Clinical trials corner: September 2017

© 2017 – IOS Press and the authors. All rights reserved. This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0).Clinical Trials Corner of Journal of Huntington’s Disease will regularly review ongoing and recently completed clinical trials in Huntington’s disease. In this inaugural issue, we list all currently registered and ongoing clinical trials, expand on LEGATO-HD and IONIS-HTTRx, and cover two recently finished trials: Amaryllis and Pride-HD.info:eu-repo/semantics/publishedVersio

The risks of converting post-hoc findings into primary outcomes in subsequent trials

© Annals of Translational Medicine. All rights reserved. This journal is a peer reviewed, open access journal. All content of the journal is published under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0).Huntington’s disease (HD) is a devastating neurodegenerative condition caused by a triplet repeat expansion of the Huntingtin gene. Although rare it is amongst the most frequent autosomal dominant causes of dementia, frequently affecting individuals in the most productive decades of their lives. Clinically, it is characterized by a classic triad of fluctuating neuropsychiatric symptoms, and progressive movement and cognitive disorders, accompanied by other symptoms such as weight loss and sleep impairment. It is severely debilitating, has a huge impact on quality of life and is fatal, with a median survival after motor onset of around a quarter of a century.info:eu-repo/semantics/publishedVersio

Huntington’s disease Clinical Trials Corner: February 2018

© 2018 – IOS Press and the authors. All rights reserved. This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0)In the second edition of the Huntington’s Disease Clinical Trials Corner we list all currently registered and ongoing clinical trials, summarise the top-line results of the recently-announced IONIS-HTTRX trial (NCT02519036), expand on Wave Life Sciences’ PRECISION-HD1 (NCT03225833) and PRECISION-HD2 (NCT03225846), and cover one recently finished trial: the FIRST-HD deutetrabenazine trial (NCT01795859).info:eu-repo/semantics/publishedVersio

Modelo animal para o estudo da fisiopatologia da hipertensão ocular - glaucoma

Relatório de projecto no âmbito de Bolsa Universidade de Lisboa/Fundação Amadeu Dias (2009/2010)Universidade de Lisboa. Faculdade de Medicina. Instituto de Medicina Molecular. Unidade de Sistema Nervoso AutónomoUniversidade de Lisboa; Fundação Amadeu Dia

Tetrabenazine versus deutetrabenazine for Huntington's disease : twins or distant cousins?

© 2017 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: Tetrabenazine is the only US Food and Drug Administration‐approved drug for Huntington's disease, and deutetrabenazine was recently tested against placebo. A switching‐trial from tetrabenazine to deutetrabenazine is underway, but no head‐to‐head, blinded, randomized controlled trial is planned. Using meta‐analytical methodology, the authors compared these molecules. Methods: RCTs comparing tetrabenazine or deutetrabenazine with placebo in Huntington's disease were searched. The authors assessed the Cochrane risk‐of‐bias tool, calculated indirect treatment comparisons, and applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Results: The evidence network for this report comprised 1 tetrabenazine trial and 1 deutetrabenazine trial, both against placebo. Risk of bias was moderate in both. Participants in the tetrabenazine and deutetrabenazine trials did not differ significantly on motor scores or adverse events. Depression and somnolence scales significantly favored deutetrabenazine. Conclusion: There is low‐quality evidence that tetrabenazine and deutetrabenazine do not differ in efficacy or safety. It is important to note that these results are likely to remain the only head‐to‐head comparison between these 2 compounds in Huntington's disease.info:eu-repo/semantics/publishedVersio

Analysis of the Cochrane review : portion, package or tableware size for changing selection and consumption of food, alcohol and tobacco : Cochrane Database Syst Rev. 2015;09: CD011045

