ABSTRACT
BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.
Subject(s)
Alzheimer Disease , Antibodies, Monoclonal, Humanized , Patient Satisfaction , Humans , Alzheimer Disease/drug therapy , Alzheimer Disease/psychology , Male , Female , Middle Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Double-Blind Method , Adult , Surveys and Questionnaires , Clinical Trials as TopicABSTRACT
In randomized clinical trials (RCTs) for Alzheimer's Disease (AD), cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers are currently used for the detection and monitoring of AD pathological features. The use of less resource-intensive plasma biomarkers could decrease the burden to study volunteers and limit costs and time for study enrollment. Blood-based markers (BBMs) could thus play an important role in improving the design and the conduct of RCTs on AD. It remains to be determined if the data available on BBMs are strong enough to replace CSF and PET biomarkers as entry criteria and monitoring tools in RCTs.
Subject(s)
Alzheimer Disease , tau Proteins , Humans , tau Proteins/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/drug therapy , Biomarkers , Positron-Emission TomographyABSTRACT
Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.
ABSTRACT
Timely and accurate diagnosis of Alzheimer's disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/drug therapy , Biomarkers , Advisory CommitteesABSTRACT
BACKGROUND: Aducanumab (ADUHELMTM) was approved for the treatment of Alzheimer's disease (AD) in the US. This approval was supported by an effect on the cerebral amyloid plaque load and evidence of cognitive efficacy to be confirmed in post-marketing trials. Other anti-amyloid antibodies are under investigation in phase III (donanemab, lecanemab, gantenerumab) and have shown preliminary evidence of a cognitive benefit in phase II trials. Although these agents target a small segment of patients with mild cognitive impairment due to AD or mild AD dementia, their advent will change the design of future clinical trials both for anti-amyloid and non-amyloid drugs. These changes will promote the selection of patients in clinical trials by amyloid and tau biomarkers that identify patients with appropriate biology and may follow the treatment response to approved amyloid antibodies. The use of these agents creates the opportunity to test combined drug therapies and to conduct comparative assessments with innovative therapies and newly approved drugs available in clinical practice. Blood-based AD biomarkers should be implemented in research and could facilitate the recruitment into clinical trials. Anti-amyloid antibodies will have positive (e.g., more early diagnosis) and negative impacts (some subjects will be reluctant to participate in trials and risk assignment to placebo) on AD trials in the immediate future. We present the results of the CTAD Task Force on this topic, in Boston, November 6, 2021.
Subject(s)
Alzheimer Disease , Clinical Trials as Topic , Alzheimer Disease/diagnosis , Amyloid , Antibodies, Monoclonal/therapeutic use , Biomarkers , Cognitive Dysfunction/drug therapy , Early Diagnosis , HumansABSTRACT
There was consensus that both amyloid and tau pathologies should be targeted in Alzheimer's disease, as well as additional pathophysiological mechanisms such as neuroinflammation. The selection of one or both of these targets may depend upon a personalized approach that takes into account the genetic and acquired factors that cause AD in any given person as well as their stage of disease as reflected in a biomarker profile. The validation of this therapeutic approach will be made possible by new methodologies for subdividing into predominant pathology, by efficient methods for identifying people in the earliest stages of disease, and by combination studies.
Subject(s)
Alzheimer Disease , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Amyloid beta-Peptides , Biomarkers , Consensus , Humans , tau ProteinsABSTRACT
The human response to the COVID-19 pandemic set in motion an unprecedented shift in human activity with unknown long-term effects. The impacts in marine systems are expected to be highly dynamic at local and global scales. However, in comparison to terrestrial ecosystems, we are not well-prepared to document these changes in marine and coastal environments. The problems are two-fold: 1) manual and siloed data collection and processing, and 2) reliance on marine professionals for observation and analysis. These problems are relevant beyond the pandemic and are a barrier to understanding rapidly evolving blue economies, the impacts of climate change, and the many other changes our modern-day oceans are undergoing. The "Our Ocean in COVID-19â³ project, which aims to track human-ocean interactions throughout the pandemic, uses the new eOceans platform (eOceans.app) to overcome these barriers. Working at local scales, a global network of ocean scientists and citizen scientists are collaborating to monitor the ocean in near real-time. The purpose of this paper is to bring this project to the attention of the marine conservation community, researchers, and the public wanting to track changes in their area. As our team continues to grow, this project will provide important baselines and temporal patterns for ocean conservation, policy, and innovation as society transitions towards a new normal. It may also provide a proof-of-concept for real-time, collaborative ocean monitoring that breaks down silos between academia, government, and at-sea stakeholders to create a stronger and more democratic blue economy with communities more resilient to ocean and global change.
