BACKGROUND: This study derived composite scores for two novel cognitive measures, the No Practice Effect (NPE) battery and the Miami Computerized Functional Skills Assessment and Training system for use in early-stage Alzheimer\'s disease (AD) clinical trials. Their psychometric properties and associations with AD risk markers were compared to those of well-established measures.
METHODS: For 291 older adults with healthy cognition or early mild cognitive impairment, Exploratory factor analyses were used to identify the factor structure of the NPE. Factor and total scores were examined for their psychometric properties and associations with AD risk biomarkers.
RESULTS: Composite scores from the novel cognitive and functional measures demonstrated better psychometric properties (distribution and test-retest reliability) and stronger associations with AD-related demographic, genetic, and brain risk markers than well-established measures, DISCUSSION: These novel measures have potential for use as primary cognitive and functional outcomes in early-stage AD clinical trials.
CONCLUSIONS: Well-established cognitive tests may not accurately detect subtle cognitive changes. No Practice Effect (NPE) and Computerized Functional Skills Assessment and Training are novel measures designed to have improved psychometric properties. NPE had Executive Function, Cognitive Control/Speed, and Episodic Memory domains. Novel measures had better psychometric properties compared to established measures. Significant associations with Alzheimer\'s disease biomarkers were found with novel measures.

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Background Internet-based participation has the potential to enhance pragmatic and decentralized trials, where representative study populations and generalizability to clinical practice are key. We aimed to study the differences between internet and noninternet/telephone participants in a large remote, pragmatic trial. Methods and Results In a subanalysis of the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) study, we compared internet participants with those who opted for noninternet participation. Study process measures examined included participant characteristics at consent, study medication adherence, and study retention. The clinical outcome examined was a composite of all-cause mortality, hospitalization for myocardial infarction, or hospitalization for stroke. Noninternet participants were older (mean 69.4 versus 67.4 years), more likely to be female (38.9% versus 30.2%), more likely to be Black (27.3% versus 6.0%) or Hispanic (11.1% versus 2.0%), and had a higher number of comorbid conditions. The composite clinical outcome was more than twice as high in noninternet participants. The hazard of nonadherence to the assigned aspirin dosage was 46% higher in noninternet participants than internet participants. Conclusions Noninternet participants differed from internet participants in notable demographic characteristics while having poorer baseline health. Over the course of ADAPTABLE, they also had worse clinical outcomes and greater likelihood of study drug nonadherence. These results suggest that trials focused on internet participation select for younger, healthier participants with a higher proportion of traditionally overrepresented patients. Allowing noninternet participation enhances diversity; however, additional steps may be needed to promote study retention and study medication adherence. Registration Information clinicaltrials.gov. Identifier: NCT02697916.

Placebo-controlled trials are the gold standard of evaluating treatment efficacy in clinical research. Neuromodulation is emerging as an important treatment pathway for many neuropsychiatric conditions, and placebo control arms of these trials require careful design with unique considerations (e.g., sham devices that mimic active stimulation, blinding effectiveness). Inherent to placebo-controlled trials are ethical concerns, such as deception, and potential harm of not receiving the active treatment. In this article, we outline important ethical considerations of placebo-controlled trials across neuromodulation approaches and provide recommendations on how ethical principles can be adhered to going forward. We specifically address issues of autonomy and respect for persons, beneficence, and justice. Within the context of this ethical framework, we also discuss factors influencing placebo effects in neuromodulation, the importance of adequate blinding, and alternative trial designs that could be considered.

We aimed to understand the effects of aspirin dose on outcomes in patients with peripheral artery disease (PAD) as well as their participation in a pragmatic randomized controlled trial.
In a subanalysis of the Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) study, we compared aspirin doses (81 vs 325 mg) among participants with PAD and study participation metrics in patients with and without PAD. The primary outcome composite was all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke.
Among 14,662 participants enrolled in ADAPTABLE with PAD status available, 3493 (23.8%) had PAD. Participants with PAD were more likely to experience the primary composite (13.76% vs 5.31%, p < 0.001), all-cause mortality (7.55% vs 3.01%, p < 0.001), myocardial infarction (5.71% vs 2.09%, p < 0.001), stroke (2.45% vs 0.86%, p < 0.001), and major bleeding (1.19% vs 0.44%, p < 0.001). A higher aspirin dose did not reduce the primary outcome in patients with PAD (13.68% vs 13.84% in 81 mg and 325 mg groups; OR 1.05, 95% CI 0.88-1.25). Participants with PAD were less likely to enroll via email (33.0% vs 41.9%, p < 0.0001), less likely to choose internet follow-up (79.2% vs 89.5%, p < 0.0001), and were more likely to change their aspirin doses (39.7% vs 30.7%, p < 0.0001).
ADAPTABLE participants with PAD did not benefit from a higher dose of aspirin and participated in the study differently from those without PAD. These results reinforce the need for additional PAD-specific research and suggest that different trial strategies may be needed for optimal engagement of patients with PAD. (ClinicalTrials.gov Identifier: NCT02697916).

