Plain English Summary
Background and study aims
Multiple Sclerosis (MS) is a progressive neurological disorder of the brain and spinal cord. It affects approximately 120,000 people in the UK and 2.5 million people globally. Most people with MS experience two stages of the disease: Early MS – Relapsing-Remitting MS (RRMS), which is partially reversible, and Late MS – Secondary Progressive MS (SPMS), which affects the majority of patients, usually after 10 to 15 years after diagnosis. SPMS results from progressive neuronal degeneration that causes accumulating and irreversible disability affecting walking, balance, manual function, vision, cognition, pain control, bladder and bowel function. The pathological process driving the accrual of disability in SPMS is not known at present. Immunomodulatory anti-inflammatory disease modifying therapies (DMTs) are increasingly effective in reducing relapse frequency in RRMS, however, they have been unsuccessful in slowing disease progression in SPMS. This is the overwhelming conclusion from an analysis of 18 phase 3 trials (n=8500), of which 70% of the population had SPMS, all performed in the last 25 years. There is no current disease modifying treatment (DMT) for SPMS. The aim of this study is to examine if repurposed Simvastatin (80mg) is a disease modifying treatment for patients with progressing Secondary Progressive Multiple Sclerosis (SPMS).
Who can participate?
Adults aged 25 to 65 who have a confirmed diagnosis of MS.
What does the study involve?
The study is designed to test the effectiveness of repurposed simvastatin (80mg) in a phase 3 double blind, randomised, placebo controlled trial (1:1) in patients with secondary progressive MS (SPMS), to determine if the rate of disability progression can be slowed over a 3 year period.
Participants will be required to complete 10 study appointments over a 36 month period. This will involve nine (9) visits to the hospital for study appointments and at least one (1) telephone call. At each study visit, participants will be asked to complete a number of study assessments including questionnaires and provide blood samples. Participants who meet all entry requirements are randomly allocated to receive either Simvastatin or Placebo. Participants will start off taking one (40mg) Simvastatin/Placebo tablet once daily at night for 1 month. The dose will increase after this and participants will take two (80mg) Simvastatin/Placebo tablets once daily at night for the next 35 months.
What are the possible benefits and risks of participating?
The results generated from this trial may help to improve the treatment options of people with MS. In addition, taking part in this trial will mean regular review by an experienced neurologist regardless of the drug that participants are randomly allocated to receive. All medical procedures involve the risk of harm, but this is usually a low risk. In addition, there might be risks associated with this study that we do not yet know about.
Simvastatin is a well-tolerated drug and side effects are rare. However, in this trial, simvastatin will be given at a higher dose than is normally given to patients who use it to lower their cholesterol levels. Side effects can occasionally include muscle pain, tummy pain, blurred vision, dizziness and very rarely severe liver damage. Minor side effects include constipation, diarrhoea, fatigue and headaches. Participants are advised to inform their study doctor/nurse if they experience any of these side effects or have any concerns regarding their health at any point during the trial. Participants may be asked to attend the clinic for any additional visit(s) for further examination or tests.
There might be a risk of serious side effects when some medications are taken with the trial drug. Participants are advised to tell the study doctor about all medications they are taking before and during the trial. This includes other prescribed medicines, over the counter medicines, recreational drugs, herbal medicines or supplements. Grapefruit juice is known to interact unfavourably with simvastatin. Participants are advised not to drink grapefruit juice for the duration of the trial. The active study drug may pose unknown risks to a pregnant woman, an unborn baby, or a breastfeeding child. As such, pregnant women are not allowed to take part in this trial. Urine samples from female participants are tested at the screening visit (visit 1) to make sure they are not pregnant. All participants (male and female) are advised to use adequate contraception for the duration of the trial. All reasonable efforts are made to make this trial safe. Despite this, some risks might not be possible to predict.
Where is the study run from?
