drug kit identification codes will be provided to Sealed Envelope and the Qualified 
Person (QP) at drug manufacturing site (Mode Pharma) who will ensure that trial drug 
and placebo packs are labelled appropriately, and that the trial team and participants 
remain blind to treatment allocation. At baseline, the investigator will enter the patient’s 
unique trial identification code into the SealedEnvelope.com website which will then 
provide the drug identification code of the active/placebo drug kit to be dispensed. 
Sufficient number of simvastatin/placebo drug kits will be provided to ensure availability 
of adequately labelled kits for Pharmacy dispensing. 
 
 
23. Statistical analysis plan 
23.1 Summary of baseline data and flow of participants 
 
 
 
 
Recruitment 
Pre-Screened for eligibility 


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23.2 Statistical Analysis Plan 
The stats analysis plan will be produced well in advance of seeing the data. It will 
specify both the primary analysis (in detail) and the secondary analyses (in less detail), 
including details of the analysis methods and any pre-specified covariates for 
adjustment such as the minimisation variables. It will also provide details of adverse 
events analyses and per-protocol analysis using adherence information. The analysis 
plan will describe contingency analysis should the assumptions of the primary methods 
not be satisfied by the data.  A CONSORT flow diagram will be produced. 
23.3 Primary outcome analysis 
The primary outcome ASL measured CBF will be compared between patients on 
simvastatin or placebo using multiple linear regressions at 16 weeks as the dependent 
variable, and age, gender or CBT at baseline and treatment group entered as covariates. 
Whenever the variable ‘treatment group’ is significant (at 5% significance level), it will be 
assumed that there is a treatment effect. The same models will be used to investigate the 
effect of simvastatin on the other imaging outcome measures.  
 
Checks for model assumptions:  
Combined Baseline/Screening  
 
Randomized 
Treatment Allocation 
Allocated to Simvastatin (n=20) 
 
Allocated to Placebo (n=20) 
 
Patients return for clinic assessments at week 4, 16, 20 and EOS follow-up 
with additional telephone safety follow-ups as per schedule of events (see 
appendix 1).  
Follow-Up 
       Data Analysed 


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For all regression-type approaches, we will assess the normality of the residuals (of 
each one of the fitted models) through q-q plots. Residual homoscedasticity will be 
assessed through two-way scatter plots of the residuals over fitted values. Once we 
build the model with all possible predictors as explanatory variables, the assumption of 
the linear relationship between the dependent variable and each one of the predictors 
individually, given the presence of the other predictors, will be assessed through 
investigating different functional forms of the predictor and their impact on the R2 of the 
model. The independence of observations will be always assumed.   
 
Violations of model assumptions:  
If the main assumption violated is that of homoscedasticity (i.e. there is residual 
heteroscedasticity), robust estimations of the standard errors (SE) of the regression 
parameters will be made, using the sandwich estimator of the SE. Whenever the 
residual distributions show a clear deviation from normality, bootstrap-based 
approaches will be used, with at least 1000 replication samples: bias-corrected and 
accelerated bootstrap-based 95% Confidence Intervals (95% CI) will be computed for 
each estimated parameter.  
23.4 Secondary outcome and other exploratory analyses  
Metrics for quantifying blood flow from retinal imaging are in development, and have not 
previously been applied in MS patients. Retinal vessel walls will be assessed in a similar 
fashion to that outlined by Chui et al (2013). Arterial wall thickness will be assessed as a 
function of lumen thickness. In the first instance normative data will be obtained from age 
matched controls prior to imaging patients with MS. Subsequently appropriate multigroup 
statistical tests will be applied. Capillary network density will be assessed using similar 
methods to those described by Tam et al., (2010). Calculating blood velocity will be done 
building up spatio-temporal analysis outlined by Tam et al., (2011). 
 
Exploratory analyses will be performed to assess the associations between ASL changes 
(dependent variable) and all secondary outcome measures (explanatory variables). An 
interaction term such as ‘secondary outcome measure change’ X ‘treatment group’ will 
be included in the model as an explanatory variable. Whenever it becomes significant it 
will indicate that simvastatin influences the association between primary and secondary 
outcome measures. Although the sample size of this study was based on the ASL, we 
estimated that the number of patients that we would need to detect a reduction in 
Glutamate of 1.824 that represents a 20% treatment effect (Azevedo et al., 2014), is 
equally 17 per arm (80% power). Similarly, an increase in neurite density of 0.128 that 
represents a 20% treatment effect (Magnollay et al., 2013) would require 13 per arm (80% 
power).  Additionally, even if the number of patients per arm will not be sufficient to see a 
significant treatment effect of this size, this study will provide information on the temporal 
behaviour of these MRI parameters that can be used to power future neuroprotective 
trials. 
 


