Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial

Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in...

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Published inLancet neurology Vol. 19; no. 3; pp. 214 - 225
Main Authors Chataway, Jeremy, De Angelis, Floriana, Connick, Peter, Parker, Richard A, Plantone, Domenico, Doshi, Anisha, John, Nevin, Stutters, Jonathan, MacManus, David, Prados Carrasco, Ferran, Barkhof, Frederik, Ourselin, Sebastien, Braisher, Marie, Ross, Moira, Cranswick, Gina, Pavitt, Sue H, Giovannoni, Gavin, Gandini Wheeler-Kingshott, Claudia Angela, Hawkins, Clive, Sharrack, Basil, Bastow, Roger, Weir, Christopher J, Stallard, Nigel, Chandran, Siddharthan, Gandini Wheeler-Kingshott, Claudia A.M., Williams, Thomas, Beyene, Tiggy, Bassan, Vanessa, Zapata, Alvin, Lyle, Dawn, Cameron, James, Mollison, Daisy, Colville, Shuna, Dhillon, Baljean, Weir, Christopher J., Parker, Richard A., Gnanapavan, Sharmilee, Nicholas, Richard, Rashid, Waqar, Aram, Julia, Ford, Helen, Overell, James, Young, Carolyn, Arndt, Heinke, Duddy, Martin, Guadagno, Joe, Evangelou, Nikolaos, Craner, Matthew, Palace, Jacqueline, Hobart, Jeremy, Paling, David, Kalra, Seema, McLean, Brendan
Format Journal Article
LanguageEnglish
Published England Elsevier Ltd 01.03.2020
Elsevier Limited
Lancet Pub. Group
Subjects
Administration, Oral
Adult
Amiloride
Amiloride - therapeutic use
Atrophy
Axon guidance
Brain
Clinical trials
Coronary artery
Coronary artery disease
Dementia
Disease Progression
Double-Blind Method
Double-blind studies
Drugs
Encephalomyelitis
Female
Fluoxetine
Fluoxetine - therapeutic use
Heart diseases
Humans
Huntingtons disease
Lung cancer
Magnetic Resonance Imaging
Male
Metabolism
Metastases
Middle Aged
Motor neurone disease
Multiple sclerosis
Multiple Sclerosis - drug therapy
Multiple Sclerosis, Chronic Progressive - drug therapy
Nervous system
Neurodegeneration
Neuroprotection
Neuroprotective Agents - therapeutic use
Parkinson's disease
Patients
Riluzole - therapeutic use
Subject heading schemes
Systematic review
Thrombosis
Treatment Outcome
United Kingdom > UK
Online AccessGet full text
ISSN1474-4422
1474-4465
1474-4465
DOI10.1016/S1474-4422(19)30485-5

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Abstract Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25–65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0–6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259. Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI −0·4 to 0·5; p=0·99]; fluoxetine vs placebo −0·1% [–0·5 to 0·3; p=0·86]; riluzole vs placebo −0·1% [–0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes. The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine. Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.
AbstractList Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25–65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0–6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259. Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI −0·4 to 0·5; p=0·99]; fluoxetine vs placebo −0·1% [–0·5 to 0·3; p=0·86]; riluzole vs placebo −0·1% [–0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes. The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine. Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.
Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259. Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes. The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine. Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.
Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.BACKGROUNDNeurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource.We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.METHODSWe did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0-6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259.Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.FINDINGSBetween Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI -0·4 to 0·5; p=0·99]; fluoxetine vs placebo -0·1% [-0·5 to 0·3; p=0·86]; riluzole vs placebo -0·1% [-0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes.The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.INTERPRETATIONThe absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine.Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.FUNDINGEfficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.
Summary Background Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. Methods We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25–65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4·0–6·5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials.gov, NCT01910259. Findings Between Jan 29, 2015, and June 22, 2016, 445 patients were randomly allocated amiloride (n=111), fluoxetine (n=111), riluzole (n=111), or placebo (n=112). The primary analysis included 393 patients who were allocated amiloride (n=99), fluoxetine (n=96), riluzole (n=99), and placebo (n=99). No difference was noted between any active treatment and placebo in PBVC (amiloride vs placebo, 0·0% [95% CI −0·4 to 0·5; p=0·99]; fluoxetine vs placebo −0·1% [–0·5 to 0·3; p=0·86]; riluzole vs placebo −0·1% [–0·6 to 0·3; p=0·77]). No emergent safety issues were reported. The incidence of serious adverse events was low and similar across study groups (ten [9%] patients in the amiloride group, seven [6%] in the fluoxetine group, 12 [11%] in the riluzole group, and 13 [12%] in the placebo group). The most common serious adverse events were infections and infestations. Three patients died during the study, from causes judged unrelated to active treatment; one patient assigned amiloride died from metastatic lung cancer, one patient assigned riluzole died from ischaemic heart disease and coronary artery thrombosis, and one patient assigned fluoxetine had a sudden death (primary cause) with multiple sclerosis and obesity listed as secondary causes. Interpretation The absence of evidence for neuroprotection in this adequately powered trial indicates that exclusively targeting these aspects of axonal pathobiology in patients with secondary progressive multiple sclerosis is insufficient to mitigate neuroaxonal loss. These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials. This trial provides a template for future simultaneous testing of multiple disease-modifying medicines in neurological medicine. Funding Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership, UK Multiple Sclerosis Society, and US National Multiple Sclerosis Society.
