R01AG078457

The Alzheimer's Disease Tau Platform Clinical Trial - Project Summary / Abstract

Tau protein is an attractive AD therapeutic target because the amount and anatomical distribution of insoluble tau at autopsy is strongly correlated with the symptoms and severity of disease during life. Multiple tau therapies are now in clinical trials for AD, with many new agents entering the clinic. New approaches to accelerating their clinical development are urgently needed.

A variety of AD biomarkers now exist, including CSF and plasma beta amyloid ratios and phosphorylated tau (P-TAU) levels, and amyloid and tau PET tracers, providing tools to measure pharmacodynamic effects of amyloid and tau therapies on the core biology of AD.

The goal of the Alzheimer's Tau Platform (ATP) trial is to conduct a randomized, placebo-controlled, phase 2 platform trial in preclinical-prodromal AD that will simultaneously test at least two different tau-directed therapies, alone or in combination with an anti-amyloid therapy, to determine safety, tolerability, and biological based proof of concept based on the tau PET tracer 18F MK6240 and other tau biomarkers.

Platform trials create efficiencies through generation of a common clinical trial protocol and shared placebo groups to allow a greater number of therapies to be tested in less time with less expense than by conducting multiple independent trials.

This trial will test 5 therapeutic hypotheses involving combinations of 3 drugs versus placebo: two tau therapies will be studied in a 2 x 3 factorial design (placebo vs. anti-amyloid [N=2] x two tau therapies or placebo [N=3]) for 24 months, in six parallel arms.

The key inclusion criteria for ATP will be >20 centiloids of amyloid PET uptake, 18F MK6240 temporal ROI SUVR >1.25, with a global clinical dementia rating (CDR) of 0 or 0.5 and MMSE >23.

Using these criteria, we estimate that 150 participants per arm will be necessary to have 80% power to detect a 30% slowing in the accumulation 18F MK6240 signal over 24 months of blinded therapy.

Key secondary endpoints will be changes in plasma P-TAU species (-217, etc.) and neurofilament light chain (NFL), clinical rating scales and volumetric MRI.

Leveraging the experience and resources of the NIH AD Clinical Trial Consortium (ACTC), we propose to enroll 900 participants at ~100 ACTC sites over 24 months, randomize them 5:1 drug:placebo for 24 months of blinded treatment, followed by a 24 month open label extension.

We aim to:
1) Test the ability of two tau-directed therapies, either alone or in combination with an anti-amyloid therapy, to slow the accumulation of tau PET signal over 24 months as compared to placebo or anti-amyloid therapy alone;
2) Test the safety and tolerability of 24 months of blinded therapy followed by an optional 24 month open label extension of combination tau/anti-amyloid therapy; and
3) Explore the ability of each of two tau-directed therapies to slow disease progression as measured by CSF and plasma biomarkers (plasma P-TAU, NFL), volumetric MRI and clinical assessments (preclinical Alzheimer's composite [PACC], etc.).

If successful, the ATP will provide data for decision-making about which tau therapies or combinations to pursue in larger efficacy studies, an ongoing resource to test new therapeutic approaches beyond tau, and will improve understanding of AD biology.

San Francisco Regents Of The University Of California

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

California United States

State-Wide

Alzheimer's Clinical Trials Consortium (ACTC) Clinical Trials (R01 Clinical Trial Required) (PAR-20-309)

Amendment Since initial award the End Date has been extended from 08/31/28 to 08/31/29 and the total obligations have increased 97% from $30,887,229 to $60,700,604.