John DeLuca1, Sven Schippling2, Xavier Montalban3, Ludwig Kappos4, Bruce A C Cree5, Giancarlo Comi6, Douglas L Arnold7, Hans-Peter Hartung8, James K Sheffield9, Hongjuan Liu10, Diego Silva11, Jeffrey A Cohen12. 1. Kessler Foundation, 1199 Pleasant Valley Way, West Orange, NJ 07052 USA and Departments of Physical Medicine and Rehabilitation, and Neurology, Rutgers - New Jersey Medical School, Newark 07103, NJ, USA. Electronic address: jdeluca@kesslerfoundation.org. 2. Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital and University of Zürich and Neuroscience Center Zürich, University of Zürich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland and Federal Institute of Technology (ETH) Zürich, Rämistrasse 101, 8092 Zürich, Switzerland. Electronic address: sven.schippling@usz.ch. 3. Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. Electronic address: xavier.montalban@cem-cat.org. 4. Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address: ludwig.kappos@usb.ch. 5. Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158 USA. Electronic address: bruce.cree@ucsf.edu. 6. Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, via Olgettina 48, 20132 Milan, Italy. Electronic address: comi.giancarlo@hsr.it. 7. NeuroRx Research and Montréal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada. Electronic address: douglas.arnold@mcgill.ca. 8. Department of Neurology, Medical Faculty, Heinrich-Heine University, University Hospital Dusseldorf, Moorenstr. 5 40225 Dusseldorf, Germany. Electronic address: hans-peter.hartung@uni-duesseldorf.de. 9. Bristol Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ 08648, USA. Electronic address: James.Sheffield@bms.com. 10. Bristol Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ 08648, USA. Electronic address: Hongjuan.Liu@bms.com. 11. Bristol Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ 08648, USA. Electronic address: Diego.Silva@bms.com. 12. Department of Neurology, Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195 USA. Electronic address: COHENJ@ccf.org.
Abstract
BACKGROUND: Cognitive dysfunction, including slowed cognitive processing speed (CPS), is one of the most disabling symptoms of multiple sclerosis (MS). The Symbol Digit Modalities Test (SDMT) is a preferred measure of CPS for MS trials and routine screening. Based on encouraging SDMT results in the phase 3 SUNBEAM trial, these post hoc, exploratory analyses were conducted to further compare effects of the sphingosine 1-phosphate receptor modulator ozanimod versus intramuscular interferon β-1a on CPS in participants with relapsing multiple sclerosis (RMS). METHODS: In the phase 3, double-blind, double-dummy, SUNBEAM study, adults (aged 18‒55 years) with RMS (N=1,346) were randomized to once-daily oral ozanimod 0.92 or 0.46 mg, or weekly intramuscular interferon β-1a 30 µg. The study continued until the last participant was treated for 12 months. CPS was measured as part of a secondary endpoint using the SDMT. Exploratory, post hoc analyses evaluated SDMT change and percentages of participants with clinically meaningful (≥4-point) SDMT improvement or worsening at months 6 and 12, and relationship between SDMT and brain volume on magnetic resonance imaging. RESULTS: Ozanimod improved SDMT scores compared with interferon β-1a at months 6 and 12. At month 12, least squares mean difference in SDMT z-scores for ozanimod 0.92 mg versus interferon β-1a was 0.102 (95% CI, 0.031‒0.174, nominal p = 0.0051; standardized mean difference = 0.1376). A greater percentage of ozanimod 0.92 mg‒treated participants had clinically meaningful improvements in SDMT scores versus interferon β-1a at month 6 (30.0% versus 22.2%) and month 12 (35.6% versus 27.9%). Of those with SDMT improvement at month 6, 66.4% of those treated with ozanimod 0.92 mg and 55.9% of those treated with interferon β-1a had sustained improvement at month 12. Brain volume loss was similar for those with SDMT improvement versus worsening at month 12. CONCLUSIONS: In these exploratory analyses, ozanimod had modestly beneficial effects on CPS in RMS participants. The effects of ozanimod on SDMT are being further evaluated in an ongoing 3-year clinical trial. SUNBEAM is registered on clinicaltrials.gov (NCT02294058) and the European Clinical Trials Database (EudraCT 2014-002320-27).
BACKGROUND: Cognitive dysfunction, including slowed cognitive processing speed (CPS), is one of the most disabling symptoms of multiple sclerosis (MS). The Symbol Digit Modalities Test (SDMT) is a preferred measure of CPS for MS trials and routine screening. Based on encouraging SDMT results in the phase 3 SUNBEAM trial, these post hoc, exploratory analyses were conducted to further compare effects of the sphingosine 1-phosphate receptor modulator ozanimod versus intramuscular interferon β-1a on CPS in participants with relapsing multiple sclerosis (RMS). METHODS: In the phase 3, double-blind, double-dummy, SUNBEAM study, adults (aged 18‒55 years) with RMS (N=1,346) were randomized to once-daily oral ozanimod 0.92 or 0.46 mg, or weekly intramuscular interferon β-1a 30 µg. The study continued until the last participant was treated for 12 months. CPS was measured as part of a secondary endpoint using the SDMT. Exploratory, post hoc analyses evaluated SDMT change and percentages of participants with clinically meaningful (≥4-point) SDMT improvement or worsening at months 6 and 12, and relationship between SDMT and brain volume on magnetic resonance imaging. RESULTS: Ozanimod improved SDMT scores compared with interferon β-1a at months 6 and 12. At month 12, least squares mean difference in SDMT z-scores for ozanimod 0.92 mg versus interferon β-1a was 0.102 (95% CI, 0.031‒0.174, nominal p = 0.0051; standardized mean difference = 0.1376). A greater percentage of ozanimod 0.92 mg‒treated participants had clinically meaningful improvements in SDMT scores versus interferon β-1a at month 6 (30.0% versus 22.2%) and month 12 (35.6% versus 27.9%). Of those with SDMT improvement at month 6, 66.4% of those treated with ozanimod 0.92 mg and 55.9% of those treated with interferon β-1a had sustained improvement at month 12. Brain volume loss was similar for those with SDMT improvement versus worsening at month 12. CONCLUSIONS: In these exploratory analyses, ozanimod had modestly beneficial effects on CPS in RMS participants. The effects of ozanimod on SDMT are being further evaluated in an ongoing 3-year clinical trial. SUNBEAM is registered on clinicaltrials.gov (NCT02294058) and the European Clinical Trials Database (EudraCT 2014-002320-27).