Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial

Summary

Background

In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria.

Methods

In this phase 3, randomised, double-blind, parallel-group study, patients aged 20–75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1–4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686.

Findings

Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was −5·01 (SE 0·64) in the edavarone group and −7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99–3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal.

Interpretation

Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria.

Lancet Neurology 2017

Total small vessel disease score and risk of recurrent stroke Validation in 2 large cohorts

Objective: In patients with TIA and ischemic stroke, we validated the total small vessel disease (SVD) score by determining its prognostic value for recurrent stroke.

Methods: Two independent prospective studies were conducted, one comprising predominantly Caucasian patients with TIA/ischemic stroke (Oxford Vascular Study [OXVASC]) and one predominantly Chinese patients with ischemic stroke (University of Hong Kong [HKU]). Cerebral MRI was performed and assessed for lacunes, microbleeds, white matter hyperintensities (WMH), and perivascular spaces (PVS). Predictive value of total SVD score for risk of recurrent stroke was determined and potential refinements considered.

Results: In 2,002 patients with TIA/ischemic stroke (OXVASC n = 1,028, HKU n = 974, 6,924 patient-years follow-up), a higher score was associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio [HR] per unit increase: 1.32, 1.16–1.51, p < 0.0001; c statistic 0.61, 0.56–0.65, p < 0.0001) and intracerebral hemorrhage (ICH) (HR 1.54, 1.11–2.13, p = 0.009; c statistic 0.65, 0.54–0.76, p = 0.006). A higher score predicted recurrent stroke in SVD and non-SVD TIA/ischemic stroke subtypes (c statistic 0.67, 0.59–0.74, p < 0.0001 and 0.60, 0.55–0.65, p < 0.0001). Including burden of microbleeds and WMH and adjusting the cutoff of basal ganglia PVS potentially improved predictive power for ICH (c statistic 0.71, 0.60–0.81, p_het = 0.45), but not for recurrent ischemic stroke (c statistic 0.60, 0.56–0.65, p_het = 0.76) on internal validation.

Conclusions: The total SVD score has predictive value for recurrent stroke after TIA/ischemic stroke. Prediction of recurrence in patients with nonlacunar events highlights the potential role of SVD in wider stroke etiology.

Neurology 2017

Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia

ABSTRACT

Objective: To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA).

Methods: We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data.

Results: A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA−). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p < 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (p < 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (p ≤ 0.03).

Conclusions: Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.

Neurology 2017

Evaluation of hyperacute infarct volume using ASPECTS and brain CT perfusion core volume

ABSTRACT

Objective: To compare the accuracy of Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and CT perfusion to detect established infarction in acute anterior circulation stroke.

Methods: We performed an observational study in 59 acute anterior circulation ischemic stroke patients who underwent brain noncontrast CT, CT perfusion, and MRI within 100 minutes from CT imaging. ASPECTS scores were calculated by 4 blinded vascular neurologists. The accuracy of ASPECTS and CT perfusion core volume to detect an acute MRI diffusion lesion of ≥70 mL was evaluated using receiver operating characteristics analysis and optimum cutoff values were calculated using Youden J.

Results: Median ASPECTS score was 8 (interquartile range [IQR] 5–9). Median CT perfusion core volume was 22 mL (IQR 10.4–71.9). Median MRI diffusion lesion volume was 24.5 mL (IQR 10–63.9). No significant difference was found between the accuracy of CT perfusion and ASPECTS (c statistic 0.95 vs 0.87, p value for difference = 0.17). The optimum ASPECTS cutoff score to detect a diffusion-weighted imaging lesion ≥70 mL was <7 (sensitivity 0.74, specificity 0.86, Youden J = 0.60) and the optimum CT perfusion core volume cutoff was ≥50 mL (sensitivity 0.86, specificity 0.97, Youden J = 0.84). The CT perfusion core lesion covered a median of 100% (IQR 86%–100%) of the acute MRI lesion volume (Pearson R = 0.88; R² = 0.77).

Conclusions: We found no significant difference between the accuracy of CT perfusion and ASPECTS to predict hyperacute MRI lesion volume in ischemic stroke.

Neurology 2017

A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination

Abstract

Objective

Our goal was to define the genetic cause of the profound hypomyelination in the taiep rat model and determine its relevance to human white matter disease.

Methods

Based on previous localization of the taiep mutation to rat chromosome 9, we tested whether the mutation resided within the Tubb4a (β-tubulin 4A) gene, because mutations in the TUBB4A gene have been described in patients with central nervous system hypomyelination. To determine whether accumulation of microtubules led to progressive demyelination, we analyzed the spinal cord and optic nerves of 2-year-old rats by light and electron microscopy. Cerebral white matter from a patient with TUBB4A Asn414Lys mutation and magnetic resonance imaging evidence of severe hypomyelination were studied similarly.

Results

As the taiep rat ages, there is progressive loss of myelin in the brain and dorsal column of the spinal cord associated with increased oligodendrocyte numbers with accumulation of microtubules. This accumulation involved the entire cell body and distal processes of oligodendrocytes, but there was no accumulation of microtubules in axons. A single point mutation in Tubb4a (p.Ala302Thr) was found in homozygous taiep samples. A similar hypomyelination associated with increased oligodendrocyte numbers and arrays of microtubules in oligodendrocytes was demonstrated in the human patient sample.

Interpretation

The taiep rat is the first animal model of TUBB4 mutations in humans and a novel system in which to test the mechanism of microtubule accumulation. The finding of microtubule accumulation in a patient with a TUBB4A mutation and leukodystrophy confirms the usefulness of taiep as a model of the human disease. 

Ann Neurol 2017

Management of diffuse low-grade gliomas in adults — use of molecular diagnostics

Diffuse WHO grade II gliomas are histologically and genetically heterogeneous. The 2016 WHO classification redefines grade II gliomas with respect to morphological and molecular tumour alterations: grade II oligodendrogliomas are defined by the presence of whole-arm codeletion in chromosomal arms 1p/19q, whereas isocitrate dehydrogenase (IDH) mutations define subclasses of astrocytoma. Although histological grade remains useful, the prognoses of patients with glioma are more tightly associated with molecular alterations than with grade, and chromosomal and gene array technologies are becoming increasingly beneficial in understanding tumour genetic heterogeneity. The indolent nature of the disease often creates subtle neurological symptoms that can be overlooked or misunderstood, resulting in delayed diagnosis. Seizures often herald the diagnosis, especially in patients who have IDH mutations, which are associated with an increased production of 2-hydroxyglutarate. Treatment paradigms have shifted, owing to new diagnostic criteria and new clinical trial evidence. Patients benefit more from chemoradiation than radiation alone, especially those with tumour IDH1 Arg132His mutations; gross total resection of the tumour, including tumours with IDH mutations, is associated with prolonged survival. Initial observation remains appropriate in patients whose rate of disease growth is not yet completely defined; such patients could include those with completely resected disease and those with 1p/19q codeleted tumours.

Nature Reviews Neurology 2017

Vaccine-based immunotherapeutic approaches to gliomas and beyond

Astrocytic and oligodendroglial gliomas are intrinsic brain tumours characterized by infiltrative growth and resistance to classic cancer therapies, which renders them inevitably lethal. Glioblastoma, the most common type of glioma, also exhibits neoangiogenesis and profound immunosuppressive properties. Accordingly, strategies to revert glioma-associated immunosuppression and promote tumour-directed immune responses have been extensively explored in rodent models and in large clinical trials of tumour immunotherapy. This Review describes vaccination approaches investigated for the treatment of glioma. Several strategies have reached phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumour lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumour-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression.

Nature Reviews Neurology 2017