Investigation of Simvastatin in Secondary Progressive Multiple Sclerosis (MS-STAT)

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

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.

Study Overview

• Status: Completed
• Conditions: Secondary Progressive Multiple Sclerosis
• Intervention / Treatment: Drug: Simvastatin; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Brighton, United Kingdom, BN2 5BE
    • Brighton & Sussex University Hospitals NHS Trust, Eastern Road
  • Buckinghamshire
    • Chalfont St. Peter, Buckinghamshire, United Kingdom, SL9 0RJ
      • MRI Unit, National Society for Epilepsy, Chesham Lane
  • London
    • Hammersmith, London, United Kingdom, W6 8RF
      • Charing Cross Hospital, Fulham Palace Road

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2; Placebo	Drug: Placebo; Oral placebo tablet once daily for 24 months
Active Comparator: 1; Simvastatin 80mg OD	Drug: Simvastatin; 80mg simvastatin oral once daily for 24 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 5"extremely". 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 5"extremely". 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 5"extremely". 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

Collaborators and Investigators

• Sponsor: Imperial College London
• Investigators: Principal Investigator: Jeremy Chataway, MB BCh, PhD, Imperial College London

Publications and helpful links

General Publications

• Chan D, Binks S, Nicholas JM, Frost C, Cardoso MJ, Ourselin S, Wilkie D, Nicholas R, Chataway J. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol. 2017 Aug;16(8):591-600. doi: 10.1016/S1474-4422(17)30113-8. Epub 2017 Jun 7.
• 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. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014 Jun 28;383(9936):2213-21. doi: 10.1016/S0140-6736(13)62242-4. Epub 2014 Mar 19.
• Williams TE, Holdsworth KP, Nicholas JM, Eshaghi A, Katsanouli T, Wellington H, Heslegrave A, Zetterberg H, Frost C, Chataway J. Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial. Neurol Neuroimmunol Neuroinflamm. 2022 Jan 14;9(2):e1130. doi: 10.1212/NXI.0000000000001130. Print 2022 Mar.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2008
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): November 1, 2011

Study Registration Dates

• First Submitted: March 26, 2008
• First Submitted That Met QC Criteria: March 28, 2008
• First Posted (Estimate): March 31, 2008

Study Record Updates

• Last Update Posted (Actual): December 12, 2019
• Last Update Submitted That Met QC Criteria: November 21, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: MRI; Simvastatin; Secondary progressive Multiple Sclerosis
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Neoplastic Processes; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Neoplasm Metastasis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: MSTC-001; MREC: 07/Q1602/73 (Other Identifier: MREC); 2006-006347-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: We are still analysing post-hoc data. The International Progressive MS Alliance have access to some of the data.
• IPD Sharing Time Frame: next 2 years
• IPD Sharing Access Criteria: via the CI
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No