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Multiple Sclerosis-Simvastatin Trial 2 (MS-STAT2)

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ClinicalTrials.gov Identifier: NCT03387670
Recruitment Status : Recruiting
First Posted : January 2, 2018
Last Update Posted : October 18, 2018
Sponsor:
Collaborators:
University of Edinburgh
Queen Mary University of London
London School of Hygiene and Tropical Medicine
University of Leeds
The Leeds Teaching Hospitals NHS Trust
Imperial College Healthcare NHS Trust
Information provided by (Responsible Party):
University College, London

Brief Summary:

Multiple Sclerosis (MS) is a progressive neurological disorder of the brain and spinal cord. It affects approximately 120,000 people in the United Kingdom 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.

In an earlier study (Multiple Sclerosis-Simvastatin 1; MS-STAT1), 140 people with SPMS were randomly assigned to receive either placebo or simvastatin for a period of two years. The investigators found that the rate of brain atrophy (loss of neurons - 'brain shrinkage'), as measured by magnetic resonance imaging (MRI), was reduced in patients receiving simvastatin compared to those taking placebo.

Several other long term studies have also reported that there might be a relationship between the rate of brain atrophy and the degree of impairment. 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.

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 patients are randomly allocated to receive.


Condition or disease Intervention/treatment Phase
Secondary Progressive Multiple Sclerosis (SPMS) Drug: Simvastatin Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : March 28, 2018
Estimated Primary Completion Date : August 31, 2023
Estimated Study Completion Date : August 31, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Simvastatin

Arm Intervention/treatment
Active Comparator: Simvastatin Drug: Simvastatin
  • One (1 = 40mg) simvastatin tablet once daily at night for 1 month
  • Two (2 = 80mg) simvastatin tablets once daily at night, for the next 35 months

Placebo Comparator: Placebo Drug: Placebo
  • One (1) placebo tablet once daily at night for 1 month
  • Two (2) placebo tablets once daily at night, for the next 35 months




Primary Outcome Measures :
  1. Time to confirmed disability progression between simvastatin and placebo arm based on change in EDSS scores compared to baseline. [ Time Frame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 ]
    The initial disability progression event is finalised as positive if disability is sustained and confirmed ≥6* months later. Progression of disability defined as an increase of at least 1 point if EDSS baseline score <6, or an increase of 0.5 point if baseline EDSS score is ≥6.


Secondary Outcome Measures :
  1. Response rate on the patient reported outcome form Multiple Sclerosis Walking Scale-12 version 2 (MSWS-12v2) [ Time Frame: Annually - baseline, month 12, 24 and 36 ]
    MSWS-12v2 is a12 item patient report measure on the impact of MS on the individual's walking ability over the previous 2 weeks. Each item will be summed to generate a total score and transformed to a scale with a range of 0 to 100 with high scores indicating greater impact on walking.

  2. Response rate on the patient reported outcome form Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) [ Time Frame: Annually - baseline, month 12, 24 and 36 ]
    MS Impact Scale-29 version 2 (MSIS-29v2) - A psychometrically validated patient-reported outcome measure increasingly used for measuring the impact of MS on people's lives. The 29-item scale assesses the impact of MS on people's health related quality of life in terms of their physical and psychological well-being over the previous 2 weeks.

  3. Cost effectiveness of intervention [ Time Frame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 ]
    To estimate the incremental cost and cost-effectiveness of simvastatin versus standard care for the trial period and for the lifetime horizon using the Client Client Services Receipt Inventory Form.

  4. Change in time taken to complete 25-Foot Timed Walk (T25FW) [ Time Frame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 ]
    T25-FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk

  5. Change in time taken to complete 9 hole peg test (9HPT) [ Time Frame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 ]
    The 9HPT is a brief, standardized, quantitative test of upper extremity function. Participants are instructed to pick up 9 pegs, one at a time, as quickly as possible and are required to insert them into 9 empty peg holes. Once all nine pegs have been inserted, the participant should immediately remove the pegs, one at a time. The total time taken to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged.

  6. Evaluating change in degree of disability based on the modified Rankin scale (mRS) [ Time Frame: Annually - baseline, month 12, 24 and 36 ]
    mRS is used to evaluate the degree of disability in daily activities of those with neurological disability.

