Multiple Sclerosis-Simvastatin Trial 2

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Secondary Progressive Multiple Sclerosis (SPMS)

Intervention / Treatment
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* Drug: Simvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 EDSS 4.0 - 6.5 (inclusive) Aged 25 to 65 years old Patients must be able and willing to comply with the terms of this protocol. Written informed consent provided Exclusion Criteria: Relapse within 3 months of baseline visit; 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) Significant organ co-morbidity e.g. cardiac failure, renal failure, malignancy; Screening levels of alanine aminotransferase (ALT) / aspartate aminotransferase (AST) or creatinine kinase (CK) ≥3 x upper limit of normal (ULN); Current use of a statin; or any use within the last 6 months; 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; Primary progressive MS; Diabetes mellitus type 1; Uncontrolled hypothyroidism; 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; Use of immunosuppressants (e.g. azathioprine, methotrexate, ciclosporine) or disease modifying treatments (avonex, rebif, betaferon, glatiramer) within the previous 6 months; Use of mitoxantrone, natalizumab, alemtuzumab, daclizumab or other monoclonal antibody treatment, if treated within the last 12 months; Use of fingolimod, fumarate, teriflunomide within the last 12 months; Use of other experimental disease modifying treatment within the last 6 months; Commencement of fampridine ≤6 months from day of randomisation; Concurrent participation in another clinical trial of an investigational medicinal product or medical device; Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Simvastatin<br> | Drug: Simvastatin<br>* 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<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* One (1) placebo tablet once daily at night for 1 month Two (2) placebo tablets once daily at night, for the next 35 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to confirmed disability progression between simvastatin and placebo arm based on change in EDSS scores compared to baseline. | 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. | 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate on the patient reported outcome form Multiple Sclerosis Walking Scale-12 version 2 (MSWS-12v2) | 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. | Annually - baseline, month 12, 24 and 36 | 
| Response rate on the patient reported outcome form Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) | 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. | Annually - baseline, month 12, 24 and 36 | 
| Cost effectiveness of intervention | 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. | 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 | 
| Change in time taken to complete 25-Foot Timed Walk (T25FW) | T25-FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk | 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 | 
| Change in time taken to complete 9 hole peg test (9HPT) | 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 monthly - baseline, month 6, 12, 18, 24, 30, 36 | 
| Evaluating change in degree of disability based on the modified Rankin scale (mRS) | mRS is used to evaluate the degree of disability in daily activities of those with neurological disability. | Annually - baseline, month 12, 24 and 36 | 
| Difference in the number and severity of multiple sclerosis related relapse events between treatment groups | 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. | 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 | 
| Change in visual function based on the Sloan Low Contrast Visual Acuity (SLCVA) | 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. | Annually - baseline, month 12, 24 and 36 | 
| Difference in patient reported quality of life based on the EuroQoL Health Related Quality of Life - 5 Dimensions - 5 Levels (EQ-5D 5L) scores | 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 | 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 | 
| Change in a modified Multiple Sclerosis Functional Composite scores | 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. | Annually - baseline, month 12, 24 and 36 | 
| Change in cognitive performance as measured by Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) | 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) | Baseline and month 36 | 
| Change in cognitive impairment based on Symbol Digit Modalities Test (SDMT) scores | 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. | Annually - baseline, month 12, 24 and 36 | 
| Evaluating the time to disability progression based on a secondary composite progression outcome measure | 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) | 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 | 
| Change in fatigue as measured by the Chalder Fatigue Scale | A questionnaire measuring the severity of physical and mental fatigue. The total score range is minimum of 0 and maximum of 33. For the subscales, physical fatigue score has a minimum of 0 and maximum of 21. The Mental fatigue score has a minimum of 0 and maximum of 12. | Annually - baseline, month 12, 24 and 36 | 
| Change in rates of service utilisation as measured by the Client Service Receipt Inventory (CSRI) questionnaire | The CSRI is a questionnaire that collects information on service utilisation, income, accommodation and other cost-related variables. Its primary purpose is to allow resource use patterns in each of the two arms to be described, and support costs to be estimated for health economics purposes. | 6 monthly - baseline, month 6, 12, 18, 24, 30, 36 |