Consensus on early detection of disease progression in patients with multiple sclerosis

Consensus; Early detection; Secondary progressive multiple sclerosisConsenso; Detección precoz; Esclerosis múltiple progresiva secundariaConsens; Detecció precoç; Esclerosi múltiple progressiva secundàriaBackground: Early identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) can be challenging for clinicians, as diagnostic criteria for SPMS are primarily based on physical disability and a holistic interpretation. Objective: To establish a consensus on patient monitoring to identify promptly disease progression and the most useful clinical and paraclinical variables for early identification of disease progression in MS. Methods: A RAND/UCLA Appropriateness Method was used to establish the level of agreement among a panel of 15 medical experts in MS. Eighty-three items were circulated to the experts for confidential rating of the grade of agreement and recommendation. Consensus was defined when ≥66% agreement or disagreement was achieved. Results: Consensus was reached in 72 out of 83 items (86.7%). The items addressed frequency of follow-up visits, definition of progression, identification of clinical, cognitive, and radiological assessments as variables of suspected or confirmed SPMS diagnosis, the need for more accurate assessment tools, and the use of promising molecular and imaging biomarkers to predict disease progression and/or diagnose SPMS. Conclusion: Consensus achieved on these topics could guide neurologists to identify earlier disease progression and to plan targeted clinical and therapeutic interventions during the earliest stages of SPMS.This work was supported by Novartis. Meetings, data analysis, and medical writing assistance were funded by Novartis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Consenso de expertos sobre el uso de alemtuzumab en la práctica clínica diaria en España

Alemtuzumab; Eficacia; Práctica clínica habitualAlemtuzumab; Effectiveness; Daily clinical practiceAlemtuzumab; Eficàcia; Pràctica clínica habitualIntroduction Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. Objective A consensus document was drafted on the management of alemtuzumab in routine clinical practice in Spain. Development A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug's efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recommendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group. Conclusion The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practice.Introducción Alemtuzumab es un fármaco de alta eficacia aprobado por la Agencia Europea de Medicamentos como tratamiento modificador de la enfermedad en pacientes con esclerosis múltiple remitente recurrente. Objetivo Elaborar un documento de consenso sobre el manejo de alemtuzumab en la práctica clínica habitual, que sea de aplicación en el ámbito español. Desarrollo Un grupo de expertos en esclerosis múltiple revisó las publicaciones disponibles hasta diciembre de 2017, de tratamiento con alemtuzumab y esclerosis múltiple. Se incluyeron trabajos sobre eficacia, efectividad y seguridad, despistaje de infecciones y vacunación, administración y monitorización. La propuesta inicial de recomendaciones fue desarrollada por un grupo coordinador con base en la evidencia disponible y en su experiencia clínica. El proceso de consenso se llevó a cabo en 2 etapas; se estableció como porcentaje inicial de acuerdo grupal el 80%. El documento final con todas las recomendaciones acordadas por el grupo de trabajo se sometió a revisión externa y los comentarios recibidos fueron considerados por el grupo coordinador. Conclusiones El documento aportado pretende ser una herramienta útil para facilitar el manejo del fármaco en condiciones de práctica clínica habitual.Sanofi-Genzyme provided financial support to this project

Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis : APLIOS, a randomized phase-2 study

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed. Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion

Consenso de expertos sobre el uso de alemtuzumab en la práctica clínica diaria en España

Introducción: Alemtuzumab es un fármaco de alta eficacia aprobado por la Agencia Europea de Medicamentos como tratamiento modificador de la enfermedad en pacientes con esclerosis múltiple remitente recurrente. Objetivo: Elaborar un documento de consenso sobre el manejo de alemtuzumab en la práctica clínica habitual, que sea de aplicación en el ámbito español. Desarrollo: Un grupo de expertos en esclerosis múltiple revisó las publicaciones disponibles hasta diciembre de 2017, de tratamiento con alemtuzumab y esclerosis múltiple. Se incluyeron trabajos sobre eficacia, efectividad y seguridad, despistaje de infecciones y vacunación, administración y monitorización. La propuesta inicial de recomendaciones fue desarrollada por un grupo coordinador con base en la evidencia disponible y en su experiencia clínica. El proceso de consenso se llevó a cabo en 2 etapas; se estableció como porcentaje inicial de acuerdo grupal el 80%. El documento final con todas las recomendaciones acordadas por el grupo de trabajo se sometió a revisión externa y los comentarios recibidos fueron considerados por el grupo coordinador. Conclusiones: El documento aportado pretende ser una herramienta útil para facilitar el manejo del fármaco en condiciones de práctica clínica habitual.Introduction: Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. Objective: A consensus document was drafted on the management of alemtuzumab in routine clinical practice in Spain. Development: A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug's efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recommendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group. Conclusion: The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practice

Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial

Background Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis.Methods We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18-60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972.Findings Between Dec 26, 2018, and Aug 30,2019,605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0.20 (95% CI 0.07-0-63) in the once every 6 weeks group and 0.05 (0.01-0-22) in the once every 4 weeks group (mean lesion ratio 4.24 [95% CI 0.86-20-85]; p=0.076) under the primary estimand, and 0.31 (95% CI 0.12-0-82) and 0.06 (0.01-0-31; mean lesion ratio 4.93 [95% CI 1.05-23.20]; p=0.044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (>= 25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic.Interpretation We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Copyright (C) 2022 Elsevier Ltd. All rights reserved

Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA) : a randomised, controlled, open-label, phase 3b trial

Background Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis.Methods We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18-60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972.Findings Between Dec 26, 2018, and Aug 30,2019,605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0.20 (95% CI 0.07-0-63) in the once every 6 weeks group and 0.05 (0.01-0-22) in the once every 4 weeks group (mean lesion ratio 4.24 [95% CI 0.86-20-85]; p=0.076) under the primary estimand, and 0.31 (95% CI 0.12-0-82) and 0.06 (0.01-0-31; mean lesion ratio 4.93 [95% CI 1.05-23.20]; p=0.044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (>= 25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic.Interpretation We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Copyright (C) 2022 Elsevier Ltd. All rights reserved