Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Klinische Umsetzbarkeit der kognitiven Screeningbatterie BICAMS bei Patienten mit Multipler Sklerose: Ergebnisse der Machbarkeitsstudie in Deutschland

Hintergrund: Patienten mit Multipler Sklerose (MS) leiden in 40-70 % der Fälle unter kognitiven Störungen. Der kognitive Status gilt erwiesenermaßen als Prädiktor für Berufsfähigkeit und frühzeitige Berentung. Eine regelmäßige Erfassung der kognitiven Leistungsfähigkeit ist somit dringend indiziert. Zielsetzung: Die deutsche Fassung der international empfohlenen BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis)-Batterie wurde auf Praktikabilität in der klinischen Routine neurologischer Praxen in Deutschland multizentrisch überprüft. Material und Methoden: Medizinische Fachangestellte (MFAs) wurden hinsichtlich der Durchführung und Auswertung von BICAMS geschult. Alle ausgewerteten Testbögen wurden von unabhängigen neuropsychologischen Experten überprüft. Ergebnisse: Insgesamt 1606 BICAMS-Datensätze wurden in 65 Zentren erhoben. Von diesen konnten 1573 analysiert werden. 49,7 % der erhobenen Datensätze wurden inklusive aller Auswerteschritte korrekt durchgeführt. Bei den anderen 50,3 % fanden sich Durchführungs-, Auswerte- oder Transformationsfehler. Nach Bereinigung der Stichprobe durch fehlerbehaftete Fälle ergaben sich Werte der Interrater-Reliabilität pro Testverfahren in Höhe von ICC >= 0,953. Diskussion: Grundsätzlich ist BICAMS für den Einsatz im klinischen Alltag sehr zu empfehlen. Es bleibt allerdings zu betonen, dass obgleich die Interrater-Reliabilität für die final bereinigte Stichprobe sehr hoch war, im Gesamtdatensatz 50,3 % Durchführungs-, Auswerte- oder Transformationsfehler gefunden wurden. Daraus lässt sich die Notwendigkeit ableiten, nicht-psychologisches Personal noch eingehender in der Anwendung und Auswertung von BICAMS durch Experten zu schulen und zu supervidieren

A Comprehensive Monitoring Study on Electrocardiographic Assessments and Cardiac Events After Fingolimod First Dose-Possible Predictors of Cardiac Outcomes

Background:First dose observation for cardiac effects is required for fingolimod. Previous results in patients with relapsing remitting multiple sclerosis (RRMS) suggest that transient bradycardia and conduction abnormalities during the observation phase are rare, benign and reversible. Prior analyses corroborate these findings. The present large scale dataset allows subgroup analyses for differences in the incidence of cardiac findings depending on patient characteristics. Methods:START was an open-label, multi-center study that enrolled 6,998 RRMS patients. Primary endpoints were incidence of bradycardia (heart rate = 50 years;p= 0.014 vs. patients 35-49 years). Second- or third-degree AV blocks were more frequent in females (87.5% of all patients with a second- or third-degree AV block;p< 0.001), while bradycardia occurred more often in males (58.7% of all bradycardia events;p< 0.001). Furthermore, patients with a BMI below 25 had a higher incidence of second- or third-degree AV block. Conclusions:In summary, transient bradycardia and AV conduction abnormalities after the first dose of fingolimod were rare and asymptomatic. When compared to females, male patients might have a higher risk for bradycardia during treatment initiation, presumably due to a lower resting heart rate. Furthermore, a low heart rate before treatment initiation, low body weight, or low BMI possibly increases the risk for bradycardia. Second- or third-degree AV blocks were more frequent in females, older patients and patients with a low BMI. Nevertheless, these cardiac events remained rare and benign, confirming the favorable cardiac safety profile of fingolimod upon treatment initiation in MS patients without cardiovascular comorbidities

Long‑term real‑world effectiveness and safety of fingolimod over 5 years in Germany

Objective: To evaluate the 5-year real-world benefit–risk profile of fingolimod in patients with relapsing–remitting MS (RRMS) in Germany. Methods: Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) is a non-interventional realworld study to prospectively assess the effectiveness and safety of fingolimod in routine clinical practice in Germany. The follow-up period comprised 5 years. Patients were included if they had been diagnosed with RRMS and had been prescribed fingolimod as part of clinical routine. There were no exclusion criteria except the contraindications for fingolimod as defined in the European label. The effectiveness and safety analysis set comprised 4032 and 4067 RRMS patients, respectively. Results: At the time of the 5-year follow-up of PANGAEA, 66.57% of patients still continued fingolimod therapy. Annualized relapse rates decreased from baseline 1.5 ± 1.15 to 0.42 ± 0.734 at year 1 and 0.21 ± 0.483 at year 5, and the disability status remained stable, as demonstrated by the Expanded Disability Status Scale mean change from baseline (0.1 ± 2.51), the decrease of the Multiple Sclerosis Severity Score from 5.1 ± 2.59 at baseline to 3.9 ± 2.31 at the 60-months follow-up, and the percentage of patients with ‘no change’ in the Clinical Global Impression scale at the 60-months follow-up (78.11%). Adverse events (AE) occurring in 75.04% of patients were in line with the known safety profile of fingolimod and were mostly non-serious AE (33.62%) and non-serious adverse drug reactions (50.59%; serious AE 4.98%; serious ADR 10.82%). Conclusions: PANGAEA demonstrated the sustained beneficial effectiveness and safety of fingolimod in the long-term realworld treatment of patients with RRMS

Electrocardiographic assessments and cardiac events after fingolimod first dose - a comprehensive monitoring study

Background: First dose observation for cardiac effects is required for fingolimod, but recommendations on the extent vary. This study aims to assess cardiac safety of fingolimod first dose. Individual bradyarrhythmic episodes were evaluated to assess the relevance of continuous electrocardiogram (ECG) monitoring. Methods: START is an ongoing open-label, multi-center study. At the time of analysis 3951 patients were enrolled. The primary endpoints are the incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree AV blocks during treatment initiation. The relevance of Holter was assessed by matching ECG findings with the occurrence of clinical symptoms as well as by rigorous analysis of AV blocks with regard to the duration of pauses and the minimal heart rate recorded during AV block. Results: Thirty-one patients (0.8%) developed bradycardia (< 45 bpm), 62 patients (1.6%) had second-degree Mobitz I and/or 2: 1 AV blocks with a lowest reading (i.e. mean of ten consecutive beats) of 35 bpm and the longest pause lasting for 2.6 s. No Mobitz II or third-degree AV blocks were observed. Only one patient complained about mild chest discomfort and fatigue. After 1 week, there was no second-/third-degree AV block. Conclusions: Continuous Holter ECG monitoring in this large real-life cohort revealed that bradycardia and AV conduction abnormalities were rare, transient and benign. No further unexpected abnormalities were detected. The data presented here give an indication that continuous Holter ECG monitoring does not add clinically relevant value to patients' safety

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

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