ABSTRACT
A diverse range of platforms has been established to increase the efficiency and speed of clinical trials for Alzheimer's disease (AD). These platforms enable parallel assessment of multiple therapeutics, treatment regimens, or participant groups; use uniform protocols and outcome measures; and may allow treatment arms to be added or dropped based on interim analyses of outcomes. The EU/US CTAD Task Force discussed the lessons learned from the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) platform trial and the challenges addressed by other platform trials that have launched or are in the planning stages. The landscape of clinical trial platforms in the AD space includes those testing experimental therapies such as DIAN-TU, platforms designed to test multidomain interventions, and those designed to streamline trial recruitment by building trial-ready cohorts. The heterogeneity of the AD patient population, AD drugs, treatment regimens, and analytical methods complicates the design and execution of platform trials, yet Task Force members concluded that platform trials are essential to advance the search for effective AD treatments, including combination therapies.
Subject(s)
Advisory Committees , Alzheimer Disease , Antibodies, Monoclonal, Humanized/therapeutic use , Drug Development/standards , Research Design , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Amyloid beta-Peptides , Asymptomatic Diseases , Biomarkers , Humans , Outcome Assessment, Health Care , tau ProteinsABSTRACT
BACKGROUND: Brain amyloid-beta (Aß) plaques, a hallmark of the pathophysiology of Alzheimer's disease, have been associated with frailty. Whether the plasma Aß markers show similar relationship with frailty is unknown. OBJECTIVES: To investigate the prospective associations between plasma Aß42/40 ratio and overtime frailty in community-dwelling older adults. METHODS: From the 5-year Multidomain Alzheimer Preventive Trial (MAPT), we included 477 adults ≥70 years with available data on plasma Aß42/40 ratio (lower is worse). Fried frailty phenotype (robust, pre-frail and frail) was assessed at the same time-point of plasma Aß measures and after until the end of follow-up. The outcomes of interest were the change in the frailty phenotype over time (examined by mixed-effect ordinal logistic regressions) and incident frailty (examined by Cox proportional hazard models). RESULTS: Plasma Aß42/40 did not show significant associations with incident frailty; however, after adjusting for Apolipoprotein E (APOE) ε4 genotype, people in the lower quartile of plasma Aß42/40 (≤0.103) had higher risk of incident frailty (HR=2.63; 95% CI, 1.00 to 6.89), compared to those in the upper quartile (>0.123). Exploratory analysis found a significant association between the lower quartile of plasma Aß42/40 and incident frailty among APOE ε4 non-carriers (HR=3.48; 95% CI, 1.19 to 10.16), but not among carriers. No associations between plasma Aß42/40 and evolution of frailty were observed. CONCLUSION: No significant associations between plasma Aß42/40 and frailty were found when APOE ε4 status was not accounted into the model. Nevertheless, APOE ε4 non-carriers with high Aß burden might be more susceptible to develop frailty.
Subject(s)
Amyloid beta-Peptides/blood , Frailty/blood , Independent Living/statistics & numerical data , Peptide Fragments/blood , Aged , Aged, 80 and over , Apolipoprotein E4/genetics , Biomarkers/blood , Disease Progression , Female , Follow-Up Studies , Frailty/diagnosis , Frailty/genetics , Humans , Longitudinal Studies , Male , Proportional Hazards ModelsABSTRACT
Efforts to develop effective disease-modifying treatments for Alzheimer's disease (AD) have mostly targeted the amyloid ß (Aß) protein; however, there has recently been increased interest in other targets including phosphorylated tau and other forms of tau. Aggregated tau appears to spread in a characteristic pattern throughout the brain and is thought to drive neurodegeneration. Both neuropathological and imaging studies indicate that tau first appears in the entorhinal cortex and then spreads to the neocortex. Anti-tau therapies currently in Phase 1 or 2 trials include passive and active immunotherapies designed to prevent aggregation, seeding, and spreading, as well as small molecules that modulate tau metabolism and function. EU/US/CTAD Task Force members support advancing the development of anti-tau therapies, which will require novel imaging agents and biomarkers, a deeper understanding of tau biology and the dynamic interaction of tau and Aß protein, and development of multiple targets and candidate agents addressing the tauopathy of AD. Incorporating tau biomarkers in AD clinical trials will provide additional knowledge about the potential to treat AD by targeting tau.
