Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK

James Blackstone; Thomas Williams; Jennifer M Nicholas; Ekaterina Bordea; Floriana De Angelis; Alessia Bianchi; Alberto Calvi; Anisha Doshi; Nevin John; Sean Apap Mangion; Charles Wade; Rachel Merry; Gil Barton; Dawn Lyle; Elisabeth Jarman; Don Mahad; Abdullah Shehu; Tarunya Arun; Gavin McDonnell; Ruth Geraldes; Matthew Craner; Charles Hillier; Jeban Ganesalingam; Leonora Fisniku; Jeremy Hobart; Cord Spilker; Neil Robertson; Seema Kalra; Stefano Pluchino; Sreedharan Harikrishnan; Miriam Mattoscio; Timothy Harrower; Carolyn Young; Martin Lee; Suresh Chhetri; Fayyaz Ahmed; David Rog; Eli Silber; Paul Gallagher; Martin Duddy; Agne Straukiene; Richard Nicholas; Claire Rice; Stuart J Nixon; Judy Beveridge; Annie Hawton; Susan Tebbs; Marie Braisher; Gavin Giovannoni; Olga Ciccarelli; John Greenwood; Alan J Thompson; Rachael Hunter; Sue Pavitt; Owen Pearson; Nikos Evangelou; Basil Sharrack; Ian Galea; Siddharthan Chandran; Helen L Ford; Chris Frost; Jeremy Chataway

doi:10.1136/bmjopen-2024-086414

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK

James Blackstone, Thomas Williams, Jennifer M Nicholas, Ekaterina Bordea, Floriana De Angelis, Alessia Bianchi, Alberto Calvi, Anisha Doshi, Nevin John, Sean Apap Mangion, Charles Wade, Rachel Merry, Gil Barton, Dawn Lyle, Elisabeth Jarman, Don Mahad, Abdullah Shehu, Tarunya Arun, Gavin McDonnell, Ruth GeraldesMatthew Craner, Charles Hillier, Jeban Ganesalingam, Leonora Fisniku, Jeremy Hobart, Cord Spilker, Neil Robertson, Seema Kalra, Stefano Pluchino, Sreedharan Harikrishnan, Miriam Mattoscio, Timothy Harrower, Carolyn Young, Martin Lee, Suresh Chhetri, Fayyaz Ahmed, David Rog, Eli Silber, Paul Gallagher, Martin Duddy, Agne Straukiene, Richard Nicholas, Claire Rice, Stuart J Nixon, Judy Beveridge, Annie Hawton, Susan Tebbs, Marie Braisher, Gavin Giovannoni, Olga Ciccarelli, John Greenwood, Alan J Thompson, Rachael Hunter, Sue Pavitt, Owen Pearson, Nikos Evangelou, Basil Sharrack, Ian Galea, Siddharthan Chandran, Helen L Ford, Chris Frost, Jeremy Chataway^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS.

METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur.

ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations.

TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

Original language	English
Pages (from-to)	e086414
Journal	BMJ Open
Volume	14
Issue number	9
DOIs	https://doi.org/10.1136/bmjopen-2024-086414
Publication status	Published - 16 Sept 2024

Keywords / Materials (for Non-textual outputs)

Humans
Simvastatin/therapeutic use
Double-Blind Method
Multiple Sclerosis, Chronic Progressive/drug therapy
Disease Progression
United Kingdom
Middle Aged
Adult
Multicenter Studies as Topic
Clinical Trials, Phase III as Topic
Cost-Benefit Analysis
Male
Female
Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
Randomized Controlled Trials as Topic
Disability Evaluation
Aged
Treatment Outcome

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Blackstone, J., Williams, T., Nicholas, J. M., Bordea, E., De Angelis, F., Bianchi, A., Calvi, A., Doshi, A., John, N., Apap Mangion, S., Wade, C., Merry, R., Barton, G., Lyle, D., Jarman, E., Mahad, D., Shehu, A., Arun, T., McDonnell, G., ... Chataway, J. (2024). Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK. BMJ Open, 14(9), e086414. https://doi.org/10.1136/bmjopen-2024-086414

@article{a4f30453ebb14da78c1a8545bf08ab7f,

title = "Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK",

abstract = "INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS.METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur.ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations.TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.",

keywords = "Humans, Simvastatin/therapeutic use, Double-Blind Method, Multiple Sclerosis, Chronic Progressive/drug therapy, Disease Progression, United Kingdom, Middle Aged, Adult, Multicenter Studies as Topic, Clinical Trials, Phase III as Topic, Cost-Benefit Analysis, Male, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use, Randomized Controlled Trials as Topic, Disability Evaluation, Aged, Treatment Outcome",

author = "James Blackstone and Thomas Williams and Nicholas, {Jennifer M} and Ekaterina Bordea and {De Angelis}, Floriana and Alessia Bianchi and Alberto Calvi and Anisha Doshi and Nevin John and {Apap Mangion}, Sean and Charles Wade and Rachel Merry and Gil Barton and Dawn Lyle and Elisabeth Jarman and Don Mahad and Abdullah Shehu and Tarunya Arun and Gavin McDonnell and Ruth Geraldes and Matthew Craner and Charles Hillier and Jeban Ganesalingam and Leonora Fisniku and Jeremy Hobart and Cord Spilker and Neil Robertson and Seema Kalra and Stefano Pluchino and Sreedharan Harikrishnan and Miriam Mattoscio and Timothy Harrower and Carolyn Young and Martin Lee and Suresh Chhetri and Fayyaz Ahmed and David Rog and Eli Silber and Paul Gallagher and Martin Duddy and Agne Straukiene and Richard Nicholas and Claire Rice and Nixon, {Stuart J} and Judy Beveridge and Annie Hawton and Susan Tebbs and Marie Braisher and Gavin Giovannoni and Olga Ciccarelli and John Greenwood and Thompson, {Alan J} and Rachael Hunter and Sue Pavitt and Owen Pearson and Nikos Evangelou and Basil Sharrack and Ian Galea and Siddharthan Chandran and Ford, {Helen L} and Chris Frost and Jeremy Chataway",

