Natural cubic splines for the analysis of Alzheimer's clinical trials.

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical-time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.

Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the second Latinos & Alzheimer's Symposium.

The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD.

Alzheimer's disease research progress in the Mediterranean region: The Alzheimer's Association International Conference Satellite Symposium.

As research and services in the Mediterranean region continue to increase, so do opportunities for global collaboration. To support such collaborations, the Alzheimer's Association was due to hold its seventh Alzheimer's Association International Conference Satellite Symposium in Athens, Greece in 2021. Due to the COVID-19 pandemic, the meeting was held virtually, which enabled attendees from around the world to hear about research efforts in Greece and the surrounding Mediterranean countries. Research updates spanned understanding the biology of, treatments for, and care of people with Alzheimer's disease (AD_ and other dementias. Researchers in the Mediterranean region have outlined the local epidemiology of AD and dementia, and have identified regional populations that may expedite genetic studies. Development of biomarkers is expected to aid early and accurate diagnosis. Numerous efforts have been made to develop culturally specific interventions to both reduce risk of dementia, and to improve quality of life for people living with dementia.

Infusing Representativeness and Cultivating Harmonization in Alzheimer’s Trials: World Wide FINGERS

World Wide Fingers is a network involving over 30 countries organized to conduct randomized controlled clinical trials to slow the progression of cognitive decline and reduce dementia risks. Trials are designed to parallel the successful Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial of a multidomain lifestyle intervention featuring increased physical activity, improved diet, cognitive training, and metabolic risk factor monitoring. While FINGER found that its intervention significantly benefited cognitive function, it is not clear whether this approach might be successfully tailored to other cultures and environments to yield similar results. This is the goal of World Wide FINGERS. It infuses representativeness by enrolling cohorts that reflect the communities in which it is conducted. For findings across the many trials to be integrated, it is necessary for protocols to be harmonized as much as possible. The COVID-19 pandemic presents special challenges towards harmonization as its disruptions of trial protocols and conduct vary among countries and over time. This symposium is organized to provide the scientific background and framework for the World Wide FINGERS. Novel grassroots efforts towards enrolling representative cohorts in the US will be described. Plans for harmonization and federated data analyses spanning international boundaries and regulations will be outlined. Integrated approaches to challenges of COVID-19 pandemic across trials will be presented. The conclusion of this session will be a discussion of how World Wide FINGERS may serve as a model for collaborative approaches to identify effective, translatable approaches to reduce risks for Alzheimer’s disease.

U.S. POINTER: Lessons learned about delivery of a multi-domain lifestyle intervention during the COVID-19 pandemic

Background U.S. POINTER is testing whether multidomain lifestyle interventions focused on physical exercise, nutrition, cognitive challenge, and risk factor management reduces risk of cognitive decline in a heterogeneous population of at-risk older adults in America. The study adapts the FINGER (Finnish Intervention Geriatric Study to Prevent Cognitive Impairment and Disability) interventions to fit the United States culture and delivers the intervention within the community at 5 sites across the country. Method U.S. POINTER is a 2-year RCT that will enroll 2000 cognitively unimpaired older adults who are at risk for cognitive decline due sedentary lifestyle, poor diet and other factors. Participants are randomized to one of two lifestyle intervention groups that differ in format and intensity. In 2020, the COVID-19 pandemic presented a number of challenges for the study that affected recruitment, assessment schedules, and intervention delivery. Result As of March 2020, when COVID-19 incidence was on an exponential rise in the US, 240 participants had been enrolled in U.S. POINTER. In response to local and national safety mandates, study activities were paused from March 23rd to July 13th. During the pause, sites remained in contact with study candidates and enrolled participants to provide ongoing support to keep them engaged in the trial. Enrollees also received regular telephone calls to encourage continued adherence to their assigned lifestyle intervention. In response to the multiple pandemic-related challenges, study protocols and procedures were adapted to facilitate and encourage participant adherence to intervention activities. At study re-start, retention was 98%. Despite climbing COVID-19 infection rates nationwide, enrollment at all 5 sites has continued at a steady rate (N=540 as of Jan2021), virtual Team Meeting attendance for both lifestyle groups exceeds 80%, and participants continue to successfully work toward their intervention goals. Conclusion The COVID-19 pandemic presented unprecedented challenges, but it also provided a unique opportunity to adapt intervention delivery so that a nonpharmacological community-based trial could continue ? even during a debilitating global health crisis. U.S. POINTER?s adaptations to pandemic-related challenges may ultimately increase the resilience of its interventions to even the most challenging of circumstances that older adults will face now and in the future.

Methodological challenges across WW-FINGERS Studies: Impact of COVID-19 pandemic on statistical design and analysis plans for multidomain RCTs

Background The coronavirus disease-19 (COVID-19) pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions. Method World-Wide FINGERS is an international network of clinical trials to assess the impact of multidomain lifestyle intervention on cognitive decline in at-risk adults. Individual trials are tailoring successful approaches from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) to local cultures and environments. The network convened forums for researchers to discuss statistical design and analysis issues they faced during the pandemic. We will provide an updated report on experiences of trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials. Result The pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessments protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within site stratification, interim power projections, and sensitivity analyses. Conclusion Robust approaches to study design and analysis are critical to negotiate issues related to the intervention. The World Wide Network of similarly oriented clinical trials will allow us to evaluate the effectiveness of responses to the pandemic across cultures, local environments, and phases of the pandemic.

Impact of the COVID-19 pandemic on statistical design and analysis plans for multidomain intervention clinical trials: Experience from World-Wide FINGERS.

INTRODUCTION: The coronavirus disease-19 (COVID-19) pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions. METHODS: World-Wide FINGERS is an international network of clinical trials to assess the impact of multidomain lifestyle intervention on cognitive decline in at-risk adults. Individual trials are tailoring successful approaches from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) to local cultures and environments. The network convened a forum for researchers to discuss statistical design and analysis issues they faced during the pandemic. We report on experiences of three trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials. RESULTS: The pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessment protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within-site stratification, interim power projections, and sensitivity analyses. DISCUSSION: Robust approaches to study design and analysis are critical to negotiate issues related to the intervention. The world-wide network of similarly oriented clinical trials will allow us to evaluate the effectiveness of responses to the pandemic across cultures, local environments, and phases of the pandemic.