Notice of Intent to Publish a Notice of Funding Opportunity for Early- and Late-Stage Clinical Trials for the Spectrum of Alzheimer's Disease/Alzheimer's Disease-Related Dementias and Age-Related Cognitive Decline (R01 Clinical Trial Optional)

Key Dates

• July 1, 2024 - Early- and Late-Stage Clinical Trials for the Spectrum of Alzheimer's Disease/Alzheimer's Disease-Related Dementias and Age-Related Cognitive Decline (R01 Clinical Trial Optional). See NOFO RFA-AG-25-011.

National Institute on Aging (NIA)

The National Institute on Aging intends to publish a Notice of Funding Opportunity (NOFO) to 1) invite applications that propose to develop and implement early- to late-stage clinical trials of promising pharmacological and non-pharmacological interventions to prevent and/or treat the cognitive, behavioral, and neuropsychiatric changes associated with age-related cognitive decline and Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD), and 2) stimulate studies to enhance trial design and methods. This NOFO will be a reissue of RFA-AG-25-011.

This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. 

The NOFO is expected to be published in December 2024 with expected application due dates in March 2025, June 2025, and October 2025.

This NOFO will utilize the R01 activity code. Details of the planned NOFO are provided below.

To meet the congressionally mandated goal of preventing and treating AD/ADRD, it is critical that we have efficient mechanisms to fund clinical trials pursuing a variety of therapeutic targets and approaches to prevent, delay, and treat AD/ADRD. The work of this NOFO will enable the early- to late-stage testing of promising pharmacological and non-pharmacological interventions that target deleterious cognitive, behavioral, and neuropsychiatric changes associated with age-related cognitive decline and AD/ADRD across the spectrum from pre-symptomatic to more severe stages of disease.

Research Objectives

This NOFO invites research grant applications that enable the early- to late-stage testing of promising pharmacological and non-pharmacological interventions to prevent (e.g., primary, secondary prevention) and/or treat deleterious cognitive, behavioral, and neuropsychiatric changes associated with age-related cognitive decline and AD/ADRD across the spectrum from pre-symptomatic to more severe stages of disease.  

A 2017 report from the National Academies of Sciences, Engineering, and Medicine (NASEM) on “Preventing Cognitive Decline and Dementia” suggested numerous ways to construct a stronger evidence base for the prevention of cognitive decline and AD/ADRD. A separate 2020 Agency for Healthcare Research and Quality (AHRQ) report on “Care Interventions for People Living With Dementia and Their Caregivers” highlighted the more general need for rigorous, well-powered, replicable research addressing issues of intervention fidelity and efficacy, as well as potential mechanisms of action (e.g., cognitive, behavioral, biological). Two issues that were highlighted in these reports were the need to identify how and why interventions work (i.e., the mechanism of action of non-pharmacological (e.g. cognitive, behavioral) interventions), and the need to ensure that complex interventions can be delivered with fidelity in “real-world” settings. The NIH Stage Model is a conceptual framework for non-pharmacological intervention development that directly addresses these two issues by: 1) offering a mechanisms-focused framework to intervention development and testing, with the goal of producing interventions defined by their principles and; 2) addressing issues related to ultimate implementation, such as determining ways to ensure that interventions can be delivered in the community with fidelity.

Early-stage clinical trials and non-clinical trial studies of pharmacological interventions (Phase I/Phase II) and trials/studies of non-pharmacological interventions (Stage I - III) 

This NOFO supports 1) early-stage clinical testing of promising pharmacological and non-pharmacological interventions to prevent and/or treat cognitive, behavioral, and neuropsychiatric changes associated with age-related cognitive decline and AD/ADRD, and 2) studies to enhance trial design and methods. Investigators will be expected to collect DNA and other biospecimens from these studies to enable subsequent interrogation of treatment responsiveness, as well as examination of predictors of decline in the groups receiving placebo.

This NOFO encourages clinical trial applications including, but not limited to, the following focus areas:

• Studies to refine the intervention strategy. These studies could include work to determine appropriate dosage of drugs, duration of treatment, and the delivery system. For non-pharmacological interventions, such work might examine the intensity or duration of therapy required. This can also include modifying an intervention (consistent with its principles) to make it more scalable, and testing it to determine if it retains its potency. This can also include the modification and testing of interventions shown to be efficacious in a non-AD/ADRD population, for an AD/ADRD population. For all interventions, the potential synergistic effects of combined interventions could be explored.
• Studies to evaluate the safety and/or efficacy of the intervention(s).
• Studies that elucidate mechanism of action. In some cases, there may be interventions that have some level of demonstrated efficacy (e.g., exercise for age-related cognitive decline), but lack a real understanding of the mechanism of action. Work in this area could use a variety of approaches appropriate to the intervention in order to elucidate the mechanism of action, which could allow both the confirmation of engagement of the intervention target and the potential to optimize the intervention.

This NOFO also encourages both clinical trial and non-clinical trial applications in the following focus areas:

• Studies to define and refine the target population and ensure adequate enrollment, protocol adherence, and subject retention.
• Studies that address heterogeneity of response. This would include the identification of specific individuals according to genetic profiles, behavioral factors, and/or sociocultural or demographic factors who are more likely or less likely to benefit from the intervention(s). Mediators of the therapeutic intervention, such as continued educational opportunities and continued engagement in driving or financial decision-making, may facilitate real-life function and should be considered.
• Studies to establish/validate trial outcome measures. These measures may include clinical/neuropsychological/behavioral measures, neuroimaging measures, and other biological measures in blood and cerebrospinal fluid.

Examples of interventions for evaluation that are appropriate for this NOFO include, but are not limited to, the following:

• Pharmacological interventions (e.g., small molecules/biologics) that target prevention or slowing of disease progression;
• Pharmacological interventions (e.g., small molecules/biologics) that target disease symptomatology including neuropsychiatric symptoms;
• Repurposed drugs that have promise for AD/ADRD treatment such as chemotherapeutic agents or drugs for insulin dysregulation/diabetes;
• Neuromodulation;
• Assistive technology interventions;
• Novel cognitive training or cognitive engagement approaches;
• Aerobic exercise and/or other movement therapies, such as Tai Chi;
• Sleep enhancement;
• Mindfulness-based stress reduction;
• Nutritional supplementation or adoption of specific dietary programs; and/or
• Combinations of interventions including the mixture of pharmacological with non-pharmacological therapeutics.
  This NOFO is not intended for applications that bundle independent phase 1 and phase 2 pharmacological clinical trial proposals.  Such applications may be more appropriate for PAR-25-226.

Late-stage clinical trials of pharmacological interventions (Phase II/III and III) and trials of non-pharmacological interventions (Stage IV):

This NOFO supports pivotal late-stage clinical trials testing pharmacological (small molecules and biologics) and non-pharmacological interventions, using a combination of biomarkers (fluid and imaging), cognitive measures, and functional measures as outcomes. These applications may include trials testing combinations of interventions that may act synergistically to produce a more robust and long-lasting response, as well as combinations of interventions that attempt to address multiple risk factors simultaneously (e.g., obesity, hypertension, diabetes, physical inactivity, anxiety, and depression). Investigators will be expected to collect DNA and other biospecimens from these studies to enable subsequent interrogation of treatment responsiveness, as well as examination of predictors of decline in the groups receiving placebo.

Late-stage pharmacological clinical trial applications that are appropriate for this NOFO will have established proof of mechanism or target engagement at earlier stages of clinical development for the intervention(s) being tested. The intervention(s) being tested in late-stage trials should also have adequate safety data for the populations under study. Late-stage non-pharmacological clinical trial applications will have also established that there are tested and validated procedures in place to ensure that the intervention can be delivered with fidelity to its principles (mechanisms of action) by real-world practitioners.

Studies designed to address heterogeneity of response are strongly encouraged. This would include the identification of specific individuals according to genetic profiles, behavioral factors, and/or sociocultural or demographic factors who are more likely or less likely to benefit from the intervention(s). Potential mediators of the therapeutic intervention, such as continued educational opportunities, social network exposure and engagement, and continued engagement in driving or financial decision-making, may facilitate effective real-life function and should be considered in interpreting therapeutic outcomes.

Examples of interventions for evaluation that are appropriate for this NOFO include, but are not limited to, the following:

• Pharmacological interventions (e.g., small molecules/biologics) that target prevention or slowing of disease progression;
• Pharmacological interventions (e.g., small molecules/biologics) that target disease symptomatology including neuropsychiatric symptoms;
• Repurposed drugs that have promise for AD/ADRD treatment such as chemotherapeutic agents or drugs for insulin dysregulation/diabetes;
• Neuromodulation;
• Assistive technology interventions;
• Novel cognitive training or cognitive engagement approaches;
• Aerobic exercise and/or other movement therapies, such as Tai Chi;
• Sleep enhancement;
• Mindfulness-based stress reduction;
• Nutritional supplementation or adoption of specific dietary programs; and/or
• Combinations of interventions including the mixture of pharmacological with non-pharmacological therapeutics, as well as combinations of non-pharmacological interventions.
• Applications that bundle independent phase 1 and phase 2 pharmacological clinical trial proposals.

Design, Analysis, and Sample Size for Studies to Evaluate Group-Based Interventions: Investigators who wish to evaluate the effect of an intervention on a health-related biomedical or behavioral outcome may propose a study in which (1) groups or clusters are assigned to study arms and individual observations are analyzed to evaluate the effect of the intervention, or (2) participants are assigned individually to study arms but receive at least some of their intervention in a real or virtual group or through a shared facilitator. Such studies may propose a parallel group- or cluster-randomized trial, an individually randomized group-treatment trial, a stepped-wedge design, or a quasi-experimental version of one of these designs. In these studies, special methods may be warranted for analysis and sample size estimation. Applicants should show that their methods are appropriate given their plans for assignment of participants and delivery of interventions.

Non-responsiveness Criteria

The following types of applications will be considered non-responsive to this NOFO and will be administratively withdrawn prior to scientific peer review:

• Applications that bundle independent phase 1 and phase 2 pharmacological clinical trial proposals.

Funding Information

Public/State Controlled Institution of Higher Education
Private Institution of Higher Education
Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education)
Small Business
For-Profit Organization (Other than Small Business)
State Government
Indian/Native American Tribal Government (Federally Recognized)
County governments
Independent school districts
Public housing authorities/Indian housing authorities
Indian/Native American Tribally Designated Organization (Native American tribal organizations (other than Federally recognized tribal governments)
U.S. Territory or Possession
Indian/Native American Tribal Government (Other than Federally Recognized)
Non-domestic (non-U.S.) Entity (Foreign Organization)
Regional Organization
Eligible Agencies of the Federal Government

Applications are not being solicited at this time. 

Inquiries

Please direct all inquiries to:

Laurie Ryan, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

Kristina McLinden, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

Akanni Clarke, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

Luke E. Stoeckel, Ph.D.
National Institute on Aging (NIA)
Telephone: 202-570-9388
Email: [email protected]