Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial

<p><b>Background and Purpose:</b> NXY-059 is a free radical-trapping neuroprotectant demonstrated to reduce disability from ischemic stroke. We conducted analyses on additional end points and sensitivity analyses to confirm our findings.</p> <p><b>Methods:</b> We randomized 1722 patients with acute ischemic stroke to a 72-hour infusion of placebo or intravenous NXY-059 within 6 hours of stroke onset. The primary outcome was disability at 90 days, as measured by the modified Rankin Scale (mRS), a 6-point scale ranging from 0 (no residual symptoms) to 5 (bed-bound, requiring constant care). Additional and exploratory analyses included mRS at 7 and 30 days; subgroup interactions with final mRS; assessments of activities of daily living by Barthel index; and National Institutes of Health Stroke Scale (NIHSS) neurological scores at 7 and 90 days.</p> <p><b>Results:</b> NXY-059 significantly improved the distribution of the mRS disability score compared with placebo at 7, 30, and 90 days (Cochran-Mantel-Haenszel test P=0.002, 0.004, 0.038, respectively; 90-day common odds ratio 1.20; 95% CI, 1.01 to 1.42). The benefit was not attributable to any specific baseline characteristic, stratification variable or subgroup interaction. Neurological scores were improved at 7 days (odds ratio [OR], 1.46; 95% CI, 1.13, 1.89; P=0.003) and the Barthel index was improved at 7 and 30 days (OR, 1.55; 95% CI, 1.22, 1.98; P<0.0001; OR, 1.27; 95% CI, 1.01, 1.59; P=0.02).</p> <p><b>Conclusions:</b> NXY-059 within 6 hours of acute ischemic stroke significantly reduced disability. Benefit on neurological scores and activities of daily living was detectable early but not significant at 90 days; however, our trial was underpowered to measure effects on the neurological examination. The benefit on disability is not confounded by interactions and is supported by other outcome measures.</p&gt

Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT trial

<p><b>Background and Purpose:</b> NXY-059 is a free radical-trapping neuroprotectant developed for use in acute ischemic stroke. To facilitate prompt administration of treatment, potentially before neuroimaging, we investigated the safety of NXY-059 in patients with intracerebral hemorrhage (ICH).</p> <p><b>Methods:</b> We randomized 607 patients within 6 hours of acute ICH to receive 2270 mg intravenous NXY-059 over 1 hour and then up to 960 mg/h over 71 hours, or matching placebo, in addition to standard care. The primary outcome was safety: the mortality and the frequency of adverse events, and the change from baseline for a variety of serum, imaging, and electrophysiological measurements. We also studied the overall distribution of disability scores on the modified Rankin Scale (mRS) and the Barthel index.</p> <p><b>Results:</b> We treated 300 patients with NXY-059 and 303 with placebo. Treatment groups were well matched for prognostic variables including Glasgow Coma Scale, risk factors, and age. The mean National Institute of Health Stroke Scale score on admission was 14 in both groups. The baseline hemorrhage volume was 22.4±20.1 mL in the NXY-059 group and 23.3±22.8 mL in the placebo group (mean±SD). Most hemorrhages were related to hypertension or anticoagulant use. Mortality was similar in both groups: 20.3% for NXY-059 and 19.8% for placebo-treated patients. The proportion of patients who experienced an adverse event was the same for both groups, whereas for serious adverse events the proportion was slightly higher in the NXY-059 group. However, no pattern emerged to indicate a safety concern. Serum potassium fell transiently in both groups, lower in the NXY-059 group. There were no differences in 3-month function, disability, or neurological deficit scores. The odds ratio for an improved outcome in 3-month mRS scores in the NXY-059 group was 1.01 (95% CI 0.75, 1.35).</p> <p><b>Conclusions:</b> NXY-059 given within 6 hours of acute ICH has a good safety and tolerability profile, with no adverse effect on important clinical outcomes.</p&gt

Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy.

Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis

NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II trials

<p><b>Background and Purpose:</b> In animal models of acute ischemic stroke (AIS), the free radical-trapping agent NXY-059 showed promise as a neuroprotectant. SAINT I and II were randomized, placebo-controlled, double-blind trials to investigate the efficacy of NXY-059 in patients with AIS.</p> <p><b>Methods:</b> Patients with AIS received an infusion of intravenous NXY-059 or placebo within 6 hours from the onset of stroke symptoms. A pooled individual patient analysis was prespecified to assess the overall efficacy and to examine subgroups. The primary end point was the distribution of disability scores measured on the modified Rankin scale (mRS) at 90 days. Neurologic and activities of daily living scores were investigated as secondary end points. We also evaluated whether treatment with NXY-059 would reduce alteplase-related intracranial hemorrhages. Finally, we evaluated possible predictors of good or poor outcome.</p> <p><b>Results:</b> An intent-to-treat efficacy analysis was based on 5028 patients. Baseline parameters and prognostic factors were well balanced between treatment groups. The distribution of scores on the mRS was not different in the group treated with NXY-059 (n = 2438) compared with the placebo group (n = 2456): odds ratio for limiting disability = 1.02; 95% CI, 0.92 to 1.13 (P = 0.682, Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an absence of benefit. There was no evidence of efficacy in prespecified subgroups or from the secondary outcome analyses. Mortality was equal in the 2 groups (16.7% vs 16.5%), and adverse event rates were similar. Among patients treated with alteplase, there was no decrease in rates of symptomatic or asymptomatic hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses identified National Institutes of Health Stroke Scale score, age, markers of inflammation, blood glucose, and right-sided infarct as predictors of poor outcome.</p> <p><b>Conclusions:</b> NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. This is also true for subgroups and the prevention of alteplase-associated hemorrhage.</p&gt

Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST)

<p><b>Background and Purpose:</b> The Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST) unadjusted results demonstrated that intravenous alteplase is well tolerated and that the effects were comparable with those seen in randomized, controlled trials (RCTs) when used in routine clinical practice within 3 hours of ischemic stroke onset. We aimed to identify outcome predictors and adjust the outcomes of the SITS-MOST to the baseline characteristics of RCTs.</p> <p><b>Methods:</b> The study population was SITS-MOST (n=6483) and pooled RCTs (n=464) patients treated with intravenous alteplase within 3 hours of stroke onset. Multivariable, backward stepwise regression analyses (until P≤0.10) were performed to identify the outcome predictors for SITS-MOST. Variables appearing either in the final multivariable model or differing (P<0.10) between SITS-MOST and RCTs were included in the prediction model for the adjustment of outcomes. Main outcome measures were symptomatic intracerebral hemorrhage, defined as National Institutes of Health Stroke Scale deterioration ≥1 within 7 days with any hemorrhage (RCT definition), mortality, and independency as defined by modified Rankin Score of 0 to 2 at 3 months.</p> <p><b>Results:</b> The adjusted proportion of symptomatic intracerebral hemorrhage for SITS-MOST was 8.5% (95% CI, 7.9 to 9.0) versus 8.6% (6.3 to 11.6) for pooled RCTs; mortality was 15.5% (14.7 to 16.2) versus 17.3% (14.1 to 21.1); and independency was 50.4% (49.6 to 51.2) versus 50.1% (44.5 to 54.7), respectively. In the multivariable analysis, older age, high blood glucose, high National Institutes of Health Stroke Scale score, and current infarction on imaging scans were related to poor outcome in all parameters. Systolic blood pressure, atrial fibrillation, and weight were additional predictors of symptomatic intracerebral hemorrhage. Current smokers had a lower rate of symptomatic intracerebral hemorrhage. Disability before current stroke (modified Rankin Score 2 to 5), diastolic blood pressure, antiplatelet other than aspirin, congestive heart failure, patients treated in new centers, and male sex were related to high mortality at 3 months.</p> <p><b>Conclusions:</b> The adjusted outcomes from SITS-MOST were almost identical to those in relevant RCTs and reinforce the conclusion drawn previously in the unadjusted analysis. We identified several important outcome predictors to better identify patients suitable for thrombolysis.</p&gt

Tracing the Evolution of Temperature in Near Fermi Energy Heavy Ion Collisions

The kinetic energy variation of emitted light clusters has been employed as a clock to explore the time evolution of the temperature for thermalizing composite systems produced in the reactions of 26A, 35A and 47A MeV $^{64}$Zn with $^{58}$Ni, $^{92}$Mo and $^{197}$Au. For each system investigated, the double isotope ratio temperature curve exhibits a high maximum apparent temperature, in the range of 10-25 MeV, at high ejectile velocity. These maximum values increase with increasing projectile energy and decrease with increasing target mass. The time at which the maximum in the temperature curve is reached ranges from 80 to 130 fm/c after contact. For each different target, the subsequent cooling curves for all three projectile energies are quite similar. Temperatures comparable to those of limiting temperature systematics are reached 30 to 40 fm/c after the times corresponding to the maxima, at a time when AMD-V transport model calculations predict entry into the final evaporative or fragmentation stage of de-excitation of the hot composite systems. Evidence for the establishment of thermal and chemical equilibrium is discussed.Comment: 9 pages, 5 figure