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Model assumptions will be also checked as described above (23.3), and any violations of 
the model assumptions will be dealt with in a similar way.   
23.5 Sensitivity and other planned analyses 
The Trial Statistician will be responsible for all statistical aspects of the trial from design 
through to analysis and dissemination.  
An analysis of the missingness patterns in the data will be performed. Baseline clinical, 
demographical and neuroimaging characteristics of those patients with missing visits will 
be compared with those of patients without missing values, to investigate the assumption 
of missing at random (MAR). If there is no evidence against MAR, multiple imputation 
methods will be performed, and any serious discrepancy between the complete case 
results and the imputation results will be reported. Worst and best case sensitivity 
analyses will also be performed. 
In general, given that we will use randomisation with minimisation, we do not expect major 
imbalances at baseline. However, should there be any, we will consider adjusting the 
models for the imbalanced variable.   
23.6 Interim analysis 
Due to the short-term nature of the study and small sample size, an interim analysis will 
not be required. 
23.7 Other Statistical Considerations 
Any deviation(s) from the original statistical plan will be described and justified in the 
protocol and/or in the final report, as appropriate. 
 
24. Record keeping and archiving 
At the end of the trial, all essential documentation will be archived securely by the CI and 
trial sites for a minimum of 5 years from the declaration of end of trial.  Any destruction of 
these essential documents will require sponsor authorisation/approval. 
Essential documents are those which enable both the conduct of the trial and the quality 
of the data produced to be evaluated and show whether the site complied with the 
principles of Good Clinical Practice and all applicable regulatory requirements.  
The sponsor will notify sites when trial documentation can be archived following 
submission of the End of Study report. All archived documents must continue to be 
available for inspection by appropriate authorities upon request.  


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25. 
Oversight Committees 
25.1 Trial Management Group (TMG) 
 
A Trial Management Group (TMG) will be set up to assist with developing the design, co-
ordination and strategic management of the trial. The membership, frequency of 
meetings, activity (including trial conduct and data review) and authority will be covered 
in the TMG terms of reference. 
The study will be overseen by two principal investigators (Prof John Greenwood and Prof 
Richard Nicholas) in close partnership with the other co-applicant (Prof Jeremy 
Chataway). Prof Richard Nicholas has experience of managing multi-centre studies and 
coordinating the appropriate approvals to deliver a successful result. Professor John 
Greenwood has managed many successful grants (both project and programme) a 
number of which have been multisite and multidisciplinary. As this is a multidisciplinary 
study effective collaboration between the different components is essential. For this 
reason a Trial Management Group (TMG), will be established and will meet every month 
with an initial meeting 1 month from trial commencement due to the short nature of the 
trial. The TMG will also comprise members of the research group.  
 
The PIs and the clinical research fellows will report the progress of the project and key 
issues related to it to the TMG, who will advise. The aim of this group is to ensure that 
the interests and needs of patients, the public, and clinicians are taken into account and 
that the project is efficiently run. This TMG will help to ensure that the milestones are met, 
and that the dissemination of findings maximises the impact of the project. 
 
We will set up a website with updates on the trials for both the lay and scientific community 
and for the patients participating in the research study. Interaction through Q&A and email 
will be encouraged. A link will be included in the UCL Institute of Neurology, Institute of 
Ophthalmology and Imperial websites. We will provide patients with a lay summary of our 
study at the end of the study and when major results are published. This will be done 
through email, by post, and by updating the study-specific website. 
26. Direct Access to Source Data/Documents 
The investigator(s)/ institution(s) will permit trial-related monitoring, audits, REC review, 
and regulatory inspection(s), providing direct access to source data/documents.  Trial 
participants are informed of this during the informed consent discussion.  Participants will 
consent to provide access to their medical notes. 
27. Ethics and regulatory requirements 
The sponsor will ensure that the trial protocol, participant information sheet, consent form, 
GP letter and submitted supporting documents have been approved by the appropriate 
regulatory body (MHRA in UK) and an appropriate research ethics committee, prior to 
any participant recruitment. The protocol, all other supporting documents including and 


