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Assessing treatment outcomes in multiple sclerosis trials and in the clinical setting

Key Points

  • Many clinical response measures are used in clinical trials: relapse-derived measures reflect the clinical effect of inflammatory activity, whereas disability-derived measures reflect the effect of neurodegeneration

  • Among the neuroimaging measures used in clinical trials, lesion-derived metrics capture inflammatory activity, whereas brain atrophy measures reflect neurodegeneration; the choice of measure should reflect the drug's mechanism of action

  • Owing to technical, financial and logistical barriers, most of the clinical and neuroimaging response measures used in trials are not used in the clinical setting

  • All clinical and neuroimaging response measures used in the clinic should have a clear meaning at the individual level

  • Combined (clinical and MRI) outcomes can be used in both trial and clinic settings, although their increased sensitivity to detect treatment effects particularly favours their use in trials

  • The use of patient-reported outcome measures is important because they capture the impact (and effects) of the intervention on clinical disability, MRI parameters, daily activities and quality of life

Abstract

Increasing numbers of drugs are being developed for the treatment of multiple sclerosis (MS). Measurement of relevant outcomes is key for assessing the efficacy of new drugs in clinical trials and for monitoring responses to disease-modifying drugs in individual patients. Most outcomes used in trial and clinical settings reflect either clinical or neuroimaging aspects of MS (such as relapse and accrual of disability or the presence of visible inflammation and brain tissue loss, respectively). However, most measures employed in clinical trials to assess treatment effects are not used in routine practice. In clinical trials, the appropriate choice of outcome measures is crucial because the results determine whether a drug is considered effective and therefore worthy of further development; in the clinic, outcome measures can guide treatment decisions, such as choosing a first-line disease-modifying drug or escalating to second-line treatment. This Review discusses clinical, neuroimaging and composite outcome measures for MS, including patient-reported outcome measures, used in both trials and the clinical setting. Its aim is to help clinicians and researchers navigate through the multiple options encountered when choosing an outcome measure. Barriers and limitations that need to be overcome to translate trial outcome measures into the clinical setting are also discussed.

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Figure 1: Trends over time in phase III clinical trials in relapsing and progressive MS.

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Acknowledgements

C.T. acknowledges financial support for her postdoctoral research fellowship from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). J.C., F.B., A.J.T. and O.C. acknowledge funding from the UK National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). J.C. also acknowledges support from the NIHR Efficacy and Mechanism Evaluation and Health Technology Assessment Programmes and the UK and US National Multiple Sclerosis (MS) Societies. F.B. also acknowledges funding from the European Community Horizon 2020 (European Union Framework Programme for Research and Innovation), the Innovative Medicines Initiative (IMI) Horizon 2020 programme, amyloid imaging to prevent Alzheimer's disease (AMYPAD), and the Dutch MS Society. A.J.T. and O.C. acknowledge funding from the UK MS Society.

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C.T., M.M. and O.C. researched data for the article. All authors wrote the manuscript and contributed substantially to discussions of content and review or editing of the manuscript before submission.

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Correspondence to Olga Ciccarelli.

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Competing interests

C.T. declares that she has received honoraria and support for travelling from Bayer Schering, Biogen, Ismar Healthcare, Merck Serono, Novartis, Sanofi–Aventis, Serono Foundation and Teva. M.M. declares that he has received honoraria and support for travelling from Almirall, Coloplast, Genzyme and Merck Serono. F.B. declares that he has received consulting fees for participating in steering committees, data-safety monitoring boards and advisory boards from Bayer Schering, Biogen, Genzyme, Jansen Research, Merck Serono, Novartis, Roche, Sanofi–Aventis, Synthon and Teva. J.C. declares that he has been a principal investigator for trials in multiple sclerosis funded by Biogen, Novartis and Receptos and additionally received an investigator grant from Novartis; he has also participated in advisory boards and/or received consultancy fees from Apitope, Biogen, MedDay, Merck and Roche. J.S.-G. declares that he has received speaker's honoraria from and/or participated in advisory boards for Almirall, Biogen, Celgene, Genzyme, Merck, Novartis and Teva. A.J.T. declares that he has received honoraria and/or support for travel for consultancy from Biogen (Optum Insight), Eisai and Excemed and support for travel from the International Progressive Multiple Sclerosis Alliance (as chair of their Scientific Steering Committee) and from the US National Multiple Sclerosis Society (as a member of their Research Programs Advisory Committee); he also receives an honorarium from SAGE Publishers as Editor in Chief of Multiple Sclerosis Journal. O.C. declares that she has received fees for consultancy from Biogen, Genzyme, Novartis, Roche and Teva and an honorarium for her position as an associate editor of Neurology.

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Supplementary information S1 (table)

Clinical outcome measures in phase III trials in relapsing-remitting (RR) MS (DOC 371 kb)

Supplementary information S2 (table)

Clinical outcome measures in phase III trials in clinically isolated syndromes (CIS) (DOC 110 kb)

Supplementary information S3 (table)

Clinical outcome measures in phase III trials in progressive MS (DOC 220 kb)

Supplementary information S4 (table)

Brain MRI outcome measures in phase III trials in relapsing-remitting MS (DOC 318 kb)

Supplementary information S5 (table)

Brain MRI outcome measures in phase III trials in CIS (DOC 104 kb)

Supplementary information S6 (table)

Brain MRI outcome measures in phase III trials in progressive MS (DOC 121 kb)

Supplementary information S7 (table)

Phase II and 3 trials that used spinal cord MRI outcomes* (DOC 68 kb)

Supplementary information S8 (table)

Past and ongoing phase II and III trials which use Optical Coherence Tomography (OCT)-related measures. (DOC 90 kb)

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Tur, C., Moccia, M., Barkhof, F. et al. Assessing treatment outcomes in multiple sclerosis trials and in the clinical setting. Nat Rev Neurol 14, 75–93 (2018). https://doi.org/10.1038/nrneurol.2017.171

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