Subject(s)
Alzheimer Disease/drug therapy , tau Proteins/antagonists & inhibitors , Advisory Committees , Alzheimer Disease/diagnosis , Alzheimer Disease/metabolism , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Brain/diagnostic imaging , Brain/metabolism , Clinical Trials as Topic , Drug Development , Humans , tau Proteins/metabolismABSTRACT
There is an urgent need to develop reliable and sensitive blood-based biomarkers of Alzheimer's disease (AD) that can be used for screening and to increase the efficiency of clinical trials. The European Union-North American Clinical Trials in Alzheimer's Disease Task Force (EU/US CTAD Task Force) discussed the current status of blood-based AD biomarker development at its 2018 annual meeting in Barcelona, Spain. Recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity. Plasma neurofilament light protein appears to provide a good marker of neurodegeneration, although not specific for AD. Plasma tau shows some promising results but weak or no correlation with CSF tau levels, which may reflect rapid clearance of tau in the bloodstream. Blood samples analyzed using -omics and other approaches are also in development and may provide important insight into disease mechanisms as well as biomarker profiles for disease prediction. To advance these technologies, international multidisciplinary, multi-stakeholder collaboration is essential.
Subject(s)
Alzheimer Disease/blood , Alzheimer Disease/drug therapy , Drug Development , Advisory Committees , Alzheimer Disease/diagnosis , Amyloid beta-Peptides/blood , Biomarkers/blood , Drug Evaluation, Preclinical , Humans , Neurofilament Proteins/blood , tau Proteins/bloodABSTRACT
Although the results were disappointing from two recent clinical trials of amyloid-targeting drugs in mild-to-moderate AD, the trials provided information that will be important for future studies, according to the EU-US CTAD Task Force, which met in November 2017 to discuss the EXPEDITION3 and EPOCH trials. These trials tested two of the predominant drug development strategies for AD: amyloid immunotherapy and BACE inhibition in populations largely composed of mild AD dementia patients. The results of these trials support the emerging consensus that effective amyloid-targeted treatment will require intervention in early, even pre-symptomatic stages of the disease. Further, the Task Force suggested that a refinement of the amyloid hypothesis may be needed and that other hypotheses should be more fully explored. In addition, they called for improved biomarkers and other outcome assessments to detect the earliest changes in the development of AD.
Subject(s)
Alzheimer Disease/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Clinical Trials, Phase II as Topic/statistics & numerical data , Clinical Trials, Phase III as Topic/statistics & numerical data , Cyclic S-Oxides/therapeutic use , Early Diagnosis , Thiadiazines/therapeutic use , Advisory Committees , HumansABSTRACT
Tau neurofibrillary tangles are found in the brains of patients suffering from Alzheimer's disease and other tauopathies. The progressive spreading of tau pathology from one brain region to the next is believed to be caused by extracellular transsynaptic transmission of misfolded tau between neurons. Preclinical studies have shown that antibodies against tau can prevent this transfer of misfolded tau between cells. Thus, antibodies against tau have the potential to stop or slow the progression of tau pathology observed in human tauopathies. To test this hypothesis, a humanized anti-tau antibody (ABBV-8E12) was developed and a phase 1 clinical trial of this antibody has been completed. The double-blind, placebo-controlled phase 1 study tested single doses of ABBV-8E12 ranging from 2.5 to 50 mg/kg in 30 patients with progressive supranuclear palsy (PSP). ABBV-8E12 was found to have an acceptable safety profile with no clinically concerning trends in the number or severity of adverse events between the placebo and dosed groups. Pharmacokinetic modelling showed that the antibody has a plasma half-life and cerebrospinal fluid:plasma ratio consistent with other humanized antibodies, and there were no signs of immunogenicity against ABBV-8E12. Based on the acceptable safety and tolerability profile of single doses of ABBV-8E12, AbbVie is currently enrolling patients into two phase 2 clinical trials to assess efficacy and safety of multiple doses of ABBV-8E12 in patients with early Alzheimer's disease or PSP.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Immunologic Factors/therapeutic use , Tauopathies/therapy , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Double-Blind Method , Drug Evaluation, Preclinical , Humans , Immunologic Factors/adverse effects , Immunologic Factors/pharmacokinetics , Immunotherapy , Models, Biological , Tauopathies/blood , Tauopathies/cerebrospinal fluidABSTRACT
At a meeting of the EU/US/Clinical Trials in Alzheimer's Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials.
