MS-SMART trial design and recruitment status: a multi-arm phase IIB randomised double blind placebo-controlled clinical trial comparing the efficacy of three repositioned neuroprotective drugs in secondary progressive multiple sclerosis
Author(s): ,
P Connick
Affiliations:
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh
,
D Miller
Affiliations:
Queen Square Multiple Sclerosis Centre, NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, University College London, London
,
S Pavitt
Affiliations:
Leeds Institute of Health Sciences, University of Leeds, Leeds
,
G Giovannoni
Affiliations:
Department of Neurology, Barts and The London NHS Trust, The Royal London Hospital, London
,
C Wheeler-Kingshott
Affiliations:
Queen Square Multiple Sclerosis Centre, NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, University College London, London
,
C Weir
Affiliations:
Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh
,
N Stallard
Affiliations:
Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Warwick
,
C Hawkins
Affiliations:
Keele University Medical School, Royal Stoke University Hospital, Keele
,
B Sharrack
Affiliations:
Department of Neurology, Royal Hallamshire Hospital, Sheffield
,
G Cranswick
Affiliations:
Edinburgh Clinical Trials Unit, University of Edinburgh, Edinburgh, United Kingdom
,
S Chandran
Affiliations:
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh
,
J Chataway
Affiliations:
Queen Square Multiple Sclerosis Centre, NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, University College London, London
The MS-SMART Trialists
The MS-SMART Trialists
Affiliations:
ECTRIMS Online Library. Connick P. 09/16/16; 145886; P1203
Peter Connick
Peter Connick
Contributions
Abstract

Abstract: P1203

Type: Poster

Abstract Category: Therapy - disease modifying - Neuroprotection

Background: Drug repurposing (repositioning) provides an attractive paradigm to accelerate academic-led development of neuroprotective therapies for secondary progressive multiple sclerosis (SPMS), where there is no treatment. Having systematically reviewed all published animal and human literature to identify the leading candidates, we designed a multi-arm phase IIB trial as an efficient way to evaluate neuroprotective efficacy in SPMS.

Objectives: We will test if three candidate drugs chosen from an extensive search of published animal and human literature, will ultimately be effective in slowing the rate of brain volume loss in SPMS measured by MRI-derived atrophy rate against placebo.

Methods: The MS-SMART trial (ClinicalTrials.gov NCT01912059) is a multi-centre, multi-arm, double-blind, placebo-controlled phase IIB randomised controlled trial. 440 patients with worsening SPMS are being recruited across 13 UK sites. Patients with an EDSS score of 4.0-6.5, not on DMT, are randomised 1:1:1:1 between placebo, amiloride 5mg bd, riluzole 50mg bd and fluoxetine 20mg bd. Patients will be followed for 96 weeks with outcome data collected after 0, 24, 48 and 96 weeks. The primary endpoint is brain atrophy (percent brain volume change) on structural MR imaging at 96 weeks. Secondary endpoints are clinician and patient reported outcome measures, including Multiple Sclerosis Impact Scale v2 and Multiple Sclerosis Walking Scale v2. Exploratory endpoints include: grey and white matter, cervical cord atrophy, Magnetic Transfer Ratio and MR spectroscopy cerebrospinal fluid biomarkers and Optical Coherence Tomography (OCT).

Results: Recruitment has commenced since December 2014. Currently 321 patients have been randomised. The mean (sd) baseline features are: age 54yrs (7), duration of MS 22yrs (10), duration of SPMS 7yrs (5), and EDSS 5.9 (median 6). Significant co-morbidity (≥10%) includes: hypertension, hyperlipidaemia and hypothyroidism.

Conclusion: The cohort recruited is representative of the SPMS population. MS-SMART trial opens up a new platform for more efficient trial design and implementation in progressive MS and will report in 2018.

Disclosure: The MS-SMART trial is a project funded by Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. It is also supported by the UK Multiple Sclerosis Society, the University College London Hospitals/UCL Biomedical Research Centres funding scheme. Floriana De Angelis, Domenico Plantone, Anisha Doshi, James Cameroon, Richard Parker, Peter Connick, Christopher Weir, Nigel Stallard, Clive Hawkins, Gina Cranswick, Siddharthan Chandran, Sue Pavitt, Basil Sharrack have no conflict of interest relevant to the submitted work. Peter Connick is funded by The Wellcome Trust. Claudia Gandini Wheeler-Kingshott is on the editorial board of Functional Neurology and receives research grants (PI and co-applicant) from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis. Jeremy Chataway has support from the National Institute of Health Research (NIHR) University College London Hospitals/UCL Biomedical Research Centres funding scheme. He has attended advisory boards for Roche and Merck. He is local principal investigator for trials in multiple sclerosis funded by Novartis, Biogen, and GSK. He has an investigator grant from Novartis outside this work. David Miller has received honoraria through payments to his employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe & Bayer Schering Pharma. He has also received compensation through payments to his employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis, Apitope and Merck. The NMR Research Unit at UCL Institute of Neurology is supported by the UK MS Society and UCL-UCLH Biomedical Research Centre. Gavin Giovannoni has received compensation for serving as a consultant from AbbVie, Bayer Schering Healthcare, Biogen, Canbex, Eisai, Elan, Five Prime Therapeutics, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Ironwood Pharmaceuticals, Merck-Serono, Novartis, Pfizer, Roche, Synthon BV, Teva Pharmaceutical Industries, UCB and Vertex Pharmaceuticals. No other disclosures were reported.

