IMPORTANCE Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose.OBJECTIVE To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome. DESIGN, SETTING, AND PARTICIPANTSThis double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol. MAIN OUTCOMES AND MEASURESThe primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score. RESULTSOf 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium.CONCLUSIONS AND RELEVANCE Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety.
Data on the prevalence of multiple sclerosis (MS) in France are scarce. National and regional updated estimates are needed to better plan health policies. In this nationwide study, we provided estimates of the prevalence of MS in France in 2012 and mortality rate in 2013. MS cases were identified in the French national health insurance database (SNIIRAM-PMSI) using reimbursement data for disease-modifying treatment, long-term disease status for MS, disability pension for MS, and hospitalisa-tion for MS (MS ICD-10 code: G35). We identified 99,123 MS cases, corresponding to an overall crude prevalence rate of 151.2 per 100,000 inhabitants [95% confidence interval (CI) 150.3-152.2]: 210.0 per 100,000 in women (95% CI 208.4-211.5) and 88.7 per 100,000 in men (95% CI 87.6-89.7). The overall prevalence rate was 155.6 per 100,000 inhabitants (95% CI 154.7-156.6) after standardization on the 2013-European population. We observed a prevalence gradient with a higher prevalence (190-200 per 100,000) in NorthEastern France and a lower prevalence in Southern and Western France (126-140). The crude mortality rate in 2013 was 13.7 per 1,000 MS cases (11.4 in women and 20.3 in men). The standardized mortality ratio was 2.56 (95% CI 2.41-2.72). Our results revise upwards the estimation of MS prevalence in France and confirm the excess mortality of MS patients compared to the general population.
Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington's disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR −/− mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.aryl hydrocarbon receptor | EAE | laquinimod L aquinimod is an oral drug that is currently in late-stage clinical development for the treatment of relapsing remitting multiple sclerosis (RRMS), primary progressive MS, and Huntington's disease. Current knowledge indicates that laquinimod exerts activities both on the peripheral immune system and within the CNS. Laquinimod, at the 0.6-mg/d dose, has demonstrated efficacy in phase II and III MS clinical trials, in which it reduced relapse rate, disability progression, development of new and active MRI lesions, and brain atrophy (1-3). The clinical efficacy profile of laquinimod is characterized by a dissociation of the moderate magnitude of the effect on relapse reduction and its associated inflammatory MRI findings and the disproportionally large effect on disability progression. Such an efficacy profile in patients with RRMS may relate to a distinctive intracerebral activity potentially mediated via changes in CNS resident cell populations, potentially astrocytes and microglia.
Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.
ObjectivesCompared with controls, multiple sclerosis (MS) patients die, on average, 7–14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon β-1b, mortality was reduced by 46–47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts.DesignLong-term follow-up (LTF) of the pivotal RCT of interferon β-1b.SettingEleven North American MS-centres participated.ParticipantsIn the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment.InterventionsUsing multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients.Primary outcomeAn independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships.ResultsAmong the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths.ConclusionsIn this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.
Background Evaluating the long term benefit of therapy in multiple sclerosis (MS) is challenging. Although randomised controlled trials (RCTs) demonstrate therapeutic benefits on short term outcomes, the relationship between these outcomes and late disability is not established. Methods In a patient cohort from the pivotal interferon b-1b trial, the value of clinical and MRI measures were analysed, both at baseline and during the RCT, for predicting long term physical and cognitive outcome. Results Baseline disability correlated with both physical (R 2 ¼0.22; p<0.0001) and cognitive (R 2 ¼0.12; p<0.0001) outcome after 16 years. Accrual of disability during the RCT (R 2 ¼0.12; p<0.0001) and annualised relapse rates during the trial correlated with physical outcome (R 2 ¼0.12; p<0.0001) but not with cognition.
Objective: To examine the effects of interferon beta (IFN)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. Methods:For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFN-1b 250 g and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-totreat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary.Results: After a median of 21.1 years from RCT enrollment, 98.4% (366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFN-1b 250 g showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p ϭ 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFN-1b 250 g-treated patients (46.0% among IFN-1b 50 g-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. Conclusions:There was a significant survival advantage in this cohort of patients receiving early IFN-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFN-1b benefit on all-cause mortality. Classification of Evidence:This study provides Class III evidence that early treatment with IFN-1b is associated with prolonged survival in initially treatment-naive patients with relapsingremitting multiple sclerosis. Neurology Multiple sclerosis (MS) is a chronic, inflammatory disease of the CNS with a lifelong course, necessitating outcome assessments over both the short term and long term.1 However, randomized clinical trials (RCTs) have typically focused only on short-term outcomes such as clinical measures of relapse and physical disability, as well as MRI measures of disease activity and severity.2-8 Although survival is the ultimate long-term outcome, to date mortality in patients with MS treated with disease-modifying therapy (DMT) has not been well-studied, largely because of the length and completeness of observation needed. 9 *These authors contributed equally to this work.
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