Subject(s)
Alzheimer Disease/prevention & control , Clinical Trials as Topic , Nootropic Agents/therapeutic use , Advisory Committees , Alzheimer Disease/diagnosis , European Union , Humans , Outcome Assessment, Health Care , United StatesABSTRACT
In late 2011 the New Zealand Ministry for Primary Industries reported an increase in confirmed laboratory diagnoses of salmonellosis in dairy herds. To identify risk factors for herd-level outbreaks of salmonellosis we conducted a case-control study of New Zealand dairy herds in 2011-2012. In a multivariable analysis, use of continuous feed troughs [adjusted odds ratio (aOR) 6·2, 95% confidence interval (CI) 2·0-20], use of pelletized magnesium supplements (aOR 10, 95% CI 3·3-33) and use of palm kernel meal as a supplementary feed (aOR 8·7, 95% CI 2·5-30) were positively associated with a herd-level outbreak of salmonellosis between 1 July 2011 and 31 January 2012. We conclude that supplementary feeds used on dairy farms (regardless of type) need to be stored and handled appropriately to reduce the likelihood of bacterial contamination, particularly from birds and rodents. Magnesium supplementation in the pelletized form played a role in triggering outbreaks of acute salmonellosis in New Zealand dairy herds in 2011-2012.
Subject(s)
Cattle Diseases/epidemiology , Disease Outbreaks/veterinary , Salmonella Infections, Animal/epidemiology , Acute Disease , Animals , Case-Control Studies , Cattle , Cattle Diseases/microbiology , Dairying , New Zealand/epidemiology , Salmonella Infections, Animal/microbiologyABSTRACT
For Alzheimer's disease treatment trials that focus on the pre-dementia stage of disease, outcome measures are needed that will enable assessment of disease progression in patients who are clinically normal. The EU/US CTAD Task Force, an international collaboration of investigators from industry, academia, non-profit foundations, and regulatory agencies, met in Philadelphia, Pennsylvania, USA, on November 19, 2014 to discuss existing and novel outcome assessments that may be useful in pre-dementia trials. Composite measures that assess changes in episodic memory, executive function, global cognition, and global function have recently been developed by a number of groups and appear to be sensitive at this stage. Functional measures that involve real-life complex tasks also appear to capture early subtle changes in pre-dementia subjects and have the advantage of representing clinically meaningful change. Patient reported outcomes and novel CSF and imaging biomarkers have also shown promise. More studies are needed to validate all of these tests in the pre-dementia population. Many of them have been incorporated as exploratory measures in ongoing or planned trials.
ABSTRACT
Successful therapeutic trials require well-targeted populations to demonstrate the effectiveness of a drug candidate. Most trials in the field of Alzheimer's disease (AD) have been conducted in patients with mild to moderate dementia. However, the advent of amyloid PET imaging has demonstrated that a significant proportion of individuals enrolled in such studies do not have evidence of brain amyloidosis and may in fact not have Alzheimer's disease. Further, dementia represents an advanced stage of neurodegeneration, perhaps too late for significant benefits of disease-modifying interventions. The successful development of effective disease-slowing therapies requires a study population selected in accordance with the mechanism of the specific intervention. An international task force of investigators from academia, industry, non-profit foundations, and regulatory agencies met in San Diego, California, USA, on November 13, 2013, to address issues related to screening and identification of clinical trial participants, and the ramifications of decisions made in this regard for drug development in AD and other dementias.