Abstract: P1203

Type: Poster

Abstract Category: Therapy - disease modifying - Neuroprotection

Background: Drug repurposing (repositioning) provides an attractive paradigm to accelerate academic-led development of neuroprotective therapies for secondary progressive multiple sclerosis (SPMS), where there is no treatment. Having systematically reviewed all published animal and human literature to identify the leading candidates, we designed a multi-arm phase IIB trial as an efficient way to evaluate neuroprotective efficacy in SPMS.

Objectives: We will test if three candidate drugs chosen from an extensive search of published animal and human literature, will ultimately be effective in slowing the rate of brain volume loss in SPMS measured by MRI-derived atrophy rate against placebo.

Methods: The MS-SMART trial (ClinicalTrials.gov NCT01912059) is a multi-centre, multi-arm, double-blind, placebo-controlled phase IIB randomised controlled trial. 440 patients with worsening SPMS are being recruited across 13 UK sites. Patients with an EDSS score of 4.0-6.5, not on DMT, are randomised 1:1:1:1 between placebo, amiloride 5mg bd, riluzole 50mg bd and fluoxetine 20mg bd. Patients will be followed for 96 weeks with outcome data collected after 0, 24, 48 and 96 weeks. The primary endpoint is brain atrophy (percent brain volume change) on structural MR imaging at 96 weeks. Secondary endpoints are clinician and patient reported outcome measures, including Multiple Sclerosis Impact Scale v2 and Multiple Sclerosis Walking Scale v2. Exploratory endpoints include: grey and white matter, cervical cord atrophy, Magnetic Transfer Ratio and MR spectroscopy cerebrospinal fluid biomarkers and Optical Coherence Tomography (OCT).

Results: Recruitment has commenced since December 2014. Currently 321 patients have been randomised. The mean (sd) baseline features are: age 54yrs (7), duration of MS 22yrs (10), duration of SPMS 7yrs (5), and EDSS 5.9 (median 6). Significant co-morbidity (≥10%) includes: hypertension, hyperlipidaemia and hypothyroidism.

Conclusion: The cohort recruited is representative of the SPMS population. MS-SMART trial opens up a new platform for more efficient trial design and implementation in progressive MS and will report in 2018.

Disclosure: The MS-SMART trial is a project funded by Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. It is also supported by the UK Multiple Sclerosis Society, the University College London Hospitals/UCL Biomedical Research Centres funding scheme. Floriana De Angelis, Domenico Plantone, Anisha Doshi, James Cameroon, Richard Parker, Peter Connick, Christopher Weir, Nigel Stallard, Clive Hawkins, Gina Cranswick, Siddharthan Chandran, Sue Pavitt, Basil Sharrack have no conflict of interest relevant to the submitted work. Peter Connick is funded by The Wellcome Trust. Claudia Gandini Wheeler-Kingshott is on the editorial board of Functional Neurology and receives research grants (PI and co-applicant) from ISRT, EPSRC, Wings for Life, UK MS Society, Horizon2020, Biogen and Novartis. Jeremy Chataway has support from the National Institute of Health Research (NIHR) University College London Hospitals/UCL Biomedical Research Centres funding scheme. He has attended advisory boards for Roche and Merck. He is local principal investigator for trials in multiple sclerosis funded by Novartis, Biogen, and GSK. He has an investigator grant from Novartis outside this work. David Miller has received honoraria through payments to his employer, UCL Institute of Neurology, for Advisory Committee and/or Consultancy advice in multiple sclerosis studies from Biogen Idec, GlaxoSmithKline, Novartis, Merck, Chugai, Mitsubishi Pharma Europe & Bayer Schering Pharma. He has also received compensation through payments to his employer for performing central MRI analysis of multiple sclerosis trials from GlaxoSmithKline, Biogen Idec, Novartis, Apitope and Merck. The NMR Research Unit at UCL Institute of Neurology is supported by the UK MS Society and UCL-UCLH Biomedical Research Centre. Gavin Giovannoni has received compensation for serving as a consultant from AbbVie, Bayer Schering Healthcare, Biogen, Canbex, Eisai, Elan, Five Prime Therapeutics, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Ironwood Pharmaceuticals, Merck-Serono, Novartis, Pfizer, Roche, Synthon BV, Teva Pharmaceutical Industries, UCB and Vertex Pharmaceuticals. No other disclosures were reported.

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