Critical Behavior in Light Nuclear Systems: Experimental Aspects

An extensive experimental survey of the features of the disassembly of a small quasi-projectile system with $A \sim$ 36, produced in the reactions of 47 MeV/nucleon $^{40}$Ar + $^{27}$Al, $^{48}$Ti and $^{58}$Ni, has been carried out. Nuclei in the excitation energy range of 1-9 MeV/u have been investigated employing a new method to reconstruct the quasi-projectile source. At an excitation energy $\sim$ 5.6 MeV/nucleon many observables indicate the presence of maximal fluctuations in the de-excitation processes. The fragment topological structure shows that the rank sorted fragments obey Zipf's law at the point of largest fluctuations providing another indication of a liquid gas phase transition. The caloric curve for this system shows a monotonic increase of temperature with excitation energy and no apparent plateau. The temperature at the point of maximal fluctuations is $8.3 \pm 0.5$ MeV. Taking this temperature as the critical temperature and employing the caloric curve information we have extracted the critical exponents $\beta$, $\gamma$ and $\sigma$ from the data. Their values are also consistent with the values of the universality class of the liquid gas phase transition. Taken together, this body of evidence strongly suggests a phase change in an equilibrated mesoscopic system at, or extremely close to, the critical point.Comment: Physical Review C, in press; some discussions about the validity of excitation energy in peripheral collisions have been added; 24 pages and 32 figures; longer abstract in the preprin

Properties of the Initial Participant Matter Interaction Zone in Near Fermi-Energy Heavy Ion Collisions

The sizes, temperatures and free neutron to proton ratios of the initial interaction zones produced in the collisions of 40 MeV/nucleon $^{40}$Ar + $^{112}$Sn and 55 MeV/nucleon$^{27}$Al + $^{124}$Sn are derived using total detected neutron plus charged particle multiplicity as a measure of the impact parameter range and number of participant nucleons. The size of the initial interaction zone, determined from a coalescence model analysis, increases significantly with decreasing impact parameter. The temperatures and free neutron to proton ratios in the interaction zones are relatively similar for different impact parameter ranges and evolve in a similar fashion.Comment: 7 pages, 8 figure

A randomised feasibility study of serial magnetic resonance imaging to reduce treatment times in Charcot neuroarthropathy in people with diabetes (CADOM): A protocol

Background Charcot neuroarthropathy is a complication of peripheral neuropathy associated with diabetes which most frequently affects the lower limb. It can cause fractures and dislocations within the foot, which may progress to deformity and ulceration. Recommended treatment is immobilisation and offloading, with a below knee non-removable cast or boot. Duration of treatment varies from six months to more than one year. Small observational studies suggest that repeated assessment with Magnetic Resonance Imaging improves decision making about when to stop treatment, but this has not been tested in clinical trials. This study aims to explore the feasibility of using serial Magnetic Resonance Imaging without contrast in the monitoring of Charcot neuroarthropathy to reduce duration of immobilisation of the foot. A nested qualitative study aims to explore participants’ lived experience of Charcot neuroarthropathy and of taking part in the feasibility study. Methods We will undertake a two arm, open study, and randomise 60 people with a suspected or confirmed diagnosis of Charcot neuroarthropathy from five NHS, secondary care multidisciplinary Diabetic Foot Clinics across England. Participants will be randomised 1:1 to receive Magnetic Resonance Imaging at baseline and remission up to 12 months, with repeated foot temperature measurements and x-rays (standard care plus), or standard care plus with additional three-monthly Magnetic Resonance Imaging until remission up to 12 months (intervention). Time to confirmed remission of Charcot neuroarthropathy with off-loading treatment (days) and its variance will be used to inform sample size in a full-scale trial. We will look for opportunities to improve the protocols for monitoring techniques and the clinical, patient centred, and health economic measures used in a future study. For the nested qualitative study, we will invite a purposive sample of 10-14 people able to offer maximally varying experiences from the feasibility study to take part in semi-structured interviews to be analysed using thematic analysis. Discussion The study will inform the decision whether to proceed to a full-scale trial. It will also allow deeper understanding of the lived experience of Charcot neuroarthropathy, and factors that contribute to engagement in management and contribute to the development of more effective patient centred strategies. Trial registration ISRCTN, ISRCTN, 74101606. Registered on 6 November 2017, http://www.isrctn.com/ISRCTN74101606?q=CADom&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-searc