note = "{\textcopyright} Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.",

year = "2024",

month = sep,

day = "16",

doi = "10.1136/bmjopen-2024-086414",

language = "English",

volume = "14",

pages = "e086414",

journal = "BMJ Open",

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number = "9",

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Blackstone, J, Williams, T, Nicholas, JM, Bordea, E, De Angelis, F, Bianchi, A, Calvi, A, Doshi, A, John, N, Apap Mangion, S, Wade, C, Merry, R, Barton, G, Lyle, D, Jarman, E, Mahad, D, Shehu, A, Arun, T, McDonnell, G, Geraldes, R, Craner, M, Hillier, C, Ganesalingam, J, Fisniku, L, Hobart, J, Spilker, C, Robertson, N, Kalra, S, Pluchino, S, Harikrishnan, S, Mattoscio, M, Harrower, T, Young, C, Lee, M, Chhetri, S, Ahmed, F, Rog, D, Silber, E, Gallagher, P, Duddy, M, Straukiene, A, Nicholas, R, Rice, C, Nixon, SJ, Beveridge, J, Hawton, A, Tebbs, S, Braisher, M, Giovannoni, G, Ciccarelli, O, Greenwood, J, Thompson, AJ, Hunter, R, Pavitt, S, Pearson, O, Evangelou, N, Sharrack, B, Galea, I, Chandran, S, Ford, HL, Frost, C & Chataway, J 2024, 'Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK', BMJ Open, vol. 14, no. 9, pp. e086414. https://doi.org/10.1136/bmjopen-2024-086414

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK. / Blackstone, James; Williams, Thomas; Nicholas, Jennifer M et al.
In: BMJ Open, Vol. 14, No. 9, 16.09.2024, p. e086414.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2)

T2 - protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK

AU - Blackstone, James

AU - Williams, Thomas

AU - Nicholas, Jennifer M

AU - Bordea, Ekaterina

AU - De Angelis, Floriana

AU - Bianchi, Alessia

AU - Calvi, Alberto

AU - Doshi, Anisha

AU - John, Nevin

AU - Apap Mangion, Sean

AU - Wade, Charles

AU - Merry, Rachel

AU - Barton, Gil

AU - Lyle, Dawn

AU - Jarman, Elisabeth

AU - Mahad, Don

AU - Shehu, Abdullah

AU - Arun, Tarunya

AU - McDonnell, Gavin

AU - Geraldes, Ruth

AU - Craner, Matthew

AU - Hillier, Charles

AU - Ganesalingam, Jeban

AU - Fisniku, Leonora

AU - Hobart, Jeremy

AU - Spilker, Cord

AU - Robertson, Neil

AU - Kalra, Seema

AU - Pluchino, Stefano

AU - Harikrishnan, Sreedharan

AU - Mattoscio, Miriam

AU - Harrower, Timothy

AU - Young, Carolyn

AU - Lee, Martin

AU - Chhetri, Suresh

AU - Ahmed, Fayyaz

AU - Rog, David

AU - Silber, Eli

AU - Gallagher, Paul

AU - Duddy, Martin

AU - Straukiene, Agne

AU - Nicholas, Richard

AU - Rice, Claire

AU - Nixon, Stuart J

AU - Beveridge, Judy

AU - Hawton, Annie

AU - Tebbs, Susan

AU - Braisher, Marie

AU - Giovannoni, Gavin

AU - Ciccarelli, Olga

AU - Greenwood, John

AU - Thompson, Alan J

AU - Hunter, Rachael

AU - Pavitt, Sue

AU - Pearson, Owen

AU - Evangelou, Nikos

AU - Sharrack, Basil

AU - Galea, Ian

AU - Chandran, Siddharthan

AU - Ford, Helen L

AU - Frost, Chris

AU - Chataway, Jeremy

PY - 2024/9/16

Y1 - 2024/9/16

N2 - INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS.METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur.ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations.TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

AB - INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS.METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur.ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations.TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

KW - Humans

KW - Simvastatin/therapeutic use

KW - Double-Blind Method

KW - Multiple Sclerosis, Chronic Progressive/drug therapy

KW - Disease Progression

KW - United Kingdom

KW - Middle Aged

KW - Adult

KW - Multicenter Studies as Topic

KW - Clinical Trials, Phase III as Topic

KW - Cost-Benefit Analysis

KW - Male

KW - Female

KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use

KW - Randomized Controlled Trials as Topic

KW - Disability Evaluation

KW - Aged

KW - Treatment Outcome

U2 - 10.1136/bmjopen-2024-086414

DO - 10.1136/bmjopen-2024-086414

M3 - Article

C2 - 39284697

SN - 2044-6055

VL - 14

SP - e086414

JO - BMJ Open

JF - BMJ Open

IS - 9

ER -

Blackstone J, Williams T, Nicholas JM, Bordea E, De Angelis F, Bianchi A et al. Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK. BMJ Open. 2024 Sept 16;14(9):e086414. doi: 10.1136/bmjopen-2024-086414