Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial

Background: S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke. Methods: RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18–85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7–20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0–1 versus 2–6 and 0–2 versus 3–6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one dose of treatment. The study was registered at ClinicalTrials.gov, NCT02877615. Findings: Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819 twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819 group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%) patients in the placebo group received at least one dose of treatment and had at least one mRS score taken after day 5, and were included in efficacy analyses. 195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients in the 300 mg S44819 group, and 193 (100%) patients in the placebo group received at least one dose of treatment, and were included in safety analyses. The primary endpoint of mRS at day 90 did not differ between each of the two S44819 groups and the placebo group (OR 0·91 [95% CI 0·64–1·31]; p=0·80 for 150 mg S44819 compared with placebo and OR 1·17 [95% CI 0·81–1·67]; p=0·80 for 300 mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90 (mRS 0–2 vs 3–6 or mRS 0–1 vs 2–6) did not differ between groups. Secondary endpoints did not reveal any significant group differences. The median NIHSS score at day 90 did not differ between groups (4 [IQR 2–8] in 150 mg S44819 group, 4 [2–7] in 300 mg S44819 group, and 4 [2–6] in placebo group), nor did the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156 in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%] of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55 [34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the median MoCA score (22·0 [IQR 17·0–26·0] in 150 mg S44819 group, 23·0 [19·0–26·5] in 300 mg S44819 group, and 22·0 [17·0–26·0] in placebo group), time needed to complete parts A (50 s [IQR 42–68] in 150 mg S44819 group, 49 s [36–63] in 300 mg S44819 group, and 50 s [38–68] in placebo group) and B (107 s [81–144] in 150 mg S44819 group, 121 s [76–159] in 300 mg S44819 group, and 130 s [86–175] in placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60–100] in 150 mg S44819 group, 90 [70–100] in 300 mg S44819 group, and 90 [70–100] in placebo group) were similar in all groups. Number and type of adverse events were similar between the three groups. There were no drug-related adverse events and no drug-related deaths. Interpretation: There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans. Funding: Servier

Multiple sclerosis registries in Europe – An updated mapping survey

Highlights Nineteen questionnaires from European MS registries were analysed. Aim and focus as well as number of patients and inclusion criteria vary considerably. Most of the MS registries collect data within common general categories. There are more pronounced differences regarding specific subcategories

Global Impact of the COVID-19 Pandemic on Cerebral Venous Thrombosis and Mortality

Background and purpose: Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year. Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020). Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths. Conclusions: During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT

Global Impact of the COVID-19 Pandemic on Cerebral Venous Thrombosis and Mortality.

BACKGROUND AND PURPOSE: Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year. METHODS: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020). RESULTS: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths. CONCLUSIONS: During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT

Self-reported quality of life in multiple sclerosis patients: preliminary results based on the Polish MS Registry

Waldemar Brola,1 Piotr Sobolewski,2 Małgorzata Fudala,1 Stanisław Flaga,3 Konrad Jantarski,4 Danuta Ryglewicz,5 Andrzej Potemkowski6 1Department of Neurology, Specialist Hospital, Końskie, 2Department of Neurology, Holy Spirit Specialist Hospital, Sandomierz, 3AGH University of Science and Technology, Krakow, 4Swietokrzyski Regional Branch of the Polish National Health Fund (NFZ), Kielce, 5First Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, 6Department of Psychology, University of Szczecin, Szczecin, Poland Background: The aim of the study was to analyze selected clinical and sociodemographic factors and their effects on the quality of life (QoL) of multiple sclerosis (MS) patients registered in the Polish MS Registry.Methods: This was a cross-sectional observational study performed in Poland. Data on personal and disease-specific factors were collected between January 1, 2011, and December 31, 2015, via the web portal of the Polish MS Registry. All patients were assessed by a physician and asked to complete the Polish language versions of the following self-evaluation questionnaires: EuroQol 5-Dimensions, EuroQoL Visual Analog Scale, and Multiple Sclerosis Impact Scale. Univariate analysis and logistic regression were performed to determine the factors associated with QoL.Results: The study included 2,385 patients (female/male ratio 2.3:1) with clinically confirmed MS (mean age 37.8&plusmn;9.2 years). Average EuroQol 5-Dimensions index was 0.72&plusmn;0.24, and the mean EuroQoL Visual Analog Scale score was 64.2&plusmn;22.8. The average Multiple Sclerosis Impact Scale score was 84.6&plusmn;11.2 (62.2&plusmn;18.4 for physical condition and 23.8&plusmn;7.2 for mental condition). Lower QoL scores were significantly associated with higher level of disability (odds ratio [OR], 0.932; 95% confidence interval [CI], 0.876&ndash;0.984; P=0.001), age &gt;40 years (OR, 1.042; 95% CI, 0.924&ndash;1.158; P=0.012), longer disease duration (OR, 0.482; 95% CI, 0.224&ndash;0.998; P=0.042), and lack of disease modifying therapies (OR, 0.024; 95% CI, 0.160&ndash;0.835; P=0.024). No significant associations were found between QoL, sex, type of MS course, patient&rsquo;s education, and marital status.Conclusion: The Polish MS Registry is the first national registry for long-term observation that allows for self-evaluation of the QoL. QoL of Polish patients with MS is significantly lower compared with the rest of the population. The parameter is mainly affected by the level of disability, duration of the disease, and limited access to immunomodulatory therapy. Keywords: multiple sclerosis, patient-reported outcomes, quality of life, Polan