Copyright © Ordem dos Médicos 2016Some of the main causes of mortality and morbidity among the developed countries – such as the cardiovascular, neurological and oncologic diseases – are deeply associated with modifiable risk factors. Primordial/primary prevention strategies that alter our environment can have an impact on these risk factors. The authors of this Cochrane systematic review sought evidence from randomized controlled trials to study the effect of the size of portions, packages, dishes and cups, as well as their respective formats, on the consumption and selection of food, alcoholic and non-alcoholic beverages and tobacco products. Overall, this review concludes that the choice of larger portions results in an increased consumption in food, non-alcoholic beverages and tobacco.Algumas das principais causas de mortalidade e morbilidade nos países desenvolvidos – como as doenças cardiovasculares, neurológicas e oncológicas – são dependentes de fatores de risco modificáveis. Estratégias de prevenção primordial/primária que alterem o meio ambiente em que vivemos podem ter impacto nestes fatores de risco. Os autores desta revisão sistemática Cochrane procuraram evidência em ensaios clínicos controlados e randomizados para perceber se o tamanho das porções, embalagens, pratos e copos tinham influência no consumo e seleção de alimentos, bebidas alcoólicas e não alcoólicas e produtos derivados do tabaco, tendo concluído que as escolhas de tamanho maior estão associadas a um incremento na seleção e consumo de alimentos, bebidas não alcoólicas e cigarros.info:eu-repo/semantics/publishedVersio

Lumbar puncture safety and tolerability in premanifest and manifest Huntington’s disease: a multi‑analysis cross‑sectional study

Lumbar puncture (LP) has become increasingly common for people with Huntington’s disease (HD) both to administer intrathecal investigational medicinal products and to collect cerebrospinal fluid to develop biological markers to track disease stage and progression. We aimed to investigate the safety profile of LP in people with HD, building on a recently published work by increasing the sample size and more specifically, increasing the representation of the premanifest population and healthy controls. We conducted a multi-study cross-sectional analysis including eligible participants from the HDClarity (304 Huntington's disease gene expansion carriers and 91 controls) and HD-YAS studies (54 premanifest and 48 controls), enrolled between February 2016 and September 2019. We investigated the odds of any adverse events, headaches, and back pain independently. Intergroup comparisons and adjusted event odds were derived using hierarchical logistic regressions. A total of 669 LP procedures involving 497 participants were included in this analysis. There were 184 (27.5%) LP procedures associated with one or more adverse events. The two most common adverse events were: post LP headache and back pain. Younger age and female gender were found to be associated with a higher risk of developing adverse events. There was no difference in the rate of adverse events between the disease subgroups after adjusting for covariates such as age and gender. Our results suggest that the LP is safe and tolerable in premanifest and manifest HD subjects, providing useful reassurance about the procedure to the HD community

Thromboprophylaxis with apixaban in patients undergoing major orthopedic surgery : meta-analysis and trial-sequential analysis

© The Author(s) 2017Background: Venous thromboembolism (VTE) is a potentially fatal complication of orthopedic surgery, and until recently, few antithrombotic compounds were available for postoperative thromboprophylaxis. The introduction of the non–vitamin K antagonists oral anticoagulants (NOAC), including apixaban, has extended the therapeutic armamentarium in this field. Therefore, estimation of NOAC net clinical benefit in comparison with the established treatment is needed to inform clinical decision making. Objectives: Systematic review to assess the efficacy and safety of apixaban 2.5 mg twice a day versus low-molecular-weight heparins (LMWH) for thromboprophylaxis in patients undergoing knee or hip replacement. Data sources: MEDLINE, Embase, and CENTRAL were searched from inception to September 2016, other systematic reviews, reference lists, and experts were consulted. Study eligibility criteria, participants, and intervention: All major orthopedic surgery randomized controlled trials comparing apixaban 2.5 mg twice daily with LMWH, reporting thrombotic and bleeding events. Data extraction: Two independent reviewers, using a predetermined form. Study appraisal and synthesis methods: The Cochrane tool to assess risk bias was used by two independent authors. RevMan software was used to estimate pooled risk ratio (RR) and 95% confidence intervals (95% CI) using random-effects meta-analysis. Trial sequential analysis (TSA) was performed in statistical significant results to evaluate whether cumulative sample size was powered for the obtained effect. Overall confidence in cumulative evidence was assessed using the Grading of recommendations Assessment, Development, and Evaluation (GRADE) Working Group methodology. Results: Four studies comparing apixaban 2.5 mg twice daily with LMWH were included, with a total of 11.828 patients (55% undergoing knee and 45% hip replacement). The overall risk of bias across studies was low. In comparison with LMWH (all regimens), apixaban showed a significantly lower risk of VTE events and overall mortality combined (RR: 0.63, 95% CI: 0.42-0.95, I2 = 84%, n = 8346), but not of major VTE events (RR: 0.62, 95% CI: 0.32-1.19, I2 = 63%, n = 9493), or of symptomatic VTE events and VTE-related mortality combined (RR: 1.14, 95% CI: 0.68-1.90, I2 = 0%, n = 11 879). Trial sequential analysis showed that the risk reduction obtained for VTE and mortality was based on underpowered cumulative sample size and effect dimension. Subgroup analysis according to LMWH regimens showed that apixaban reduced the risk of VTE events and overall mortality, and major VTE events, when compared with LMWH once daily, without differences between apixaban and LMWH twice daily. Conclusions: There is low to moderate evidence that in patients undergoing knee or hip replacement, apixaban seems equally effective and safe to LMWH twice a day. When compared with LMWH once a day, apixaban seems a superior thromboprophylaxis option. However, the results are underpowered which precludes definite answers regarding the true net clinical benefit of apixaban versus LMWH in this clinical context.info:eu-repo/semantics/publishedVersio

