Abstract:
IMPORTANCE:This dose-blinded extension of the phase 2 BOLD (BAF312 on MRI Lesion Given Once Daily) Study in relapsing-remitting multiple sclerosis provides evidence on disease activity and safety of a range of siponimod doses for up to 24 months. OBJECTIVE:To assess the safety and efficacy of siponimod for up to 24 months during the dose-blinded extension of the BOLD Study. DESIGN, SETTING, AND PARTICIPANTS:At extension baseline in a randomized clinical trial, patients taking siponimod continued at the originally assigned dose and patients taking placebo were rerandomized to the 5 siponimod doses. Initial treatment was titrated over 10 days. A total of 252 eligible patients were treated at specialized multiple sclerosis centers for this study conducted from August 30, 2010, through June 3, 2013. INTERVENTIONS:Siponimod at 10-mg, 2-mg, 1.25-mg, 0.5-mg, and 0.25-mg doses. MAIN OUTCOMES AND MEASURES:Safety assessment included blood tests, documentation of adverse events at regular scheduled visits and Holter monitoring; key efficacy measures were annualized relapse rate and magnetic resonance imaging lesion activity. RESULTS:Among the 252 eligible patients, the mean (SD) ages were 37.2 (8.4) years, 35.2 (9.1) years, 34.0 (7.6) years, 35.1 (9.2) years, and 36.8 (9.1) years in the 0.25-mg, 0.5-mg, 1.25-mg, 2-mg, and 10-mg groups. Of the 252 patients, 184 (73%) entered the extension and received siponimod (10 mg: n = 33; 2 mg: n = 29; 1.25 mg: n = 43; 0.5 mg: n = 29; and 0.25 mg: n = 50); 159 (86.4%) completed the dose-blinded extension. The incidence of adverse events was similar across treatment groups (10 mg: 87.9%; 2 mg: 89.7%; 1.25 mg: 88.4%; 0.5 mg: 96.6%; and 0.25 mg: 84.0%). Nine patients reported serious adverse events (2 mg: 3/29 [10.3%], 1.25 mg: 1/43 [2.3%], 0.5 mg: 4/29 [13.8%], and 0.25 mg: 1/50 [2.0%]; no serious adverse event was reported for more than 1 patient and no new safety signals occurred compared with the BOLD Study. Dose titration mitigated symptomatic bradycardic events. Reductions in mean (95% CI) gadolinium-enhancing T1 lesion counts from the last BOLD assessment were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups (0 [0-0], 0.1 [0-1.9], 0.1 [0-2.6], and 0.1 [0-2.8] at month 24, respectively). At the 3 highest vs 2 lowest doses, the estimated new/newly enlarging T2 lesion counts (95% CIs) were lower during months 6 to 12 (0.5 [0.2-1.3], 0.4 [0.2-1.1], and 0.2 [0.1-0.6] vs 1.3 [0.6-2.8] and 1.4 [0.7-2.7]), months 12 to 18 (0.4 [0.1-1.1], 0.4 [0.1-1.3], and 0.4 [0.2-1.0] vs 1.0 [0.4-2.6] and 3.6 [1.7-7.6]), and months 18 to 24 (0 [0-not estimable], 0.9 [0.1-7.6], and 0.1 [0-1.7] vs 1.6 [0.3-7.7] and 2.0 [0.4-9.5]). Annualized relapse rates (95% CIs) up to month 24 were similarly lower for the 3 highest doses: 0.22 (0.12-0.40) for 10 mg, 0.20 (0.10-0.38) for 2 mg, and 0.14 (0.08-0.26) for 1.25 mg vs 0.33 (0.19-0.56) for 0.5 mg and 0.33 (0.21-0.50) for 0.25 mg. CONCLUSIONS AND RELEVANCE:For up to 24 months of siponimod treatment, multiple sclerosis disease activity was low and there were no new safety signals; investigation in phase 3 trials is encouraged. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT01185821.
