Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis
In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses. To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial. Three estimands, one based on principal stratum and...
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| Published in: | Multiple sclerosis Vol. 27; no. 10; p. 1564 |
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| Main Authors: | , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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01.09.2021
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| ISSN: | 1477-0970, 1477-0970 |
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| Abstract | In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.
To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.
Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.
Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.
By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses. |
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| AbstractList | In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.
To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.
Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.
Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.
By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses. In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.BACKGROUNDIn multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.OBJECTIVETo distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.METHODSThree estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.RESULTSPrincipal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.CONCLUSIONBy controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses. |
| Author | Magnusson, Baldur Fox, Robert J Cree, Bruce Ac Bar-Or, Amit Vermersch, Patrick Tomic, Davorka Rouyrre, Nicolas Karlsson, Göril Gold, Ralf Dahlke, Frank Piani Meier, Daniela Kappos, Ludwig Giovannoni, Gavin Wolf, Christian |
| Author_xml | – sequence: 1 givenname: Bruce Ac surname: Cree fullname: Cree, Bruce Ac organization: Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA – sequence: 2 givenname: Baldur surname: Magnusson fullname: Magnusson, Baldur organization: Novartis Pharma AG, Basel, Switzerland – sequence: 3 givenname: Nicolas surname: Rouyrre fullname: Rouyrre, Nicolas organization: Novartis Pharma AG, Basel, Switzerland – sequence: 4 givenname: Robert J orcidid: 0000-0002-4263-3717 surname: Fox fullname: Fox, Robert J organization: Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA – sequence: 5 givenname: Gavin surname: Giovannoni fullname: Giovannoni, Gavin organization: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK – sequence: 6 givenname: Patrick surname: Vermersch fullname: Vermersch, Patrick organization: University of Lille, CHU Lille, LIRIC-INSERM U995, Lille, France – sequence: 7 givenname: Amit surname: Bar-Or fullname: Bar-Or, Amit organization: Center for Neuroinflammation and Experimental Therapeutics and Multiple Sclerosis Division, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA/Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada – sequence: 8 givenname: Ralf surname: Gold fullname: Gold, Ralf organization: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany – sequence: 9 givenname: Daniela surname: Piani Meier fullname: Piani Meier, Daniela organization: Novartis Pharma AG, Basel, Switzerland – sequence: 10 givenname: Göril surname: Karlsson fullname: Karlsson, Göril organization: Novartis Pharma AG, Basel, Switzerland – sequence: 11 givenname: Davorka surname: Tomic fullname: Tomic, Davorka organization: Novartis Pharma AG, Basel, Switzerland – sequence: 12 givenname: Christian orcidid: 0000-0002-4683-0507 surname: Wolf fullname: Wolf, Christian organization: Lycalis sprl, Brussels, Belgium – sequence: 13 givenname: Frank surname: Dahlke fullname: Dahlke, Frank organization: Novartis Pharma AG, Basel, Switzerland – sequence: 14 givenname: Ludwig orcidid: 0000-0003-4175-5509 surname: Kappos fullname: Kappos, Ludwig organization: Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital, University of Basel, Basel, Switzerland |
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| Snippet | In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.
To distinguish siponimod's direct... In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.BACKGROUNDIn multiple sclerosis,... |
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| Title | Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis |
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