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agreed amendments, will be documented and submitted for ethical and regulatory 
approval as required. Amendments will not be implemented prior to receipt of the required 
approval(s).  
Before the site may be opened to recruit participants, the Chief Investigator/Principal 
Investigator or designee must receive HRA approval and capacity and capability 
confirmed in writing from their Trust Research & Development (R&D).  It is the 
responsibility of the CI/ PI or designee at each site to ensure that all subsequent 
amendments gain the necessary approvals, including HRA approvals (where required) at 
the site.  This does not affect the individual clinician’s responsibility to take immediate 
action if thought necessary to protect the health and interest of individual participants. 
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. The chief investigator will prepare the APR. 
Within 90 days after the end of the trial, the CI/Sponsor will ensure that the main REC 
and the MHRA are notified that the trial has finished.  If the trial is terminated prematurely, 
those reports will be made within 15 days after the end of the trial. 
The CI will supply the Sponsor with a report of the clinical trial which complies with the 
format as defined by the EMA. This will then be uploaded to EudraCT for availability to 
the MHRA and a copy of the report will be submitted to the main REC, within 1 year after 
the end of the trial.  
28. Monitoring requirement for the trial 
The sponsor will determine the appropriate level and nature of monitoring required for the 
trial.  Risk will be assessed on an ongoing basis and adjustments made accordingly. 
The degree of monitoring will be proportionate to the objective, purpose, phase, design, 
size, complexity, blinding, endpoints and risks associated with the trial. 
A trial specific oversight and monitoring plan will be established for studies. The trial will 
be monitored in accordance with the agreed plan. 
Also see section 13.1 
29. Finance 
Simvastatin in progressive MS is fully funded by an MS Society grant number 44. 
Additional funding has been secured from the Multiple Sclerosis Trials Collaboration 
(MSTC) – a registered charity (1113598). 
Prof Richard Nicholas is a trustee of MSTC. 
29.1 Insurance 
University College London holds insurance against claims from participants for injury 
caused by their participation in the clinical trial. Participants may be able to claim 


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compensation if they can prove that UCL has been negligent. However, as this clinical 
trial is being carried out in a hospital, the hospital continues to have a duty of care to the 
participant of the clinical trial.  University College London does not accept liability for any 
breach in the hospital’s duty of care, or any negligence on the part of hospital employees. 
This applies whether the hospital is an NHS Trust or otherwise.   
Participants may also be able to claim compensation for injury caused by participation in 
this clinical trial without the need to prove negligence on the part of University College 
London or another party.  Participants who sustain injury and wish to make a claim for 
compensation should do so in writing in the first instance to the Chief Investigator, who 
will pass the claim to the Sponsor’s Insurers, via the Sponsor’s office. 
Hospitals selected to participate in this clinical trial shall provide clinical negligence 
insurance cover for harm caused by their employees and a copy of the relevant insurance 
policy or summary shall be provided to University College London, upon request. 
30. Publication policy 
30.1 Trial Results 
The results of the trial will be disseminated regardless of the direction of effect. 
30.2 Authorship 
The success of the study is dependent upon the collaboration of all participants. For this 
reason, credit for the main results will be given to all those who have collaborated in the 
study, through authorship and by contribution.  
 
Uniform requirements for authorship for manuscripts submitted to medical journals will 
guide authorship decisions. These state that authorship credit should be based only on 
substantial contribution to:  
• Conception and design, or acquisition of data, or analysis and interpretation of 
data.  
• Drafting the article or revising it critically for important intellectual content.  
• Final approval of the version to be published.  
• And that all these conditions must be met (www.icmje.org).  
In light of this, the Chief Investigator and Research Team (as documented in this 
protocol) will be named as authors in any publication, and an appropriate first author 
agreed through discussion amongst the TMG members.  
The Simvastatin in progressive MS team should be acknowledged in all publications, as 
should UCL as sponsor and MS Society and MSTC as funders.  
Other key individuals will be included as authors or contributors as appropriate and at 
the discretion of the TMG. We will include collaborators who will be listed as 


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contributors for the main study publication, and for PIs we will endeavour to name them 
as co-authors on the primary publication subject to this being acceptable inclusion 
criteria by the target journal. Any disputes relating to authorship will be resolved by the 
CI in consultation with the TMG.  
30.3 Reproducible Research 
All proposed publications and presentations must be discussed with the sponsor, co-CIs 
and funders (MS Society, MSTC) prior to their release and will be in line with UCLs 
publication policy.  
 
