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- Ederle, Joerg, et al.
(author)
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Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
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In: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
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Journal article (peer-reviewed)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
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| 3. |
- Watt, F. E., et al.
(author)
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Towards prevention of post-traumatic osteoarthritis : report from an international expert working group on considerations for the design and conduct of interventional studies following acute knee injury
- 2019
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In: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 27:1, s. 23-33
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Journal article (peer-reviewed)abstract
- Objective: There are few guidelines for clinical trials of interventions for prevention of post-traumatic osteoarthritis (PTOA), reflecting challenges in this area. An international multi-disciplinary expert group including patients was convened to generate points to consider for the design and conduct of interventional studies following acute knee injury. Design: An evidence review on acute knee injury interventional studies to prevent PTOA was presented to the group, alongside overviews of challenges in this area, including potential targets, biomarkers and imaging. Working groups considered pre-identified key areas: eligibility criteria and outcomes, biomarkers, injury definition and intervention timing including multi-modality interventions. Consensus agreement within the group on points to consider was generated and is reported here after iterative review by all contributors. Results: The evidence review identified 37 studies. Study duration and outcomes varied widely and 70% examined surgical interventions. Considerations were grouped into three areas: justification of inclusion criteria including the classification of injury and participant age (as people over 35 may have pre-existing OA); careful consideration in the selection and timing of outcomes or biomarkers; definition of the intervention(s)/comparator(s) and the appropriate time-window for intervention (considerations may be particular to intervention type). Areas for further research included demonstrating the utility of patient-reported outcomes, biomarkers and imaging outcomes from ancillary/cohort studies in this area, and development of surrogate clinical trial endpoints that shorten the duration of clinical trials and are acceptable to regulatory agencies. Conclusions: These considerations represent the first international consensus on the conduct of interventional studies following acute knee joint trauma.
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| 4. |
- Beard, David J., et al.
(author)
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Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines)
- 2020
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In: The Lancet. - 0140-6736. ; 395:10226, s. 828-838
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Research review (peer-reviewed)abstract
- Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this Review is to provide a summary of knowledge on placebo controls in surgical trials. A placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. This Review outlines what a placebo control entails and present understanding of this tool in the context of surgery. We consider when placebo controls in surgery are acceptable (and when they are desirable) in terms of ethical arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be done and interpreted. Use of placebo controls is justified in randomised controlled trials of surgical interventions provided there is a strong scientific and ethical rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with high risk of bias, particularly because of the placebo effect. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. This Review forms an outline for best practice and provides guidance, in the form of the Applying Surgical Placebo in Randomised Evaluations (known as ASPIRE) checklist, for those considering the use of a placebo control in a surgical randomised controlled trial.
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| 5. |
- Beard, David J., et al.
(author)
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Placebo comparator group selection and use in surgical trials : The aspire project including expert workshop
- 2021
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In: Health Technology Assessment. - 1366-5278. ; 25:53
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Journal article (peer-reviewed)abstract
- Background: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. Objectives: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials. Design: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout. Setting: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines. Results: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect. Conclusions: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial. Limitations: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS. Future work: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space.
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| 7. |
- Andrieu, S, et al.
(author)
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IAGG Workshop: Health promotion program on prevention of late onset dementia
- 2011
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In: Journal of nutrition healt & aging. - 1279-7707. ; 15:7, s. 562-575
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Journal article (peer-reviewed)abstract
- IAGG, WHO, and SFGG organized a international workshop on Health promotion programs on prevention of late on-set dementia. Thirty world specialists coming from Europe, North America, Asia, South America, Africa and Australia, shared their experience on methods and results of large epidemiological interventions to reduce incidents of dementia or delay its on-set. Chaired by Laura FRATIGLIONI, an expert in Epidemiological studies on dementia issues, the workshop gave opportunity for discussions and controversies about the state-of-the-art. Based on different national and international trials (ADAPT, MAPT, FINGER, GUDIAGE, GEM etc) the questions remained opened for different aspects of methodology, the choice of domain or multi domain intervention, the choice and the definition of the target populations, the best age of candidates, the issues related to the discrepancy between late effects, and interventions' duration. We are please to publish in the Journal, the presentations presented to this workshop. These publications will complete previously task force published in the journal in the last two years on methodological issues for Alzheimer's trials including end point, biomarkers, and the experience of past therapeutic trials.
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| 8. |
- Sanchez-Bezanilla, S., et al.
(author)
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Growth Hormone Increases BDNF and mTOR Expression in Specific Brain Regions after Photothrombotic Stroke in Mice
- 2022
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In: Neural Plasticity. - : Hindawi Limited. - 2090-5904 .- 1687-5443. ; 2022
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Journal article (peer-reviewed)abstract
- Aims. We have shown that growth hormone (GH) treatment poststroke increases neuroplasticity in peri-infarct areas and the hippocampus, improving motor and cognitive outcomes. We aimed to explore the mechanisms of GH treatment by investigating how GH modulates pathways known to induce neuroplasticity, focusing on association between brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the peri-infarct area, hippocampus, and thalamus. Methods. Recombinant human growth hormone (r-hGH) or saline was delivered (0.25 mu l/hr, 0.04 mg/day) to mice for 28 days, commencing 48 hours after photothrombotic stroke. Protein levels of pro-BDNF, total-mTOR, phosphorylated-mTOR, total-p70S6K, and phosporylated-p70S6K within the peri-infarct area, hippocampus, and thalamus were evaluated by western blotting at 30 days poststroke. Results. r-hGH treatment significantly increased pro-BDNF in peri-infarct area, hippocampus, and thalamus (p < 0.01). r-hGH treatment significantly increased expression levels of total-mTOR in the peri-infarct area and thalamus (p < 0.05). r-hGH treatment significantly increased expression of total-p70S6K in the hippocampus (p < 0.05). Conclusion. r-hGH increases pro-BDNF within the peri-infarct area and regions that are known to experience secondary neurodegeneration after stroke. Upregulation of total-mTOR protein expression in the peri-infarct and thalamus suggests that this might be a pathway that is involved in the neurorestorative effects previously reported in these animals and warrants further investigation. These findings suggest region-specific mechanisms of action of GH treatment and provide further understanding for how GH treatment promotes neurorestorative effects after stroke.
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