Epidemiology and treatment of stroke in Pomeranian Province and Swietokrzyskie Province &#8212; data from Pomeranian Stroke Registry

Wstęp. W świetle badań z 2004 roku udar mózgu rocznie występuje u około 4 tysięcy mieszkańców województwa pomorskiego. W roku 2009 region ten został ponownie objęty pełnym monitorowaniem sytuacji epidemiologicznej, prowadzonej w ramach Pomorskiego Rejestru Udarów Mózgu (PRUM). Celem pracy było przedstawienie aktualnych danych epidemiologicznych i klinicznych dotyczących pacjentów z ostrymi incydentami mózgowo-naczyniowymi, hospitalizowanych na oddziałach udarowych województwa pomorskiego oraz ich porównanie z danymi pacjentów hospitalizowanych na wybranych oddziałach udarowych regionu świętokrzysko-sandomierskiego. Materiał i metody. Analizie poddano dane 3521 chorych, obejmujące etiologię, stan kliniczny oraz stosowane metody leczenia. Zebrane dane porównano z danymi 1079 pacjentów leczonych na oddziałach udarowych regionu świętokrzysko- -sandomierskiego. Wyniki. Nie stwierdzono istotnych różnic w zakresie częstości występowania poszczególnych typów udaru między badanymi populacjami. Analiza statystyczna wykazała większe rozpowszechnienie cukrzycy, hiperlipidemii i palenia tytoniu u pacjentów z oddziałów województwa pomorskiego. W obu populacjach tylko 1/5 osób hospitalizowano we wczesnej fazie choroby (do 3 h od zachorowania). Odsetek chorych leczonych fibrynolitycznie w województwie pomorskim był niższy niż w regionie świętokrzysko-sandomierskim (2,9 v. 8,8%; p < 0,001). W populacji pacjentów z województwa pomorskiego stwierdzono istotnie mniejszy deficyt neurologiczny przy przyjęciu do szpitala oraz mniejszą śmiertelność wewnątrzszpitalną i lepszy stan funkcjonalny przy wypisie w porównaniu z chorymi z regionu świętokrzysko-sandomierskiego. Wnioski. Istnieją istotne dysproporcje między populacjami pacjentów oddziałów udarowych województwa pomorskiego i regionu świętokrzysko-sandomierskiego, dotyczące dystrybucji czynników ryzyka oraz wdrażania obowiązujących standardów diagnostyki i leczenia udaru mózgu. Zbyt mały odsetek pacjentów jest hospitalizowany w oknie czasowym leczenia trombolitycznego, a opóźnienia wewnątrzszpitalne dodatkowo ograniczają stosowanie terapii fibrynolitycznej na oddziałach udarowych województwa pomorskiego. Udar Mózgu 2010; 12 (1&#8211;2): 1&#8211;9Background. According to the research from 2004 about 4 thousand citizens of Pomeranian Province suffer from stroke every year. In 2009 the region was subject to a close epidemiological monitoring program as a part of Pomeranian Stroke Registry. The aim of this research is to present the update on epidemiological and clinical patients with acute cerebrovascular events, hospitalized in stroke units of Pomeranian Province, and to compare them to the patients hospitalized in stroke units of Świętokrzyskie Province. Materials and methods. The analysis was carried out on a group of 3521 patients, and included etiology, clinical state, and applied therapeutic measures. The collected data were compared to the data of 1079 patients treated in stroke units of Świętokrzyskie Province. Results. There were no signifficant differences in the two populations concerning the frequency of occurrence of a given stroke type. The statistical analysis showed that diabetes, hyperlipidaemia and smoking were more common among the patients of Pomeranian Province. In the both populations only 1/5 of the patients were hospitalized within 3 hours from the stroke onset. The proportion of the thrombolyzed patients in the Pomeranian Province was lower than in the Świętokrzyskie Province (2.9 vs 8.8%, p < 0.001). The mortality rate for the Pomeranian Province patients was lower and their functional state was better, compared with the patients from the Świętokrzyskie Province. Conclusions. There are considerable differences between the stroke units patients of the Pomeranian Province and the Świętokrzyskie Province. The differences concern the prevalence of risk factors and implementation of the current guidelines for stroke management. Too few patients hospitalized within the time window for thrombolytic therapy as well as in-hospital delays limit the thrombolytic treatment in stroke units of the Pomeranian Province. Interdisciplinary Problems of Stroke 2010; 12 (1&#8211;2): 1&#8211;