Author Mollison, Daisy
Stutters, Jonathan
Colville, Shuna
Craner, Matthew
Ford, Helen
Braisher, Marie
Gandini Wheeler-Kingshott, Claudia A.M.
Paling, David
Doshi, Anisha
Hawkins, Clive
Palace, Jacqueline
Barkhof, Frederik
Nicholas, Richard
Beyene, Tiggy
Gnanapavan, Sharmilee
Bastow, Roger
Gandini Wheeler-Kingshott, Claudia Angela
Arndt, Heinke
Guadagno, Joe
McLean, Brendan
Evangelou, Nikolaos
Hobart, Jeremy
Weir, Christopher J
Dhillon, Baljean
Cameron, James
Parker, Richard A
Stallard, Nigel
Ourselin, Sebastien
John, Nevin
Overell, James
MacManus, David
Pavitt, Sue H
Ross, Moira
Chataway, Jeremy
Bassan, Vanessa
Weir, Christopher J.
Aram, Julia
Rashid, Waqar
Parker, Richard A.
Plantone, Domenico
Kalra, Seema
Young, Carolyn
Prados Carrasco, Ferran
Giovannoni, Gavin
Williams, Thomas
Chandran, Siddharthan
Lyle, Dawn
Sharrack, Basil
Zapata, Alvin
De Angelis, Floriana
Connick, Peter
Duddy, Martin
Cranswick, Gina
AuthorAffiliation h Dental Translational and Clinical Research Unit, University of Leeds, Leeds, UK
n Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
c Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
l Department of Neuroscience, Royal Hallamshire Hospital, Sheffield, UK
d Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK
b Department of Medical Physics and Biomedical Engineering, Centre for Medical Image Computing, UCL, London, UK
f Department of Radiology and Nuclear Medicine, VU University Medical Centre, Amsterdam, Netherlands
o National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK
i Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University, London, UK
k Keele Medical School and Institute for Science and Technology in Medicine, Keele University, Keele, UK
a Queen Square Multiple
AuthorAffiliation_xml – name: b Department of Medical Physics and Biomedical Engineering, Centre for Medical Image Computing, UCL, London, UK
– name: h Dental Translational and Clinical Research Unit, University of Leeds, Leeds, UK
– name: k Keele Medical School and Institute for Science and Technology in Medicine, Keele University, Keele, UK
– name: c Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
– name: m Patient Representative, Multiple Sclerosis Society, London, UK
– name: n Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK
– name: f Department of Radiology and Nuclear Medicine, VU University Medical Centre, Amsterdam, Netherlands
– name: l Department of Neuroscience, Royal Hallamshire Hospital, Sheffield, UK
– name: o National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK
– name: d Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK
– name: e Universitat Oberta de Catalunya, Barcelona, Spain
– name: a Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– name: i Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University, London, UK
– name: g School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK
– name: j Brain MRI 3T Research Center, IRCCS Mondino Foundation, Pavia, Italy
Author_xml – sequence: 1
  givenname: Jeremy
  surname: Chataway
  fullname: Chataway, Jeremy
  email: j.chataway@ucl.ac.uk
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 2
  givenname: Floriana
  surname: De Angelis
  fullname: De Angelis, Floriana
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 3
  givenname: Peter
  surname: Connick
  fullname: Connick, Peter
  organization: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
– sequence: 4
  givenname: Richard A
  surname: Parker
  fullname: Parker, Richard A
  organization: Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK
– sequence: 5
  givenname: Domenico
  surname: Plantone
  fullname: Plantone, Domenico
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 6
  givenname: Anisha
  surname: Doshi
  fullname: Doshi, Anisha
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 7
  givenname: Nevin
  surname: John
  fullname: John, Nevin
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 8
  givenname: Jonathan
  surname: Stutters
  fullname: Stutters, Jonathan
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 9
  givenname: David
  surname: MacManus
  fullname: MacManus, David
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 10
  givenname: Ferran
  surname: Prados Carrasco
  fullname: Prados Carrasco, Ferran
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 11
  givenname: Frederik
  surname: Barkhof
  fullname: Barkhof, Frederik
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 12
  givenname: Sebastien
  surname: Ourselin
  fullname: Ourselin, Sebastien
  organization: School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK
– sequence: 13
  givenname: Marie
  surname: Braisher
  fullname: Braisher, Marie
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 14
  givenname: Moira
  surname: Ross
  fullname: Ross, Moira
  organization: Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK
– sequence: 15
  givenname: Gina
  surname: Cranswick
  fullname: Cranswick, Gina
  organization: Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK
– sequence: 16
  givenname: Sue H
  surname: Pavitt
  fullname: Pavitt, Sue H
  organization: Dental Translational and Clinical Research Unit, University of Leeds, Leeds, UK
– sequence: 17
  givenname: Gavin
  surname: Giovannoni
  fullname: Giovannoni, Gavin
  organization: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University, London, UK
– sequence: 18
  givenname: Claudia Angela
  surname: Gandini Wheeler-Kingshott
  fullname: Gandini Wheeler-Kingshott, Claudia Angela
  organization: Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK
– sequence: 19
  givenname: Clive
  surname: Hawkins
  fullname: Hawkins, Clive
  organization: Keele Medical School and Institute for Science and Technology in Medicine, Keele University, Keele, UK
– sequence: 20
  givenname: Basil
  surname: Sharrack
  fullname: Sharrack, Basil
  organization: Department of Neuroscience, Royal Hallamshire Hospital, Sheffield, UK
– sequence: 21
  givenname: Roger
  surname: Bastow
  fullname: Bastow, Roger
  organization: Patient Representative, Multiple Sclerosis Society, London, UK
– sequence: 22
  givenname: Christopher J
  surname: Weir
  fullname: Weir, Christopher J
  organization: Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/31981516$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
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Hobart, Jeremy
Weir, Christopher J
Colville, Shuna
Dhillon, Baljean
Craner, Matthew
Ford, Helen
Braisher, Marie
Cameron, James
Parker, Richard A
Stallard, Nigel
John, Nevin
Paling, David
Doshi, Anisha
Hawkins, Clive
Overell, James
Ross, Moira
Palace, Jacqueline
Nicholas, Richard
Chataway, Jeremy
Bassan, Vanessa
Aram, Julia
Rashid, Waqar
Plantone, Domenico
Beyene, Tiggy
Kalra, Seema
Gnanapavan, Sharmilee
Bastow, Roger
Young, Carolyn
Arndt, Heinke
Guadagno, Joe
McLean, Brendan
Evangelou, Nikolaos
Gandini Wheeler-Kingshott, Claudia A M
Giovannoni, Gavin
Williams, Thomas
Chandran, Siddharthan
Lyle, Dawn
Zapata, Alvin
Sharrack, Basil
De Angelis, Floriana
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Copyright 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
2020. The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. This work is published under https://creativecommons.org/licenses/by/3.0/ (theLicense”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license 2020
Copyright_xml – notice: 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
– notice: Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
– notice: 2020. The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. This work is published under https://creativecommons.org/licenses/by/3.0/ (theLicense”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
– notice: 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license 2020
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Snippet Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and...
Summary Background Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of...
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SubjectTerms Administration, Oral
Adult
Amiloride
Amiloride - therapeutic use
Atrophy
Axon guidance
Brain
Clinical trials
Coronary artery
Coronary artery disease
Dementia
Disease Progression
Double-Blind Method
Double-blind studies
Drugs
Encephalomyelitis
Female
Fluoxetine
Fluoxetine - therapeutic use
Heart diseases
Humans
Huntingtons disease
Lung cancer
Magnetic Resonance Imaging
Male
Metabolism
Metastases
Middle Aged
Motor neurone disease
Multiple sclerosis
Multiple Sclerosis - drug therapy
Multiple Sclerosis, Chronic Progressive - drug therapy
Nervous system
Neurodegeneration
Neuroprotection
Neuroprotective Agents - therapeutic use
Parkinson's disease
Patients
Riluzole - therapeutic use
Subject heading schemes
Systematic review
Thrombosis
Treatment Outcome
Title Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial
URI https://www.clinicalkey.com/#!/content/1-s2.0-S1474442219304855
https://dx.doi.org/10.1016/S1474-4422(19)30485-5
https://www.ncbi.nlm.nih.gov/pubmed/31981516
https://www.proquest.com/docview/2425650730
https://www.proquest.com/docview/2345508935
https://pubmed.ncbi.nlm.nih.gov/PMC7029307
Volume 19
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