Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial

Cohen, Jeffrey A.; Coles, Alasdair; Arnold, Douglas L.; Confavreux, Christian; Fox, Edward J.; Hartung, Hans Peter; Havrdová, Eva; Selmaj, Krzysztof; Weiner, Howard L.; Fisher, Elizabeth; Brinar, Vesna; Giovannoni, Gavin; Stojanović, Miroslav; Ertik, Bella; Lake, Stephen; Margolin, David; Panzara, Michael A.; Compston, D. A. S.

doi:10.1016/s0140-6736(12)61769-3

Cited by 1,061 publications

(1,258 citation statements)

References 34 publications

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“…Studies on MS disease activity, such as clinical drug trials, indicate that the number of new MRI lesions is approximately 4–12 times larger than the number of new clinical relapses during the same time period 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. Such “clinically silent” MRI lesions stress the importance of monitoring patients with MRI even in the absence of clinical signs of disease activity.…”

Section: Resultsmentioning

confidence: 99%

“…While we acknowledge this and would like to emphasize that the MRI frequency and timing should be adapted to the clinical situation, it is our opinion that general recommendations of MRI frequency are still valuable in the clinical care of patients. The recommendations regarding MRI frequency presented here are based on clinical experience and extrapolation of study data on the level of disease activity seen in treated and untreated patients with MS in phase III studies 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20…”

Section: Resultsmentioning

confidence: 99%

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Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society

et al. 2016

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Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society

et al. 2016

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“…This may be explained by the annual dosing regimen, the low titres of circulating ADA or inhibitory ADA at initial treatment and just prior to the second course 12 months later, and the rapidity of lymphocyte depletion upon drug exposure which may occur before significant ADA and inhibitory ADA develops 41, 50.…”

Section: Discussionmentioning

confidence: 99%

Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis

Richards

Surks

et al. 2018

Clinical and Experimental Immunology

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SummaryAlemtuzumab, a humanized anti‐CD52 monoclonal antibody, is approved for treatment of relapsing multiple sclerosis (MS). In the Phase II/III trials, patients received 12 or 24 mg/day of alemtuzumab in two treatment courses (5 days for course 1 and 3 days for course 2), 12 months apart. Serum concentrations of alemtuzumab peaked on the last day of dosing in each course and mostly fell below the limit of quantitation by day 30. Alemtuzumab rapidly depleted circulating T and B lymphocytes, with the lowest observed values occurring within days. Lymphocytes repopulated over time, with B cell recovery usually complete within 6 months. T lymphocytes recovered more slowly and generally did not return to baseline by 12 months post‐treatment. Approximately 40 and 80% of patients had total lymphocyte counts, reaching the lower limit of normal by 6 and 12 months after each course, respectively. The clearance of alemtuzumab is dependent on circulating lymphocyte count. A majority of treated patients tested positive for anti‐alemtuzumab antibodies, including inhibitory antibodies, during the 2‐year studies, and a higher proportion of patients tested positive in course 2 than in course 1. The presence of anti‐alemtuzumab antibody appeared to be associated with slower clearance of alemtuzumab from the circulation but had no impact on the pharmacodynamics. No effects of age, race or gender on the pharmacokinetics or pharmacodynamics were observed. Together, the pharmacokinetics, pharmacodynamics and immunogenicity results support the continued development and use of alemtuzumab for the treatment of MS, and probably explain its sustained effects beyond the dosing interval.

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“…Some studies have reported no significant, or conflicting, effects of DMTs on brain atrophy (Bermel & Bakshi, 2006; Calabrese et al., 2012; Lublin et al., 2016; Tiberio et al., 2005). Others have reported statistically significant slowing of brain atrophy, but only after 24 months or more (Cohen et al., 2012; Coles et al., 2012; Kappos et al., 2010; Mattioli, Stampatori, Bellomi, Scarpazza, & Capra, 2015; Miller et al., 2007; Rinaldi et al., 2012). Brain atrophy is considered predictive of progression in cognitive and/or motor disability (Bermel & Bakshi, 2006; Deloire et al., 2011; Morgen et al., 2006), emphasizing a need for early intervention to prevent brain atrophy and forestall the advance of disability.…”

Section: Introductionmentioning

confidence: 99%

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

et al. 2018

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IntroductionProgressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%–70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing–remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol‐treated compared to placebo‐treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes.MethodsSixty‐two estriol‐ and forty‐nine placebo‐treated RRMS patients underwent clinical evaluations and brain MRI. Voxel‐based morphometry (VBM) was used to evaluate voxelwise GM sparing from high‐resolution T1‐weighted scans.ResultsA region of treatment‐induced sparing (TIS) was defined as the areas where GM was spared in estriol‐ as compared to placebo‐treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability‐specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol‐treated subjects that was associated with better performance on the PASAT.ConclusionsDiscovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability‐specific biomarker for clinical trials of candidate neuroprotective treatments in MS.

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Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial

Cited by 1,061 publications

References 34 publications

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society

Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

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