Secondary Progressive Multiple Sclerosis
Conditions
Keywords
Secondary progressive Multiple Sclerosis, Simvastatin, MRI
Brief summary
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
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.
Interventions
DRUGSimvastatin
80mg simvastatin oral once daily for 24 months
DRUGPlacebo
Oral placebo tablet once daily for 24 months
Sponsors
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
over-encapsulation of IMP
Intervention model description
RCT
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage Change in Whole Brain Volume | 24 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Disability (MSFC Z Score). | 24 months | Negative value implies worsening and a positive value implies improvement. |
| Evaluation of Disability (MSFC Walk). | 24 months | 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. |
| Evaluation of Disability (MSFC Peg Test). | 24 months | 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. |
| Evaluation of Disability (EDSS). | 24 months | 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. |
| Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Total Score) | 24 months | 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). |
| Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Physical Score) | 24 months | 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). |
| Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Psychological Score) | 24 months | 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). |
| Evaluation of Disability (MSFC PASAT). | 24 months | 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. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin 80mg OD Simvastatin: 80mg simvastatin oral once daily for 24 months | 70 |
| Placebo Placebo: Oral placebo tablet once daily for 24 months | 70 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | Simvastatin 80mg OD |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 70 Participants | 140 Participants | 70 Participants |
| Age, Continuous | 51.1 years STANDARD_DEVIATION 6.8 | 51.3 years STANDARD_DEVIATION 6.9 | 51.5 years STANDARD_DEVIATION 7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 63 Participants | 132 Participants | 69 Participants |
| Region of Enrollment United Kingdom | 70 Participants | 140 Participants | 70 Participants |
| Sex: Female, Male Female | 48 Participants | 97 Participants | 49 Participants |
| Sex: Female, Male Male | 22 Participants | 43 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 70 | 0 / 70 |
| other Total, other adverse events | 49 / 70 | 54 / 70 |
| serious Total, serious adverse events | 9 / 70 | 14 / 70 |
Outcome results
Primary
Percentage Change in Whole Brain Volume
Time frame: 24 months
Population: 1 participant had a missing data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80mg OD | Percentage Change in Whole Brain Volume | 0.288 percentage of brain volumen change | Standard Deviation 0.521 |
| Placebo | Percentage Change in Whole Brain Volume | 0.584 percentage of brain volumen change | Standard Deviation 0.498 |
p-value: 0.003BBSI=brain boundary shift integral
Secondary
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).
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80mg OD | Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Physical Score) | 51.7 score on a scale | Standard Deviation 11.4 |
| Placebo | Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Physical Score) | 56.3 score on a scale | Standard Deviation 11.8 |
Secondary
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).
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80mg OD | Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Psychological Score) | 18.3 score on a scale | Standard Deviation 5.8 |
| Placebo | Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Psychological Score) | 19.8 score on a scale | Standard Deviation 6 |
Secondary
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).
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80mg OD | Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Total Score) | 70.1 score on a scale | Standard Deviation 15.6 |
| Placebo | Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Total Score) | 76.1 score on a scale | Standard Deviation 16.3 |
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80mg OD | Evaluation of Disability (EDSS). | 5.93 score on a scale | Standard Deviation 1.11 |
| Placebo | Evaluation of Disability (EDSS). | 6.35 score on a scale | Standard Deviation 0.83 |
p-value: 0.05ANCOVA
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80mg OD | Evaluation of Disability (MSFC PASAT). | 38.3 score on a scale | Standard Deviation 15.4 |
| Placebo | Evaluation of Disability (MSFC PASAT). | 35.2 score on a scale | Standard Deviation 18 |
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80mg OD | Evaluation of Disability (MSFC Peg Test). | 0.033 speed per second | Standard Deviation 0.01 |
| Placebo | Evaluation of Disability (MSFC Peg Test). | 0.033 speed per second | Standard Deviation 0.01 |
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80mg OD | Evaluation of Disability (MSFC Walk). | 1.83 foot per second | Standard Deviation 1.61 |
| Placebo | Evaluation of Disability (MSFC Walk). | 1.55 foot per second | Standard Deviation 1.19 |
Secondary
Evaluation of Disability (MSFC Z Score).
Negative value implies worsening and a positive value implies improvement.
Time frame: 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin 80mg OD | Evaluation of Disability (MSFC Z Score). | -0.78 score on a scale | Standard Deviation 2.06 |
| Placebo | Evaluation of Disability (MSFC Z Score). | -1.21 score on a scale | Standard Deviation 2.59 |