The objective of this study was to evaluate how enrichment for responders increases assay sensitivity in an enriched enrollment randomized withdrawal (EERW) proof-of-concept (POC) study in neuropathic pain. Adults with moderate to severe peripheral neuropathic pain entered a 3- to 4-day screening period, followed by a 12-day titration to the highest tolerated dose that provided pain control (pregabalin 50-200mg t.i.d.), and then a 9-day maintenance period. Subjects were stratified as primary responders (⩾30%), secondary responders (⩾10% to <30%), or nonresponders (<10%) based on decrease in pain intensity and were randomized to placebo or pregabalin during the randomized withdrawal period. The primary endpoint was mean of average 24-h pain intensity during the last 3days of treatment period relative to the 3days before randomization. Time-to-efficacy-failure was the key secondary endpoint. Other features included not requiring discontinuation of current analgesic therapies and blinding investigators to study design elements that could contribute to non-treatment-related responses. Effect size (ES) (mean treatment difference/SD) was used to measure assay sensitivity. Pregabalin-treated subjects (n=52) had significantly less pain than those receiving placebo (n=51) (P⩽.003). Effect size of the primary endpoint was 0.72 for primary responders and decreased if secondary and nonresponders were included in the analysis. The highest ES (1.68) was demonstrated for the endpoint time-to-efficacy-failure seen in primary responders with painful diabetic neuropathy. The EERW trial design using time-to-efficacy-failure may provide a sensitive and efficient method to conduct POC studies of novel therapies in patients with neuropathic pain. Enriching a study population with patients who have achieved a 30% decrease in pain with an investigational therapy, and using time-to-efficacy-failure during the randomized withdrawal phase as the primary endpoint, can be used for a proof-of-concept study to optimize assay sensitivity and efficiently determine the analgesic potential of a new treatment for neuropathic pain.
To identify the level of evidence for use of nusinersen to treat spinal muscular atrophy (SMA) and review clinical considerations regarding use.
Methods
The author panel systematically reviewed nusinersen clinical trials for patients with SMA and assigned level of evidence statements based on the American Academy of Neurology9s 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed.
Results
Four published clinical trials were identified, 3 of which were rated above Class IV. There is Class III evidence that in infants with homozygous deletions or mutations of SMN1, nusinersen improves the probability of permanent ventilation-free survival at 24 months vs a well-defined historical cohort. There is Class I evidence that in term infants with SMA and 2 copies of SMN2, treatment with nusinersen started in individuals younger than 7 months results in a better motor milestone response and higher rates of event-free survival than sham control. There is Class I evidence that in children aged 2–12 years with SMA symptom onset after 6 months of age, nusinersen results in greater improvement in motor function at 15 months than sham control. Nusinersen was safe and well-tolerated.
Clinical context
Evidence of efficacy is currently highest for treatment of infantile- and childhood-onset SMA in the early and middle symptomatic phases. While approved indications for nusinersen use in North America and Europe are broad, payer coverage for populations outside those in clinical trials remain variable. Evidence, availability, cost, and patient preferences all influence decision-making regarding nusinersen use.