The clinical study report will be used for publication and presentation at scientific 
meetings.  
 
Summaries of results will also be made available to Investigators for dissemination 
within their clinics (where appropriate and according to their discretion).  
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Appendix 1 - schedule of assessments 
Visits 
Visit 0 
Pre-
screening 
Visit 1* 
(Combined 
Screening/ 
Baseline) 
Visit 2 
Visit 3* 
(End of Study 
Treatment 
Visit)  
Visit 4* 
(End of Study 
Follow-up) 
Unscheduled 
(inc. relapse if 
indicated) 
Telephone 
/ e-mail 
Follow Up 
Visit Windows 
(1 week is equivalent to 7 
days e.g. 4 weeks (1 month) 
is equivalent to 28 days) 
within 8 
weeks 
Day 0 
Week 4 
(+1 
week) 
Week 16  
(+1 week) 
Week 20 
(+2 weeks) 
Between  
V1 to EOS 
Follow-up 
As 
required 
Pre-screening questionnaire 
X 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
review 
X 
X 
 
 
 
 
X 
Informed consent 
 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Con-meds 
 
X 
X 
X 
X 
X 
X 
Medical review1 
 
X 
X 
X 
X 
X 
X 
Recording of AEs 
 
 
X 
X 
X 
X 
X 
Physical examination  
 
X 
X 
X 
X 
X 
 
Vital Signs 
 
X 
X 
X 
X 
X 
 
Disability Assessment 
(EDSS) 
 
X 
 
X 
X 
X 
 
MSFC (9HPT, 25TFW) 
 
X 
 
X 
X 
 
 
SDMT 
 
X 
 
X 
X 
 
 
FAB 
 
X 
 
 
X 
 
 
MSIS-29v2 
 
X 
 
X 
X 
 
 
MSWSv2 
 
X 
 
X 
X 
 
 
EQ5D5L 
 
X 
 
X 
X 
 
 


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Page 85 of 86 
 
Visits 
Visit 0 
Pre-
screening 
Visit 1* 
(Combined 
Screening/ 
Baseline) 
Visit 2 
Visit 3* 
(End of Study 
Treatment 
Visit)  
Visit 4* 
(End of Study 
Follow-up) 
Unscheduled 
(inc. relapse if 
indicated) 
Telephone 
/ e-mail 
Follow Up 
Visit Windows 
(1 week is equivalent to 7 
days e.g. 4 weeks (1 month) 
is equivalent to 28 days) 
within 8 
weeks 
Day 0 
Week 4 
(+1 
week) 
Week 16  
(+1 week) 
Week 20 
(+2 weeks) 
Between  
V1 to EOS 
Follow-up 
As 
required 
Safety bloods 
(see section 11.1 for list of 
laboratory tests) 
 
X 
X 
X 
X 
X 
 
Urine pregnancy test4 
 
X 
 
X 
X 
 
 
Immunology and biomarkers 
 
X 
X 
X 
X 
 
 
MRI  
 
X 
 
X 
X 
 
 
ASL questionnaire 
 
X 
 
 
 
 
 
ASL questionnaire follow-up 
 
 
 
X 
X 
 
 
Visual assessment 
 
X 
 
 
 
 
 
Retinal Imaging Vascular 
Assessment Questionnaire 
 
X 
 
X 
X 
 
 
Advanced retinal imaging 
inc. OCT* 
 
X 
 
X 
X 
 
 
Randomisation 
 
X 
 
 
 
 
 
Drug dispensed3 
 
X (40mg) 
 
 
 
 
 
Drug uptitration3 
 
 
X (80 mg) 
 
 
 
 
Drug Diary issued 
 
X 
 
 
 
 
 
Confirmation to dose2 
 
X 
 
 
 
 
 
Drug accountability (diary)5 
 
 
X 
X 
 
 
 
Drug compliance5 
 
 
X 
X 
 
 
X 
Telephone contact 
 
 
 
 
 
 
X 


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Page 86 of 86 
* This visit will take place across two sites. The assessments may be split across two days. Day 1 assessments will take place at the UCL Institute 
of Neurology & National hospital for neurology and neurosurgery and day 2 assessments (visual assessment and Advanced Retinal Imaging) 
will take place at Moorfields Eye Hospital. Patients will be dispensed the drug on Day 1 of  visit 1 but will be instructed not to take the drug 
until the evening of Day 2 of visit 1 (if over 2 days) after all ophthalmic assessments are completed. See Section 10 for full details. 
 
