Investigation of Simvastatin in Secondary Progressive Multiple Sclerosis

Study Overview
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Brief Summary
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To determine whether simvastatin at a dose of 80mg can reduce the rate of whole brain atrophy, as measured by MRI, over a 2-year time-period when compared to placebo.

Detailed Description
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The study has now completed see Primary publication: Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, Anderson V, Bangham CR, Clegg S, Nielsen C, Fox NC, Wilkie D, Nicholas JM, Calder VL, Greenwood J, Frost C, Nicholas R. Lancet. 2014 Jun 28;383(9936):2213-21. doi: 10.1016/S0140-6736(13)62242-4.

Official Title
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A Phase II Randomised, Placebo-controlled Clinical Trial of Simvastatin in Patients With Secondary Progressive Multiple Sclerosis.

Conditions
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Secondary Progressive Multiple Sclerosis

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 must have a confirmed diagnosis of multiple sclerosis and at randomisation 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 one point on the EDSS or clinical documentation of increasing disability. EDSS 4.0 - 6.5 inclusive Women of childbearing age will be required to use appropriate methods of contraception to avoid the unlikely teratogenic effects of simvastatin. Able to give written informed consent 18 - 65 years Exclusion Criteria: Unable to give informed consent Primary progressive MS Those that have experienced a relapse or have been treated with steroids (both i.v. and oral) 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. Patient is already taking or is anticipated to be taking a statin. Any medications that unfavourably interact with statins: fibrates, nicotinic acid, cyclosporine, azole anti-fungal preparations, macrolideantibiotics, protease inhibitors, nefazodone, verapamil, amiodarone, large amounts of grapefruit juice or alcohol abuse. The use of immunosuppressants (e.g. azathioprine, methotrexate, cyclosporine) or disease modifying treatments (avonex, rebif, betaferon, glatiramer) within the previous 6 months. The use of mitoxantrone if treated within the last 12 months. If the patient has ever been treated with alemtuzumab. If screening levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) or creatine kinase (CK) are three times the upper limit of normal patients should be excluded. Patient unable to tolerate baseline scan or scan not of adequate quality for analysis (e.g. too much movement artefact). If a female patient is pregnant or breast feeding

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: RCT
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Simvastatin 80mg OD | Drug: Simvastatin<br>* 80mg simvastatin oral once daily for 24 months<br>|
| Placebo Comparator: 2<br>Placebo | Drug: Placebo<br>* Oral placebo tablet once daily for 24 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in Whole Brain Volume |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Disability (EDSS). | Score (0 to 10), lower score less disability and better progression. For EDSS, mean score at 24 months was compared between treatment groups using an ANCOVA model adjusting for baseline score and minimisation variables. | 24 months | 
| Evaluation of Disability (MSFC Z Score). | Negative value implies worsening and a positive value implies improvement. | 24 months | 
| Evaluation of Disability (MSFC Walk). | The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the patient has reached the 25-foot mark. | 24 months | 
| Evaluation of Disability (MSFC Peg Test). | The patient is seated at a table with a small, shallow container holding nine pegs and a wood or plastic block containing nine empty holes. On a start command when a stopwatch is started, the patient picks up the nine pegs one at a time as quickly as possible, puts them in the nine holes, and, once they are in the holes, removes them again as quickly as possible one at a time, replacing them into the shallow container. The total time to complete the task is recorded. | 24 months | 
| Evaluation of Disability (MSFC PASAT). | The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. Single digits are presented every 3 seconds and the patient must add each new digit to the one immediately prior to it. Shorter inter-stimulus intervals, e.g., 2 seconds or less have also been used with the PASAT but tend to increase the difficulty of the task. Score 0 to 60, higher score less disability. | 24 months | 
| Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Total Score) | The MSIS-29 is a 29-item self-report measure with 20 items associated with a physical scale and 9 items with a psychological scale. Items ask about the impact of MS on day-to-day life in the past two weeks. All items have 5 response options: 1 not at all to 5extremely. Each of the two scales is scored by summing the responses across items, then converting to a 0-100 scale where 100 indicates a greater impact of the disease on daily function (worse health). | 24 months | 
| Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Physical Score) | The MSIS-29 is a 29-item self-report measure with 20 items associated with a physical scale and 9 items with a psychological scale. Items ask about the impact of MS on day-to-day life in the past two weeks. All items have 5 response options: 1 not at all to 5extremely. Each of the two scales are scored by summing the responses across items, then converting to a 0-100 scale where 100 indicates greater impact of disease on daily function (worse health). | 24 months | 
| Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Psychological Score) | The MSIS-29 is a 29-item self-report measure with 20 items associated with a physical scale and 9 items with a psychological scale. Items ask about the impact of MS on day-to-day life in the past two weeks. All items have 5 response options: 1 not at all to 5extremely. Each of the two scales is scored by summing the responses across items, then converting to a 0-100 scale where 100 indicates a greater impact of the disease on daily function (worse health). | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRI, Secondary progressive Multiple Sclerosis, Simvastatin