Sleep disturbance and insomnia are common in patients with Alzheimer’s disease (AD) but evidence for the efficacy of sleep medications in this population is limited. Suvorexant, a first-in-class orexin receptor antagonist that enables sleep to occur via competitive antagonism of wake-promoting orexins, is approved for treating insomnia in elderly and non-elderly adults. We conducted a clinical trial to evaluate its efficacy and safety for treating insomnia in patients with AD using sleep laboratory polysomnography (PSG) assessments. This randomized, placebo-controlled trial consisted of a 3-week screening period followed by a double-blind 4-week treatment period (ClinicalTrials.gov: NCT02750306). Patients met diagnostic criteria for both AD and insomnia and had a qualified trial partner/caregiver. Participants were randomized to an initial dose of suvorexant 10mg, that could be increased to 20mg based on clinical response, or matching placebo. Assessments included overnight sleep laboratory PSG visits, a sleep diary completed by the trial partner, an activity/sleep watch worn by the patient, and exploratory measures of cognition and neuropsychiatric behavior. The primary objective was to test the hypothesis that suvorexant would be superior to placebo in improving PSG-derived total sleep time (TST) at Week-4. A total of 285 participants (suvorexant N=142, placebo N=143) were randomized from 35 sites in 8 countries worldwide. Of these, 277 (97%) completed the study (suvorexant N=136, placebo N=141). One patient in each group discontinued study treatment due to an adverse event. Mean (SD) TST at baseline was 278 (77) minutes for suvorexant and 274 (84) minutes for placebo. At Week-4, the model-based least squares mean changes-from-baseline were 73 minutes for suvorexant and 45 minutes for placebo (difference = 28 minutes [95% CI:11,45], p<0.005). Regarding safety, 22.5% of suvorexant-treated patients and 16.1% of placebo-treated patients experienced ≥1 adverse events. Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients. Suvorexant was effective and generally well-tolerated for treating insomnia in patients with AD. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
The authors report a case of fatal acute encephalopathy following influenza infection, with slightly atypical pathological and imaging findings. A healthy 8-year-old boy with probable recent influenza A/B infection admitted for refractory seizures was placed on phenobarbital coma and later developed hemodynamic instability. Magnetic resonance imaging revealed bilateral cerebral and cerebellar white matter lesions and microhemorrhages. Following his demise, the autopsy revealed a large area of necrosis in the right centrum semiovale with similar lesions in the temporal and cerebellar regions. Microscopically, there was extensive coagulative necrosis, compatible with necrotizing white matter encephalopathy, and neuronal loss suggesting superimposed hypoxic-ischemia. The acute progressive neurologic deterioration was partly reminiscent on acute necrotizing encephalopathy, a condition recently associated with influenza A. In acute necrotizing encephalopathy, typical brain findings are characterized by bilateral thalamic necrosis/petechiae with variable white matter edema. The somewhat atypical findings in our case can relate to superadded cardiovascular collapse and hypoxic-ischemic effects.
In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.
In the phase-3 APECS trial, the BACE inhibitor verubecestat failed to improve clinical outcomes in participants with prodromal AD and was associated with worsening on some measures, notably cognition. Worsening relative to placebo was apparent early but did not progress further over time. We performed analyses to evaluate whether this early-onset worsening of cognition was consistent across participant subgroups and cognitive domains, and the possible relationship with adverse events. Participants aged 55–85 years who had memory impairment and elevated brain amyloid but without significant functional impairment were randomized in a double-blind, placebo-controlled, 104-week trial of verubecestat 12mg and 40mg. Cognition was assessed by the ADAS-Cog13 and a 3-domain composite cognition score (CCS-3D) which included tests of episodic memory, executive function, and attention/processing speed. Analyses were exploratory and intended to be hypothesis-generating. As previously reported, total score on the ADAS-Cog13 and CCS-3D worsened in each verubecestat group relative to placebo at the earliest evaluation time point of Week-13. There was no observed effect of age, baseline severity, APOE4 genotype, use of AD treatment at baseline, PET brain amyloid load, or MRI brain volume on treatment response on the ADAS-Cog13 at Week-13. There did not appear to be a relationship among groupings of adverse events (e.g. those potentially related to cognition, psychiatric adverse events, or falls) within the first 13 weeks and treatment response on the ADAS-Cog13 at Week-13. Analysis of components of CCS-3D suggested that the Week-13 verubecestat worsening relative to placebo was driven by worse scores on episodic memory and attention/processing speed domains. In contrast, verubecestat was associated with better performance on letter and category fluency tests in the executive function domain at Week-13. The early-onset worsening of cognition by verubecestat in participants with prodromal AD was consistent across subgroups and did not appear to be influenced by adverse events. Verubecestat appeared to have differential effects on different cognitive domains at Week-13, but this could be a chance finding given the large number of exploratory comparisons performed. If replicated in other data sets, this observation might provide insights into the role of BACE inhibition in cognition.