  7. Change in frontal lobe function based on Frontal Assessment Battery (FAB) scores [ Time Frame: Annually - baseline, month 12, 24 and 36 ]
    FAB is a brief battery of six neuropsychological tasks designed to assess frontal lobe function. The six FAB tasks assess conceptualisation (abstract reasoning), item flexibility (verbal fluency), motor programming (organisation, maintenance and execution of successive actions), sensitivity to interference (conflicting instructions), inhibitory control (inhibit inappropriate responses), and environmental autonomy. The test takes approximately 10 minutes to complete.

  8. Difference in the number and severity of multiple sclerosis related relapse events between treatment groups [ Time Frame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 ]
    A relapse will be defined as new or worsening neurological symptom(s) in the absence of fever, lasting for more than 24 hours, and have been preceded by a period of clinical stability of at least 30 days, with no other explanation than MS.

  9. Change in visual function based on the Sloan Low Contrast Visual Acuity (SLCVA) [ Time Frame: Annually - baseline, month 12, 24 and 36 ]
    Sloan chart testing is a reliable, quantitative, and clinically practical measure of visual function that will be administered by trained assessors. The chart consists of rows of grey letters on a white background. Letters are displayed in decreasing order from the top of the chart to the bottom. Testing will be conducted at three different contrast levels (100%, 2.5% and 1.25%). The chart will be scored based on the number of letters correctly identified out of 60.

  10. Difference in patient reported quality of life based on the EuroQoL Health Related Quality of Life - 5 Dimensions - 5 Levels (EQ-5D 5L) scores [ Time Frame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 ]
    EQ-5D 5L is a 5 item questionnaire (assessing - mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and visual analogue scale (VAS) enables calculation of quality adjusted life years (QALY) to enable health economic analyses to be performed. Each dimension assessed has 5 response scales to select from: no problems, slight problems, moderate problems, severe problems, and extreme problems

  11. Change in a modified Multiple Sclerosis Functional Composite scores [ Time Frame: Annually - baseline, month 12, 24 and 36 ]
    A Modified Multiple Sclerosis Functional Composite (MSFC) score comprised of 3 components (T25FW, 9HPT, SDMT). The Symbol digit modalities test (SDMT) will replace the Paced Auditory Serial Addition Test (PASAT), one of the three components in the Standard MSFC.

  12. Change in cognitive performance as measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) [ Time Frame: Baseline and month 36 ]
    BICAMS is a composite cognitive assessment tool comprising of the three components : Symbol Digit Modalities Test (SDMT) , California Verbal Learning Test-II (CVLT-II) and Brief visuospatial memory test- Revised (BVMT-R)

  13. Change in cognitive impairment based on Symbol Digit Modalities Test (SDMT) scores [ Time Frame: Annually - baseline, month 12, 24 and 36 ]
    SDMT is a brief measure of cognitive processing speed. It measures information processing speed for visually presented stimuli, but is self-paced, with at least equal reliability and sensitivity to the presence of worsening cognitive impairment.

  14. Evaluating the time to disability progression based on a secondary composite progression outcome measure [ Time Frame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 ]
    A secondary composite progression outcome measure defined as one or more of: ≥20% increase in time taken to complete the 25 Foot Walk (T25FW); or ≥20% increase in time to complete 9 Hole Peg Test (9HPT); or increase in EDSS (0.5 point increase if baseline ≥6 /1.0 point increase if baseline <6). The initial disability progression event will be finalised as positive if it is sustained and confirmed ≥6 months later*. The time to event analysis will be from randomisation until date of the initial disability progression (if subsequently confirmed)

  15. Change in fatigue as measured by the Chalder Fatigue Scale [ Time Frame: Annually - baseline, month 12, 24 and 36 ]
    A questionnaire measuring the severty of physical and mental fatigue on two seperate subscales

  16. Change in service utilisation [ Time Frame: 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 ]
    A questionnaire that collects information on service utilisation, income, accommodation and other cost-related variables. Its primary purpose is to allow resource use patterns to be described and support costs to be estimated for health economics purposes



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   25 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  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 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 old
  4. Patients must be able and willing to comply with the terms of this protocol.
  5. Written informed consent provided

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) ≥3 x 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 months 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03387670


Contacts
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Contact: Jeremy Chataway 020 7679 6154 J.chataway@ucl.ac.uk
Contact: Liz Deane 020 7907 4672 ms-stat2@ucl.ac.uk

