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Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

In this multicenter, randomized trial, the administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic–ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment at 22 to 36 months of age than placebo and was associated with a higher rate of serious adverse events.

A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov, number NCT01280123. 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55–6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17–7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35–8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1·83 (80% CI −3·56 to −0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was −1·12 (80% CI −2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. National Institute of Neurological Disorders and Stroke.

Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0–2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0–1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0–2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96–1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Nerinetide is a neuroprotectant effective in preclinical models of acute ischaemic stroke when administered within 3 h of onset. However, the clinical evaluation of neuroprotectants in this short timeframe is challenging. We sought to establish the feasibility, safety, and effectiveness of nerinetide when given before hospital arrival within 3 h of symptom onset of suspected stroke. In this multicentre, randomised, double-blind, placebo-controlled study, paramedics enrolled participants aged 40–95 years within 3 h of suspected severe stroke onset, who were previously independent, and were being taken to one of seven stroke centres in Ontario or British Columbia, Canada. The primary hypothesis was that the administration of nerinetide would result in a higher rate of good functional outcomes. Participants were randomly assigned 1:1 to intravenous nerinetide (2·6 mg/kg) or placebo, each in visually identical vials. Paramedics, hospital care providers, and outcome evaluators were masked to treatment assignment. The primary outcome was good functional outcome on a sliding dichotomy of the modified Rankin Scale at 90 days. Participants were assessed on day 4, 30, and 90 by the stroke center research team, in person or over the telephone. Outcomes, adjusted for age and stroke severity, were evaluated in the modified intention-to-treat (mITT) population, and in the target population of those with acute ischaemic stroke. The safety population included all participants who received the study drug. This study is registered with ClinicalTrials.gov (NCT02315443), and trial enrolment has concluded. Between March 26, 2015, and March 27, 2023, 532 participants received nerinetide (n=265) or placebo (n=267). The mITT population of suspected stroke (n=507; 254 nerinetide and 253 placebo) included 321 (63%) with acute ischaemic stroke, 93 (18%) with intracranial haemorrhage, 44 (9%) with transient ischaemic attack, and 49 (10%) with stroke-mimicking conditions. Treatment began a median of 64 min (IQR 47–100) from symptom onset. Participants randomly assigned to nerinetide had more severe strokes compared with those receiving placebo (median National Institutes of Health Stroke Scale (NIHSS) 12, IQR 5–19 vs 10, 4–18 in mITT, and 14, 7–19 vs 10, 4–18 in the acute ischaemic stroke subgroup). Overall, 145 (57%) of 254 participants in the nerinetide group and 147 (58%) of 253 in the placebo group had the primary outcome of a favourable functional outcome using the prespecified sliding dichotomy at 90 days (adjusted odds ratio 1·05, 95% CI 0·73–1·51; adjusted risk ratio 1·04, 95% CI 0·85–1·25). In the 302 patients with ischaemic stroke, the favourable functional outcome adjusted for arrival NIHSS and age favoured nerinetide (odds ratio 1·53, 0·93–2·52 and risk ratio 1·21, 0·97–1·52). In those given reperfusion therapies (thrombolysis or endovascular thrombectomy, or both) nerinetide was associated with improved favourable functional outcomes (adjusted odds ratio 1·84, 1·03–3·28; adjusted risk ratio 1·29, 1·01–1·65). There was no apparent benefit in haemorrhagic stroke or acute ischaemic stroke without reperfusion. There were no safety concerns. Prehospital nerinetide did not improve neurological functional outcomes in all patients with suspected ischaemic stroke in the mITT population. Nerinetide might benefit patients with acute ischaemic stroke who are selected for reperfusion therapies within 3 h of symptom onset. This finding should be confirmed in a future trial. Brain Canada and NoNO.

Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3–25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in all patients who received one or more doses of the study drug. The trial is registered with ClinicalTrials.gov, number NCT01302600. The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and −1·82 for placebo (treatment difference 2·00 points, 96% CI −0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. AFM Téléthon and Trophos SA.

Background The CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death. Methods The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis. Results There were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58–0.94). There was no evidence of heterogeneity by severity ( p  = 0.64) or country income ( p  = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69–1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83–1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70–0.87) and death within 28 days (RR 0.88, 95% CI 0.82–0.94). Conclusions Tranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury. Trial registration ISRCTN15088122 , registered on 19 July 2011; NCT01402882 , registered on 26 July 2011.