The study is being co-ordinated by the Comprehensive Clinical Trials Unit (UCL). Participants will have their study appointments at up to 30 participating Hospitals across the UK (England, Wales, Scotland, and Northern Ireland) and Eire. The lead site is based at UCL (National Hospital for Neurology & Neurosurgery)
When is the study starting and how long is it expected to run for?
March 2017 to August 2023
Who is funding the study?
National Institute for Health Research (UK)
Who is the main contact?
1. Dr Martha Bajwa Joseph
ms-stat2@ucl.ac.uk
Martha.joseph@ucl.ac.uk
2. Dr Jeremy Chataway
j.chataway@ucl.ac.uk
Trial website
Contact information
Type
Public
Primary contact
Ms Liz Deane
ORCID ID
http://orcid.org/0000-0002-1503-7768
Contact details
Comprehensive Clinical Trials Unit at UCL
Institute of Clinical Trials & Methodology
London
WC1V 6LJ
United Kingdom
+44 20 7907 4672
ms-stat2@ucl.ac.uk
Type
Scientific
Additional contact
Dr Jeremy Chataway
ORCID ID
http://orcid.org/0000-0001-7286-6901
Contact details
Institute of Neurology
University College London (UCL)
Queen Square
London
WC1N 3BG
United Kingdom
-
jeremy.chataway@uclh.nhs.uk
Additional identifiers
EudraCT number
2017-003328-56
ClinicalTrials.gov number
Protocol/serial number
35831
Study information
Scientific title
A phase 3 randomised, double blind, clinical trial investigating the effectiveness of repurposed simvastatin compared to placebo, in secondary progressive multiple sclerosis, in slowing the progression of disability
Acronym
MS-STAT2
Study hypothesis
The hypothesis is that repurposed Simvastatin (80mg) is a disease modifying treatment for patients with progressing Secondary Progressive Multiple Sclerosis (SPMS).
Ethics approval
London - Westminster Research Ethics Committee, 09/10/2017, ref: 17/LO/1509
Study design
Randomised; Interventional; Design type: Treatment, Drug
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Multiple Sclerosis
Intervention
Participants are randomly allocated to one of two groups:
Simvastatin (Active Treatment):
Participants in this group start off taking one tablet. The number of tablets increases to two after a month.
1. One (1 = 40mg) simvastatin tablet once daily at night for one month
2. Two (2 = 80mg) simvastatin tablets once daily at night, for the next 35 months
Placebo:
Participants in this group start off taking one tablet. The number of tablets increases to two after a month.
1. One (1) placebo tablet once daily at night for one month
2. Two (2) placebo tablets once daily at night, for the next 35 months
Participants are followed up on a six month basis from baseline using the Expanded Disability Status Scale (EDSS) until the participant attends the last clinical appointment via telephone.
Intervention type
Other
Phase
Phase III
Drug names
Primary outcome measure
Time to initial disability progression between treatment arms is measured using the Expanded Disability Status Scale (EDSS) at baseline and then on a 6 month basis until last available EDSS score recorded at last attended clinic appointment/via telephone.
Secondary outcome measures
Current secondary outcome measures as of 19/10/2018:
1. The clinical effect of neuroprotection based on clinician- and patient-reported outcome measures
2. The incremental cost and cost-effectiveness of simvastatin versus standard care for the trial period and for the lifetime horizon
Clinician-reported outcome measures:
1. A modified Multiple Sclerosis Functional Composite (MSFC) outcome measure comprised of three components. The Symbol Digit Modalities Test (SDMT) will replace the Paced Auditory Serial Addition Test (PASAT), one of the three components in the standard MSFC.