1 This will encompass any medical or MS-related symptoms that have arisen between Visit 1 and subsequent visits. 
 
2 Study medication must only be dispensed after randomisation once all day 1 of  visit 1 assessments have been completed and the relevant safety 
reports have been obtained.  Patients will be dispensed the drug on Day 1 of  visit 1 but will be instructed not to take the drug until the evening 
of Day 2 (if over 2 days) of visit 1 after all ophthalmic assessments are completed. See Section 10 for full details.  
 
3 Participants will be allocated 220 tablets each for the duration of the study. There will therefore be one drug release at baseline and the patient 
will be reminded to uptitrate after one month at Visit 2.  The patient will take 40mg x 2 tablets for the dose of 80mg for a period of 12 weeks. The 
neurologist will issue the drugs, diary and record compliance at the relevant visits. 
For the purpose of safety, the study participant will be contacted by telephone and adverse events assessed by the neurologist.  If there are no 
issues identified, the participant will be advised to take the study medication and encouraged to contact a member of the research team if 
problems subsequently arise. 
 
4 For female subjects only 
 
5 This will include a drug diary review and pills count. 
 

SAP_001.pdf: 
 
 
 
MS-OPT Trial – Statistical analysis plan 
 
 
 
 
MS-OPT Trial: Simvastatin in progressive multiple sclerosis 
Statistical analysis plan 
 
Protocol number  
Version 1.7 dated 18/10/2022  
(EudraCT no: 2017-003008-30) 
Trial Title 
A double-blind, randomised, placebo-controlled single-site study of high dose 
simvastatin treatment for secondary progressive multiple sclerosis: impact on 
vascular perfusion and oxidative damage 
Name of CI / PI 
Richard Nicholas 
Site Name 
UCL University College London 
ClinicalTrials.gov Identifier 
NCT03896217 
Document Date 
1st March 2024 
 
 
The general aim of the study is to determine the effect high-dose Simvastatin treatment has on vascular 
perfusion and oxidative damage in progressive multiple sclerosis. 
 
Hypothesis:  
Simvastatin reduces the progression of progressive multiple sclerosis (P-MS) by increasing 
vascular perfusion and reducing oxidative damage as demonstrated by measuring cerebral blood 
flow in people with secondary progressive MS SP-MS and primary progressive MS (PP-MS). 
 
1. 
Aims: 
• Primary: to test against placebo the efficacy and mechanism of simvastatin in progressive MS. 
 
• Secondary: to advance our understanding of the mechanisms of efficacy, and how vascular perfusion and 
oxidative damage is affected in progressive MS both in the presence and absence of simvastatin. 


 
 
 
MS-OPT Trial – Statistical analysis plan 
 
 
 
 
- To establish whether ASL and AOSLO measurements of blood flow are useful correlates for cerebral 
blood flow measurement on and off treatment.  
- To evaluate whether ASL and high-resolution retinal neuronal structural data including the retinal nerve 
fibre layer (RNFL) are useful correlates for cerebral blood flow measurement on and off treatment. 
- To Investigate the effect statins may have on retinal parameters such as blood flow, oxygen saturation, 
structure of vascular plexuses, neuronal structure and retinal layer thicknesses. 
- To explore whether statin reduce the rate of brain atrophy on MRI (excluding the effect of pseudo-
atrophy, which is a temporary response to the drug rather than an actual loss of tissue). 
- To explore whether statin modulate the changes in advanced MRI measurements (diffusion imaging, 
macromolecular tissue volume). 
- To examine the clinical effect of simvastatin treatment as reported by the clinician (EDSS, SDMT, MSFC 
inc. 9HPT and 25FTW) and patient reported outcome measures (MSIS-29v2, and MSWSv2). 
- To examine the clinical effect of simvastatin treatment on frontal executive functioning (FAB). 
- To collect health economic data (EQ5D5L) to inform future phase III trials. 
 