Locations
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Ireland
St Vincent's University Hospital Not yet recruiting
Dublin, Ireland, D04 T6F4
Principal Investigator: Christopher McGuigan         
United Kingdom
Belfast City Hospital Not yet recruiting
Belfast, United Kingdom, BT9 7AB
Principal Investigator: Gavin McDonnell         
Royal Sussex County Hospital Not yet recruiting
Brighton, United Kingdom, BN2 5BE
Principal Investigator: Marco Bozazali         
Addenbrooke's Hospital Recruiting
Cambridge, United Kingdom, CB2 0QQ
Principal Investigator: Stefano Pluchino         
University Hospital of Wales Not yet recruiting
Cardiff, United Kingdom, CF14 4XW
Principal Investigator: Neil Robertson         
The Anne Rowling Regenerative Neurology Clinic Recruiting
Edinburgh, United Kingdom, EH16 4SB
Principal Investigator: Siddharthan Chandran         
Royal Devon and Exeter Hospital Recruiting
Exeter, United Kingdom, EX2 5DW
Principal Investigator: Timothy Harrower         
The Queen Elizabeth University Hospital Not yet recruiting
Glasgow, United Kingdom, G51 4TF
Principal Investigator: James Overell         
Leeds General Infirmary Recruiting
Leeds, United Kingdom, LS1 3EX
Principal Investigator: Helen Ford         
The Leeds Teaching Hospital Not yet recruiting
Leeds, United Kingdom, LS1 3EX
The Walton Centre NHS Foundation Trust Not yet recruiting
Liverpool, United Kingdom, L9 7LJ
Principal Investigator: Carolyn Young         
Queen's Hospital, Barking, Havering and Redbridge University Hospitals Not yet recruiting
London, United Kingdom, RM7 0AG
Principal Investigator: Miriam Mattoscio         
King's College Hopsital Not yet recruiting
London, United Kingdom, SE5 8EF
Principal Investigator: Eli Silber         
Charing Cross Hospital Not yet recruiting
London, United Kingdom, W6 8RF
Principal Investigator: Richard Nicholas         
University College London Hospital Recruiting
London, United Kingdom, WC1N 3BG
Principal Investigator: Jeremy Chataway         
Salford Royal Hospital Recruiting
Manchester, United Kingdom, M6 8HD
Principal Investigator: David Rog         
Royal Victoria Infirmary Not yet recruiting
Newcastle Upon Tyne, United Kingdom, NE1 4LP
Principal Investigator: Martin Duddy         
Nottingham Teaching Hospitals Not yet recruiting
Nottingham, United Kingdom, NG5 1PB
Principal Investigator: Nikos Evangelou         
Queen's Medical Centre Not yet recruiting
Nottingham, United Kingdom, NG7 2UH
John Radcliffe Hospital Not yet recruiting
Oxford, United Kingdom, OX3 9DU
Principal Investigator: Matthew Craner         
Derriford Hospital Not yet recruiting
Plymouth, United Kingdom, PL6 8BH
Principal Investigator: Jeremy Hobart         
Poole Hospital Recruiting
Poole, United Kingdom, BH15 2JB
Principal Investigator: Charles Hillier         
Royal Hallamshire Hospital Recruiting
Sheffield, United Kingdom, S10 2JF
Principal Investigator: Basil Sharrack         
University Hospital of North Staffordshire Not yet recruiting
Stoke-on-Trent, United Kingdom, ST4 6QG
Principal Investigator: Seema Kalra         
Morriston & Neath Port Talbot Hospitals (Abertawe Bro Morgannwg University Local Health Board) Recruiting
Swansea, United Kingdom
Principal Investigator: Owen Pearson         
Sponsors and Collaborators
University College, London
University of Edinburgh
Queen Mary University of London
London School of Hygiene and Tropical Medicine
University of Leeds
The Leeds Teaching Hospitals NHS Trust
Imperial College Healthcare NHS Trust

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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT03387670     History of Changes
Other Study ID Numbers: 17/0158
2017-003328-56 ( EudraCT Number )
First Posted: January 2, 2018    Key Record Dates
Last Update Posted: October 18, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Sclerosis
Multiple Sclerosis
Neoplasm Metastasis
Multiple Sclerosis, Chronic Progressive
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Neoplastic Processes
Neoplasms
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors