Digital endpoints in clinical trials of Alzheimer’s disease and other neurodegenerative diseases: challenges and opportunities

Abstract

Alzheimer’s disease (AD) and other neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD (Remote assessment of disease and relapse—Alzheimer’s disease), IDEA-FAST (Identifying digital endpoints to assess fatigue, sleep and ADL in neurodegenerative disorders and immune-mediated inflammatory diseases) and Mobilise-D (Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement) aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing.

Digital Health Technologies for Alzheimer’s Disease and Related Dementias: Initial Results from a Landscape Analysis and Community Collaborative Effort

“…Although there is a recent example elsewhere in clinical research using a DHT as a primary clinical endpoint (31), this is not current practice in the ADRD space. However, the growing acceptance of DHTs as secondary endpoints in ADRD research (32, 33) is slowly moving the field towards this possibility (34, 35). In our results, studies employed DHTs for monitoring response to treatment in a variety of ways, such as using actigraphy to discern impacts of Mevidalen on activity and sleep within Lewy Body dementia cohorts (36, 37) or using smartwatches to detect suvorexant-induced changes in sleeping patterns for persons with Alzheimer’s experiencing insomnia (38).…”

“…Although there is a recent example elsewhere in clinical research using a DHT as a primary clinical endpoint[32], this is not current practice in the ADRD space. However, the growing acceptance of DHTs as secondary endpoints in ADRD research [33,34] is slowly moving the field towards this possibility [35,36].…”

The SLaM Brain Health Clinic: a remote biomarker enhanced memory clinic for patients with mild cognitive impairment within an NHS mental health trust

“…There are now rapid advances in digital, imaging, and molecular biomarkers of AD (9)(10)(11)(12)(13), remote assessment opportunities (14,15), alongside the emergence of new therapies and knowledge of targeting modifiable risk factors (16). Early accurate aetiological diagnosis of AD is crucial to enable adequate treatment and is in line with public attitudes (17), but the uptake of the diagnostic biomarkers is extremely low in some countries, including the UK (18).…”

A wearable sensor and machine learning estimate step length in older adults and patients with neurological disorders

“…These snapshot observations may be biased by many factors, such as the time of the day, medication, affect, and white coat syndrome 18 – 21 . Indeed, a growing body of literature suggests that continuous (e.g., 24/7) monitoring of gait is clinically meaningful and that it captures information that cannot be measured by conventional test of walking ability in the clinic or lab (such as variations in the gait pattern across the week) 1 , 18 – 27 . Moreover, continuous monitoring bridges the gap between measures of gait taken during daily living and those taken in a lab 1 , 22 – 24 .…”

“…The latter may reflect capacity, while the former captures actual, real-world function. To optimally characterize the gait of an older adult and patients with neurological diseases, it may, therefore, be helpful to measure gait over an extended period of time 25 – 27 Camera-based systems and instrumented gait mats cannot be used for that purpose but inertial measurement units have the potential to meet that goal.…”