• Exploratory objectives: to advance our understanding of the mechanisms of efficacy, and how vascular 
perfusion and oxidative damage is affected in progressive MS both in the presence and absence of simvastatin. 
- To investigate phenotypic immune markers in whole blood to determine effect simvastatin has on 
immune function. 
- To measure biomarkers of blood brain barrier dysfunction, vascular leakage and oxidative damage in 
participants treated with statins and placebo. 
- To investigate levels of circulating cholesterol. 
 
 
 
 


 
 
 
MS-OPT Trial – Statistical analysis plan 
 
 
 
 
2. 
Statistical Analysis Plan: 
• Primary outcome analysis. The ASL-measured CBF in white matter (), grey matter, deep grey matter, and 
thalamus will be compared between patients on simvastatin or placebo using multiple linear regressions at 16 
weeks as the dependent variable, and age, gender or CBF at baseline and treatment group entered as 
covariates. Whenever the variable ‘treatment group’ is significant (at 5% significance level), it will be assumed 
that there is a treatment effect. The same models will be used to investigate the effect of simvastatin on the 
other imaging outcome measures. 
 
• Checks for model assumptions. For all regression-type approaches, we will assess the normality of the 
residuals (of each one of the fitted models) through q-q plots. Residual homoscedasticity will be assessed 
through two-way scatter plots of the residuals over fitted values. Once we build the model with all possible 
predictors as explanatory variables, the assumption of the linear relationship between the dependent variable 
and each one of the predictors individually, given the presence of the other predictors, will be assessed through 
investigating different functional forms of the predictor and their impact on the R2 of the model. The 
independence of observations will be always assumed. 
 
• Violations of model assumptions. If the main assumption violated is that of homoscedasticity (i.e. there is 
residual heteroscedasticity), robust estimations of the standard errors (SE) of the regression parameters will 
be made, using the sandwich estimator of the SE. Whenever the residual distributions show a clear deviation 
from normality, bootstrap-based approaches will be used, with at least 1000 replication samples: bias-
corrected and accelerated bootstrap-based 95% Confidence Intervals (95% CI) will be computed for each 
estimated parameter. 
 
• Secondary outcome analysis. Metrics for quantifying blood flow from retinal imaging are in development, and 
have not previously been applied in MS patients. Retinal vessel walls will be assessed in a similar fashion to 
that outlined by Chui et al (2013). Arterial wall thickness will be assessed as a function of lumen thickness. In 
the first instance normative data will be obtained from age-matched controls prior to imaging patients with 
MS. Subsequently appropriate multigroup statistical tests will be applied. Capillary network density will be 
assessed using similar methods to those described by Tam et al. (2010) and blood velocity will be calculated 
building up spatio-temporal analysis outlined by Tam et al. (2011).  
 
• Exploratory analyses. Exploratory analyses will be performed to assess the associations between ASL changes 
(dependent variable) and all secondary outcome measures (explanatory variables). An interaction term such 
as ‘secondary outcome measure change’ X ‘treatment group’ will be included in the model as an explanatory 


 
 
 
MS-OPT Trial – Statistical analysis plan 
 
 
 
 
variable. Whenever it becomes significant it will indicate that simvastatin influences the association between 
primary and secondary outcome measures.  
Although the sample size of this study was based on the ASL, we estimated that the number of patients that 
we would need to detect an increase in neurite density of 0.128 that represents a 20% treatment effect 
(Magnollay et al., 2013) would require 13 per arm (80% power). Additionally, even if the number of patients 
per arm will not be sufficient to see a significant treatment effect of this size, this study will provide information 
on the temporal behaviour of these MRI parameters that can be used to power future neuroprotective trials. 
Model assumptions will be also checked as described above and any violations of the model assumptions will 
be dealt with in a similar way. 
 
• Sensitivity and other planned analyses. Baseline clinical, demographical and neuroimaging characteristics of 
those patients with missing visits will be compared with those of patients without missing values, to investigate 
the assumption of missing at random (MAR). If there is no evidence against MAR, multiple imputation methods 
will be performed, and any serious discrepancy between the complete case results and the imputation results 
will be reported. Worst- and best-case sensitivity analyses will also be performed.  
In general, given that we will use randomisation with minimisation, we do not expect major imbalances at 
baseline. However, should there be any, we will consider adjusting the models for the imbalanced variable. 
 
• Interim analysis. Due to the short-term nature of the study and small sample size, an interim analysis will not 
be required. 
 
 
 


 
 
 
MS-OPT Trial – Statistical analysis plan 
 
 
 
 
3. 
CONSORT 2010 Flow Diagram