The use of target-oriented drugs is profoundly changing the anti-cancer treatments. This new and expanding therapeutic context relies on the translation of biomarkers expression (laboratory testing) into clinical practice (treatment). Progression-free survival is a primary or co-primary endpoint in the large part of comparative clinical trials about biologic anti-cancer agents. Here, we describe the \"border time\" bias represented by specific time points and intervals that are an underestimated source of methodologic heterogeneity and can contribute to wrong evaluation of time-to-outcome. These issues are concentrated at the beginning (head: pre-screening and screening activities) and at the end (tail: modalities of disease reassessment) of the anti-cancer treatment and can represent a time-related bias. Reporting, and ideally shortening, the time spent in pre-screening and screening activities with synthetic and innovative methodological tools as well as more harmonized rules about timing of disease reassessment can contribute to reduce, or even prevent, this bias in clinical studies.

Dementia prevention research has progressed rapidly in recent years, with publication of several large lifestyle intervention trials, and renewed interest in pharmacological interventions, notably for individuals with Alzheimer\'s disease biomarkers, warranting an updated review of results and methodology. We identified 112 completed trials testing the efficacy of single-domain pharmacological (n = 33, 29%), nutritional (n = 27, 24%), physical activity (n = 18, 16%) and cognitive stimulation (n = 13, 12%), or multidomain (n = 22, 20%) interventions on incident dementia, or a relevant intermediate marker (e.g. cognitive function, biomarkers or dementia risk scores) in people without dementia. The earliest trials tested pharmacological interventions or nutritional supplements, but lifestyle interventions predominated in the last decade. In total, 21 (19%) trials demonstrated a clear beneficial effect on the pre-specified primary outcome (or all co-primary outcomes), but only two (10%) were large-scale (testing blood pressure lowering (Syst-Eur) or multidomain (FINGER) interventions on incident dementia and cognitive change in cognitive function, respectively). Of the 116 ongoing trials, 40% (n = 46) are testing multidomain interventions. Recent methodological shifts concern target populations, primary outcome measures, and intervention design, but study design remains constant (parallel group randomised controlled trial). Future trials may consider using adaptive trials or interventions, and more targeted approaches, since certain interventions may be more effective in certain subgroups of the population, and at specific times in the life-course. Efforts should also be made to increase the representativeness and diversity of prevention trial populations.

OBJECTIVE: The primary hypothesis of a trial must be explicitly formulated. The primary hypothesis is essential for the proper interpretation of trial results.
METHODS: We review the seminal Finnish randomized trial on the timing of aneurysm surgery, and re-examine how trial results could have been interpreted at the time had a precise primary hypothesis been pre-specified. Finally, we compare the power of this single center randomized trial with the multicenter International Cooperative (observational) Study that examined the same clinical problem.
RESULTS: Had the Finnish authors worked under a pragmatic hypothesis in favor of early surgery (within 3days) versus delayed surgery, the trial results could have been interpreted as conclusive. The randomized trial was more appropriate, more ethical, and more efficient than the inconclusive International Cooperative study.
CONCLUSIONS: The randomized trial on the timing of aneurysm surgery was a landmark in neurovascular research. A precise pragmatic primary hypothesis is a crucial step in trial design and interpretation.

Meta-analyses guide planning of clinical trials and clinical care, but are subject to all the methodologic problems and potential biases present in the underlying trials. Furthermore, publication bias often contributes to overestimated benefit in meta-analyses of small trials, which are often \'corrected\' by subsequent large trials. Meta-analyses are no substitute for large robust trials.

OBJECTIVE: The project aims to build a framework for conducting clinical trials for long-term interplanetary missions to contribute to innovation in clinical trials on Earth, especially around patient involvement and ownership.
METHODS: We conducted two workshops in which participants were immersed in the speculative scenario of an interplanetary mission in which health problems emerged that required medical trials to resolve. The workshops used virtual reality and live simulation to mimic a zero-gravity environment and visual perception shifts and were followed by group discussion.
RESULTS: Some key aspects for the framework that emerged from the workshops included: (a) approaches to be inclusive in the management of the trial, (b) approaches to be inclusive in designing the research project (patient preference trials, n-of-1 trials, designing clinical trials to be part of a future prospective meta-analysis, etc), (c) balancing the research needs and the community needs (eg, allocation of the participants based on both research and community need), (d) ethics and partnerships (ethics and consent issues and how they relate to partnerships and relationships).
CONCLUSIONS: In identifying some key areas that need to be incorporated in future planning of clinical trials for interplanetary missions, we also identified areas that are relevant to engaging patients in clinical trials on Earth. We will suggest using the same methodology to facilitate more in-depth discussions on specific aspects of clinical trials in aerospace medicine. The methodology can be more widely used in other areas to open new inclusive conversations around innovating research methodology.