1.1. 25 foot walk (T25FW)
1.2. 9 Hole peg test (9HPT)
1.3. Symbol digit modalities test (SDMT)
2. Sloan Low Contrast Visual Acuity (SLCVA)
3. Relapse assessment – number and severity
4. Frontal Assessment Battery (FAB)
5. Modified Rankin Scale (mRS)
6. Brief International Cognitive Assessment For Multiple Sclerosis (BICAMS), a composite cognitive assessment tool comprising of the three components namely:
6.1. Symbol Digit Modalities Test (SDMT)
6.2. California Verbal Learning Test-2(CVLT-2)
6.3. Brief Visuospatial Memory Test- Revised (BVMT-R)
Patient-reported outcome measures:
1. MS Impact Scale-29 v2 (MSIS-29v2)
2. MS Walking Scale-12 v2 (MSWS-12v2)
3. EQ-5D 5L
Previous secondary outcome measures:
1. The clinical effect of neuroprotection based on clinician and patient reported outcome measures
2. The incremental cost and cost-effectiveness of simvastatin versus standard care for the trial period and for the lifetime horizon
Clinician reported outcome measures:
1. A modified Multiple Sclerosis Functional Composite (MSFC) outcome measure comprised of three components. The Symbol Digit Modalities Test (SDMT) will replace the Paced Auditory Serial Addition Test (PASAT), one of the three components in the standard MSFC.
1.1. 25 foot walk (T25FW)
1.2. 9 Hole peg test (9HPT)
1.3. Symbol digit modalities test (SDMT)
2. Sloan Low Contrast Visual Acuity (SLCVA)
3. Relapse assessment – number and severity
4. Frontal Assessment Battery (FAB)
5. Modified Rankin Scale (mRS)
6. Brief International Cognitive Assessment For Multiple Sclerosis (BICAMS), a composite cognitive assessment tool comprising of the three components namely:
6.1. Symbol Digit Modalities Test (SDMT)
6.2. California Verbal Learning Test-2(CVLT-2)
6.3. Brief Visuospatial Memory Test- Revised (BVMT-R)
Patient reported outcome measures:
1. MS Impact Scale-29 v2 (MSIS-29v2)
2. MS Walking Scale-12 v2 (MSWS-12v2)
3. ABILHAND-56
4. EQ-5D 5L
5. SF-36 v2
Overall trial start date
01/03/2017
Overall trial end date
31/08/2023
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Current participant inclusion criteria as of 19/10/2018:
1. Patients with a confirmed diagnosis of multiple sclerosis (MS) that have entered the secondary progressive stage. 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 1 point if on the Expanded Disability Status Scale (EDSS) score <6, or an increase of 0.5 point if EDSS score ≥6, or clinical documentation of increasing disability
2. EDSS 4.0 - 6.5 (inclusive)
3. Aged 25 to 65 years
4. Patients must be able and willing to comply with the terms of this protocol
5. Written informed consent provided
Previous participant inclusion criteria:
1. Patients with a confirmed diagnosis of multiple sclerosis (MS) that have entered the secondary progressive stage at randomisation. 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 Expanded Disability Status Scale (EDSS), or clinical documentation of increasing disability