journal_name
JAMA Neuroljournal_title
JAMA neurologyauthors
Kappos L,Li DK,Stüve O,Hartung HP,Freedman MS,Hemmer B,Rieckmann P,Montalban X,Ziemssen T,Hunter B,Arnould S,Wallström E,Selmaj Kdoi
10.1001/jamaneurol.2016.1451subject
Has Abstractpub_date
2016-09-01 00:00:00pages
1089-98issue
9eissn
2168-6149issn
2168-6157pii
2532101journal_volume
73pub_type
杂志文章,随机对照试验相关文献
JAMA Neurology文献大全abstract:IMPORTANCE:Limbic encephalitis that is associated with anti-voltage-gated potassium channel complex (VGKCC) antibodies (VGKCC syndrome) is an autoimmune, usually nonparaneoplastic form of encephalitis that is responsive to immunotherapy. Differentiating this treatable disease from others that have a similar presentatio...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2013.5179
更新日期:2014-01-01 00:00:00
abstract:Importance:Biomarkers do not determine conversion to Alzheimer disease (AD) perfectly, and criteria do not specify how to take patient characteristics into account. Consequently, biomarker use may be challenging for clinicians, especially in patients with mild cognitive impairment (MCI). Objective:To construct biomark...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2017.2712
更新日期:2017-12-01 00:00:00
abstract:Importance:Atabecestat, a nonselective oral β-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). Objective:To report efficacy, ...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2020.4857
更新日期:2021-01-19 00:00:00
abstract:Importance:Prolonged seizures in super-refractory status epilepticus (SRSE) have been shown to cause neuronal death and reorganization, and visual inspection in individual case studies has demonstrated progressive cortical and subcortical atrophy. At present, magnetic resonance imaging (MRI) studies that evaluate brain...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2016.1572
更新日期:2016-10-01 00:00:00
abstract:IMPORTANCE:The frequency and distribution of synucleinopathies and tauopathies manifesting with parkinsonism in the general population are poorly understood, thus affecting health care planning and research. OBJECTIVE:To investigate the incidence and distribution of specific types of parkinsonism and related proteinop...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2013.114
更新日期:2013-07-01 00:00:00
abstract:Importance:The central vein sign has been proposed as a specific imaging biomarker for distinguishing between multiple sclerosis (MS) and not MS, mainly based on findings from ultrahigh-field magnetic resonance imaging (MRI) studies. The diagnostic value of the central vein sign in a multicenter setting with a variety ...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2019.2478
更新日期:2019-12-01 00:00:00
abstract::A young man with normal neurodevelopment presented with 3 years of medically refractory, progressive epilepsy and myoclonus. Initial examination included neuroimaging, electroencephalography, and biochemical analyses, all of which were unremarkable except for mildly enlarged ventricles. Over the following year, the pa...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2016.3195
更新日期:2017-06-01 00:00:00
abstract:Importance:Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian). Objectives:To identify novel genome-wide significant loci for PD in Asian indivi...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2020.0428
更新日期:2020-06-01 00:00:00
abstract:Importance:It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS). Objective:To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to asse...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2020.2453
更新日期:2020-07-27 00:00:00
abstract:Importance:This study reports the long-term epidemiologic trends of amyotrophic lateral sclerosis (ALS) based on a prospective register. Objective:To examine the 20-year epidemiologic trends of ALS in the Piemonte and Valle d'Aosta regions of Italy. Design, Setting, and Participants:The Piemonte and Valle d'Aosta Reg...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2017.1387
更新日期:2017-09-01 00:00:00
abstract:IMPORTANCE:Alzheimer disease (AD) is a neurodegenerative disorder with no effective therapies. In 1984, the National Institute on Aging created the first 5 AD centers (ADCs) in an effort to coordinate research efforts into the pathology and treatment of the disease. Since that time, the ADC program has expanded to incl...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2013.6225
更新日期:2014-04-01 00:00:00
abstract:IMPORTANCE:Metabolic syndrome (MetS) is thought to influence several autoimmune diseases, including multiple sclerosis (MS). Anti-inflammatory effects of treatments used for MetS, such as metformin hydrochloride and pioglitazone hydrochloride, have been demonstrated, although clinical evidence supporting use of these t...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2015.4807
更新日期:2016-05-01 00:00:00
abstract:IMPORTANCE:There is a deficit of pituitary adenylate cyclase-activating polypeptide (PACAP) in patients with neuropathologically confirmed Alzheimer dementia. However, whether this deficit is associated with the earlier stages of Alzheimer disease (AD) is unknown. This study was conducted to clarify the association bet...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2014.3625
更新日期:2015-03-01 00:00:00
abstract:Importance:Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles. Objective:To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. Design,...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2019.1456
更新日期:2019-06-10 00:00:00
abstract:Importance:Randomized clinical trials have shown the efficacy of thrombectomy of large intracranial vessel occlusions in adults; however, any association of therapy with clinical outcomes in children is unknown. Objective:To evaluate the use of endovascular recanalization in pediatric patients with arterial ischemic s...
journal_title:JAMA neurology
pub_type: 杂志文章,多中心研究
doi:10.1001/jamaneurol.2019.3403
更新日期:2020-01-01 00:00:00
abstract:Importance:Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome. Objective:To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome. Design, Setting, and Participants:The prospective International Deep Br...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2017.4317
更新日期:2018-03-01 00:00:00
abstract:IMPORTANCE:To provide clinical and genetic diagnoses for patients' conditions, it is important to identify and characterize the different subtypes of spinocerebellar ataxia (SCA). OBJECTIVE:To clinically and genetically characterize a Spanish kindred with pure SCA presenting with altered vertical eye movements. DESIGN...
