NIH – Treatments for Lewy Body Dementias and Frontotemporal Dementias–Exploratory Clinical Trial (U01 Clinical Trial Required)

May 27, 2022 by


This Funding Opportunity Announcement invites applications from investigators seeking to conduct exploratory clinical trials designed to test new treatments for patients with Lewy Body Dementia (LBD) or Frontotemporal Dementia (FTD). Applicants may propose to conduct either Phase I or Phase II clinical trials depending on the developmental stage of the potential therapeutic, but all trials must include patients with either LBD or FTD. Proposed therapies may include novel or existing treatments that are potentially beneficial but not currently approved for use in patients with LBD or FTD. Interventions intended to prevent or delay disease progression, as well as therapies to alleviate existing clinical symptoms, are both of interest.


In 2011, the National Alzheimer’s Project Act (NAPA) allocated resources “to prevent and effectively treat Alzheimer’s by 2025.” Since then, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held multiple research summits to assess the needs and opportunities relevant to this goal for Alzheimer’s Disease (AD) and Alzheimer’s Disease Related Dementias (ADRD).  In particular, the NINDS has convened expert panels in 20132016, and 2019 that were tasked with recommending research priorities for advancing the state-of-the-science for the Lewy Body Dementias (LBD) and Frontotemporal Dementia (FTD), among other types of non-Alzheimers disease dementias. The expert panel tasked with making research recommendations for FTD has highlighted the importance of clinical trials at multiple Summits, and the LBD expert panel has repeatedly identified the need for clinical trials as the highest priority recommendation at all three summits.

The LBDs, which include Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD), present clinically with the motor symptoms typical of Parkinson’s disease (PD) in addition to cognitive deficits as may be seen in Alzheimer’s disease (AD). This combined clinical picture is reflected in the neuropathology, which in LBD is characterized by the accumulation of alpha-synuclein in Lewy Bodies (as seen in PD) as well as tau neurofibrillary tangles and beta-amyloid plaques (as seen in AD). The LBDs are relatively unique among dementias in that abnormal alpha-synuclein accumulates in cortical regions, and this may be related to some of the classic symptoms (e.g., hallucinations, fluctuating cognition, etc.) that are seen more commonly in the LBDs.

The FTDs, also referred to as Frontotemporal Lobar Degenerations/Dementias (FTLD), are a clinically and pathologically heterogeneous group of dementias that include Behavioral Variant FTD, Primary Progressive Aphasia (Semantic Variant and Nonfluent Variant), FTD with motor neuron disease, Progressive Supranuclear Palsy, and Corticobasal Degeneration. FTDs are classically characterized by impaired behavior and language, but motor symptoms are prominent in some variants. Atrophy in the frontal and temporal lobes is typical and may be associated with accumulations of abnormal tau, TDP-43 or FUS proteins. The FTDs are relatively unique among dementias in that some variants are highly heritable with symptom onset tending to occur at a younger age.

No treatments exist to prevent the onset of or to substantially slow disease progression in either LBD or FTD. Several symptomatic therapies that are approved to treat diseases that present similarly (e.g., Alzheimer’s disease, Parkinson’s disease, psychiatric disease, etc.) have been tested for their ability to improve symptoms in these patients. For the most part, these trials have involved small sample sizes and/or shown conflicting results, so many of these potential therapies are not widely adopted, and most medications tested remain off-label for use in these patients.

Several factors make the conduct of clinical trials in these specific patient populations unusually difficult. Despite the publication of consensus-based diagnostic criteria, the diagnosis of LBDs and FTDs can be missed or significantly delayed due to symptom overlap with AD or other disorders. Impairments in comprehension, attention, language, visuospatial abilities, and/or abnormal behaviors often complicate clinical trial efforts to ensure compliance with a treatment regimen, timely follow-up, and accurate assessment of treatment efficacy. LBD patients are highly susceptible to medication side effects, often due to the need for conflicting pharmacologic approaches to treat their symptom profiles (e.g., dopamine agonists for motor symptoms, dopamine antagonists for psychiatric symptoms).  Finally, many FTD variants are rare and phenotypically heterogeneous, making it extremely challenging to enroll enough subjects to adequately power a clinical trial.

Key Dates:

Open Date (Earliest Submission Date): October 21, 2022
Letter of Intent Due Date(s): Not Applicable
Applications Due: November 21, 2022

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Filed Under: Funding Opportunities