Morphine in acute coronary syndrome : systematic review and meta-analysis

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Objective: Morphine is frequently used in acute coronary syndrome (ACS) due to its analgesic effect, it being recommended in the main cardiology guidelines in Europe and the USA. However, controversy exists regarding its routine use due to potential safety concerns. We conducted a systematic review of randomised-controlled trials (RCTs) and observational studies to synthesise the available evidence. Design: Systematic review and meta-analysis. Data sources: CENTRAL, MEDLINE, EMBASE and trial registries. Eligibility criteria for selecting studies: We included RCTs and observational studies evaluating the impact of morphine in cardiovascular outcomes or platelet reactivity measures. Data extraction and synthesis: Data were screened, extracted and appraised by two independent reviewers. The data were pooled results using a random-effects model. Outcomes included in-hospital mortality, major adverse cardiovascular events (MACE), platelet reactivity (using VerifyNow) and bleeding, reported as relative risk (RR) with 95%CI. We assessed the confidence in the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. We followed the Metaanalysis Of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and MetaAnalyses guidelines. Results: Five RCTs and 12 observational studies were included, enrolling 69 993 participants. Pooled results showed an increased risk of in-hospital mortality (RR 1.45 [95% CI 1.10 to 1.91], low GRADE confidence), MACE (RR 1.21, 95%CI 1.02 to 1.45) and an increased platelet reactivity at 1 and 2 hours (59.37 platelet reactivity units [PRU], 95%CI 36.04 to 82.71; 68.28 PRU, 95%CI 37.01 to 99.55, high GRADE confidence) associated with morphine. We found no significant difference in the risk of bleeding. We found no differences in subgroup analyses based on study design and ACS subtype. Conclusions: Morphine was associated with an increased risk of in-hospital mortality and MACE but the high risk of bias leads to low result confidence. There is high confidence that morphine decreases the antiplatelet effect of P2Y12 inhibitors.UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/ Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado.info:eu-repo/semantics/publishedVersio

PO104 placebo and nocebo responses in RLS : a meta-analysis

Objective: Our goals were to estimate the placebo and nocebo responses in restless legs syndrome (RLS). Methods: Databases were searched up to October 2015. Randomised, double-blind, placebo-controlled trials of RLS patient were included. ‘Placebo response’ was defined as the within-group change from baseline, using any scale measuring RLS severity or disability. ‘Nocebo response’ was defined as the proportion of patients experiencing adverse events in the placebo arm. Random-effects meta-analysis was used to pool data. Results: We included 5046 participants. Pooled placebo response effect size was −1.41 (95%CI:−1.56-−1.25), corresponding to −6.58 points in the International RLS Study Group Scale (IRLS). Pooled nocebo response was 45.36% (95%CI:40.47%–50.29%). The placebo and nocebo responses were greater in trials with longer duration, evaluating pharmacological interventions and idiopathic RLS, and in industry funded and unpublished studies. The placebo response was considerable smaller in objective as compared to subjective outcomes. In addition, the nocebo response increases proportionally with the placebo response, and has the same predictors. Conclusions: The magnitude of the placebo response in RLS is above the threshold of minimal clinical important difference, and the frequency of adverse events is also considerable. These results are relevant to inform the design and interpretation of future clinical trials.info:eu-repo/semantics/publishedVersio