journal_title:JAMA neurology
pub_type: 杂志文章,多中心研究
doi:10.1001/jamaneurol.2013.2311
更新日期:2013-06-01 00:00:00
abstract:Importance:Cerebrospinal fluid (CSF) core Alzheimer disease (AD) biomarkers have shown an excellent capacity for the in vivo detection of AD. Previous studies have shown that CSF levels of phosphorylated tau (p-tau) also correlate with tau pathology in frontotemporal lobar degeneration (FTLD) after accounting for AD co...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2018.0118
更新日期:2018-06-01 00:00:00
abstract:Importance:Although endovascular thrombectomy (EVT) in acute ischemic stroke is recommended by guidelines to improve functional recovery, thus far there are insufficient data on its association with mortality. Objective:To identify guideline-relevant trials of EVT vs medical therapy reporting 90-day mortality and perf...
journal_title:JAMA neurology
pub_type: 杂志文章,meta分析
doi:10.1001/jamaneurol.2019.0525
更新日期:2019-07-01 00:00:00
abstract:Importance:Mild traumatic brain injury (TBI) is experienced by 55.9 million people globally each year. The symptoms of mild TBI are diverse and sometimes long-lasting, requiring frequent use of pharmacological interventions to mitigate them. A thorough understanding of the data supporting pharmacological interventions ...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2020.5079
更新日期:2021-01-19 00:00:00
abstract:Importance:Apolipoprotein E ε4 (APOEε4) is the single most important genetic risk factor for Alzheimer disease. While APOEε4 is associated with increased amyloid-β burden, its association with cerebral tau pathology has been controversial. Objective:To determine whether APOEε4 is associated with medial temporal tau pa...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2019.4421
更新日期:2020-04-01 00:00:00
abstract:IMPORTANCE:Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)-associated proteins (NDAPs) (ie, tau, Aβ, and α-synuclein) suggests possible similarities to the infectious prion protein (PrPsc) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2013.1933
更新日期:2013-04-01 00:00:00
abstract:IMPORTANCE:Understanding the relationships between age-related changes in brain structure and cognitive function has been limited by inconsistent methods for assessing brain imaging, small sample sizes, and racially/ethnically homogeneous cohorts with biased selection based on risk factors. These limitations have preve...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2014.3418
更新日期:2015-02-01 00:00:00
abstract:Importance:Prognostication of neurologic outcome after cardiac arrest is an important but challenging aspect of patient therapy management in critical care units. Objective:To determine whether serum neurofilament light chain (NFL) levels can be used for prognostication of neurologic outcome after cardiac arrest. Des...
journal_title:JAMA neurology
pub_type: 杂志文章,多中心研究
doi:10.1001/jamaneurol.2018.3223
更新日期:2019-01-01 00:00:00
abstract:Importance:Endovascular therapy (ET) is typically not considered for patients with large baseline ischemic cores (irreversibly injured tissue). Computed tomographic perfusion (CTP) imaging may identify a subset of patients with large ischemic cores who remain at risk for significant infarct expansion and thus could sti...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2016.3954
更新日期:2017-01-01 00:00:00
abstract:Importance:Periodic discharges (PDs) that do not meet seizure criteria, also termed the ictal interictal continuum, are pervasive on electroencephalographic (EEG) recordings after acute brain injury. However, their association with brain homeostasis and the need for clinical intervention remain unknown. Objective:To d...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2016.5325
更新日期:2017-03-01 00:00:00
abstract:Importance:Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention. Objective:To assess whether at least 1 dose of galcanezumab was superior to placebo for episodic migraine prevention. Design, Setting, and Partic...
journal_title:JAMA neurology
pub_type: 杂志文章,随机对照试验
doi:10.1001/jamaneurol.2017.3859
更新日期:2018-02-01 00:00:00
abstract:IMPORTANCE:Cerebrospinal fluid (CSF) is the compartment in closest proximity to the central nervous system (CNS) parenchyma and might reflect immune pathology in inflammatory CNS disorders like multiple sclerosis (MS). Multiparameter flow cytometry is used to characterize immunological alterations in the CSF of patient...
journal_title:JAMA neurology
pub_type: 杂志文章,评审
doi:10.1001/jamaneurol.2014.395
更新日期:2014-07-01 00:00:00
abstract:Importance:The development and expansion of intracranial hematoma are associated with adverse outcomes. Use of tranexamic acid might limit intracranial hematoma formation, but its association with outcomes of severe traumatic brain injury (TBI) is unclear. Objective:To assess whether prehospital administration of tran...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/jamaneurol.2020.4596
更新日期:2020-12-07 00:00:00
abstract:IMPORTANCE:β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI's influence on cognition and clinical impairment, separate fro...
journal_title:JAMA neurology
pub_type: 杂志文章
doi:10.1001/2013.jamaneurol.405
更新日期:2013-04-01 00:00:00