2. EDSS 4.0 - 6.5 (inclusive)
3. Aged 25 to 65 years old
4. Male or Female
5. Patients must be able and willing to comply with the terms of this protocol.
6. Written informed consent provided
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 1180; UK Sample Size: 1144
Participant exclusion criteria
Current participant exclusion criteria as of 19/10/2018:
1. Relapse within 3 months of baseline visit
2. Patients that have been treated with steroids (intravenous and/or oral) due to MS relapse/progression within 3 months of baseline 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 (Note: Patients on steroids for another medical condition may be included in the trial provided the steroid prescription is not for MS relapse/progression)
3. Significant organ co-morbidity e.g. cardiac failure, renal failure, malignancy
4. Screening levels of alanine aminotransferase (ALT) / aspartate aminotransferase (AST) or creatinine kinase (CK) > = 3x upper limit of normal (ULN)
5. Current use of a statin; or any use within the last 6 months
6. Medications that interact unfavourably with simvastatin as outlined in the current summary of product characteristics (SmPC); including but not limited to CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, fluconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, erythromycin, clarithromycin, telithromycin, telaprevir, nefazodone, fibrates (including fenofibrates), nicotinic acid ( or products containing niacin), azole anti-fungal preparations, macrolide antibiotics, protease inhibitors, verapamil, amiodarone, amlodipine, gemfibrozil, ciclosporin, danazol , diltiazem, rifampicin , fusidic acid, grapefruit juice or alcohol abuse
7. Primary progressive MS
8. Diabetes Mellitus Type 1
9. Uncontrolled hypothyroidism
10. Female participants that are pregnant or breast feeding. Women of child bearing potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period, and up to 4 weeks after the last dose of study drug
11. Use of immunosuppressants (e.g. azathioprine, methotrexate, ciclosporine) or disease modifying treatments (avonex, rebif, betaferon, glatiramer) within the previous 6 months
12. Use of mitoxantrone, natalizumab, alemtuzumab, daclizumab or other monoclonal antibody treatment, if treated within the last 12 months
13. Use of fingolimod, fumarate, teriflunomide within the last 12 months
14. Use of other experimental disease modifying treatment within the last 6 months
15. Commencement of Fampridine < = 6 month from day of randomisation
16. Concurrent participation in another clinical trial of an investigational medicinal product or medical device
17. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
Previous participant exclusion criteria:
1. Relapse within 3 months of baseline visit
2. Patients that have been treated with steroids (intravenous and/or oral) due to MS relapse/progression within 3 months of baseline 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 (Note: Patients on steroids for another medical condition may be included in the trial provided the steroid prescription is not for MS relapse/progression)
3. Significant organ co-morbidity e.g. cardiac failure, renal failure, malignancy
4. Screening levels of alanine aminotransferase (ALT) / aspartate aminotransferase (AST) or creatinine kinase (CK) > = 3x upper limit of normal (ULN)
5. Current use of a statin; or any use within the last 6 months
6. Medications that interact unfavourably with simvastatin as outlined in the current summary of product characteristics (SmPC); including but not limited to CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, fluconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, erythromycin, clarithromycin, telithromycin, telaprevir, nefazodone, fibrates (including fenofibrates), nicotinic acid ( or products containing niacin), azole anti-fungal preparations, macrolide antibiotics, protease inhibitors, verapamil, amiodarone, amlodipine, gemfibrozil, ciclosporin, danazol , diltiazem, rifampicin , fusidic acid, grapefruit juice or alcohol abuse
7. Primary progressive MS
8. Diabetes Mellitus Type 1
9. Uncontrolled hypothyroidism
10. Female participants that are pregnant or breast feeding. Women of child bearing potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period, and up to 4 weeks after the last dose of study drug
11. Use of immunosuppressants (e.g. azathioprine, methotrexate, ciclosporine) or disease modifying treatments (avonex, rebif, betaferon, glatiramer) within the previous 6 months
12. Use of mitoxantrone, natalizumab, alemtuzumab, daclizumab or other monoclonal antibody treatment, if treated within the last 12 months
13. Use of fingolimod, fumarate, teriflunomide within the last 12 months
14. Use of other experimental disease modifying treatment within the last 6 months
15. Commencement of Fampridine < = 6 month from day of randomisation
16. Concurrent participation in another clinical trial of an investigational medicinal product or medical device
Recruitment start date
28/03/2018
Recruitment end date
30/11/2019
Locations
Countries of recruitment
Ireland, United Kingdom
Trial participating centre
UCL - National Hospital for Neurology & Neurosurgery
Queen Square
London
WC1N 3BG
United Kingdom
Funders
Funder type
Government
Funder name
National Institute for Health Research
Alternative name(s)
NIHR
Funding Body Type
government organisation
Funding Body Subtype
Federal/National Government
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Trial results will be published in a high-impact peer reviewed journal.
IPD sharing statement:
The datasets generated during and/or analysed during the current study is not expected to be made available. Patient identifiable data will not be published. The anonymity of all participants will be maintained at all times and results published in aggregate form.
Intention to publish date
31/08/2023
Participant level data
Not expected to be available
Basic results (scientific)
Publication list