Amyotrophic lateral sclerosis (ALS) is a life-threatening disease characterised by progressive loss of motor neurons with few therapeutic options. The MIROCALS study tested the hypothesis that low-dose interleukin-2 (IL-2LD) improves survival and function in ALS. In this randomised, double-blind, placebo-controlled trial, male and female riluzole-naive participants, with either a possible, laboratory-supported probable, probable, or definite ALS diagnosis (revised El Escorial criteria), aged 18–76 years, with symptom duration of 24 months or fewer, and slow vital capacity of 70% or more, underwent a riluzole-only 12–18 week run-in period before randomisation in a 1:1 ratio to either 2 million international units (MIU) IL-2LD or placebo by subcutaneous injection daily for 5 days every 28 days over 18 months. The primary endpoint was survival at 640 days (21 months). Secondary outcomes included safety, ALS Functional Rating Scale-Revised (ALSFRS-R) score, and biomarker measurements including regulatory T-cells (Tregs), cerebrospinal fluid (CSF)-phosphorylated-neurofilament heavy-chain (CSF-pNFH), and plasma and CSF-chemokine ligand 2 (CCL2). The primary endpoint analysis used unadjusted log-rank and Cox's model adjusted analyses using pre-defined prognostic covariates to control for the disease and treatment response heterogeneity. The study was 80% powered to detect a two-fold decrease in the risk of death by the log-rank test in the intention-to-treat (ITT) population, including all randomly allocated participants. MIROCALS is registered with ClinicalTrials.gov (NCT03039673) and is complete. From June 19, 2017, to Oct 16, 2019, 304 participants were screened, of whom 220 (72%) met all criteria for random allocation after the 12-to-18-week run-in period on riluzole. 136 (62%) of participants were male and 84 participants (38%) were female. 25 (11%) of the 220 randomly allocated participants were defined as having possible ALS under El Escorial criteria. At the cutoff date there was no loss to follow-up, and all 220 patients who were randomly allocated were documented as either deceased (90 [41%]) or alive (130 [59%]), so all participants were included in the ITT and safety populations. The primary endpoint unadjusted analysis showed a non-significant 19% decrease in risk of death with IL-2LD (hazard ratio 0·81 [95% CI 0·54–1·22], p=0·33), failing to demonstrate the expected two-fold decrease in risk of death. The analysis of the primary endpoint adjusted on prognostic covariates, all measured at time of random allocation, showed a significant decrease of the risk of death with IL-2LD (0·32 [0·14–0·73], p=0·007), with a significant treatment by CSF-pNFH interaction (1·0003 [1·0001–1·0005], p=0·001). IL-2LD was safe, and significantly increased Tregs and decreased plasma-CCL2 at all timepoints. Stratification on CSF-pNFH levels measured at random allocation showed that IL-2LD was associated with a significant 48% decrease in risk of death (0·52 [0·30–0·89], p=0·016) in the 70% of the population with low (750–3700 pg/mL) CSF-pNFH levels, while in the 21% with high levels (>3700 pg/mL), there was no significant difference (1·37 [0·68–2·75], p=0·38). With this treatment schedule, IL-2LD resulted in a non-significant reduction in mortality in the primary unadjusted analysis. However, the difference between the results of unadjusted and adjusted analyses of the primary endpoint emphasises the importance of controlling for disease heterogeneity in ALS randomised controlled trials. The decrease in risk of death achieved by IL-2LD therapy in the trial population with low CSF-pNFH levels requires further investigation of the potential benefit of this therapy in ALS. European Commission H2020 Programme; French Health Ministry PHRC2014; and Motor Neurone Disease Association.

In this randomized trial involving patients with acute stroke, prehospital administration of magnesium sulfate by paramedics within 2 hours after the onset of stroke symptoms (within 1 hour for 74% of patients) did not improve neurologic outcomes. Stroke is the second leading cause of death and a leading cause of adult disability worldwide. Unfortunately, currently available therapies for acute ischemic stroke, which are all reperfusion-based, are only moderately effective. 1 , 2 Treatment with tissue plasminogen activator (t-PA), the only pharmacologic treatment approved by a regulatory agency for the treatment of acute ischemic stroke, results in early reperfusion in less than half of treated patients, can be started only after neuroimaging has ruled out intracerebral hemorrhage, and is used in only 2 to 7% of patients with acute ischemic stroke in the United States. 1 Mechanical thrombectomy devices improve patient . . .

In three neuroprotection trials of nerinetide for acute ischaemic stroke, inconclusive results have been reported with respect to the prespecified primary outcome. However, none of the trials faithfully replicated the inclusion criteria of the animal studies that provided the rationale for the clinical trials—ie, treatment within 3 h of stroke onset and selected for reperfusion without previous thrombolysis. We aimed to investigate whether a clinical benefit of nerinetide might be seen in the subgroup of patients enrolled in these three clinical trials who met the criteria used in the animal studies. In this post-hoc individual patient data meta-analysis, we pooled data from the ESCAPE-NA1, ESCAPE-NEXT, and FRONTIER trials, which were done at 135 stroke centres in 13 countries (Canada, Australia, Germany, Ireland, Italy, the Netherlands, Norway, Singapore, South Korea, Sweden, Switzerland, the UK, and the USA). We included all participants who were enrolled within 3 h of acute ischaemic stroke onset, treated with study drug (nerinetide or placebo; randomised 1:1), and selected for reperfusion with thrombolysis, endovascular thrombectomy, or both. The primary endpoint was the number of responders at day 90, which was defined as people with a favourable outcome as per the primary endpoint prespecified in their respective trial. The primary endpoint was analysed by logistic regression, adjusted for age, stroke severity, and trial. Between March 26, 2015, and Jan 31, 2023, 2487 participants were enrolled in the three trials, of whom 690 met criteria for this pooled analysis (389 participants in the nerinetide group and 301 participants in the placebo group). 364 (53%) of 690 participants were men and 326 (47%) were women. The median age of participants was 76 years (IQR 66–83) and median baseline National Institutes of Health Stroke Scale score was 17 (11–21). 216 (56%) of 389 participants were responders at day 90 in the nerinetide group compared with 144 (48%) of 301 in the placebo group (adjusted odds ratio [aOR] 1·48, 95% CI 1·07–2·06; p=0·017). 62 (16%) of 389 people in the nerinetide group died compared with 55 (18%) of 301 people in the placebo group (aOR 0·81, 95% CI 0·53–1·24; p=0·34). No safety concerns were identified in either group. Nerinetide showed a clinically significant benefit over several outcome measures, including the modified Rankin Scale score, the incidence of stroke worsening, and infarction volumes. Neuroprotection with nerinetide might, therefore, be indicated for patients within 3 h of stroke onset and who are selected for reperfusion. These inclusion criteria should be tested in a future trial. None.