Abstract Details

Title Allopregnanolone as a Regenerative Therapeutic for Alzheimer’s Disease (AD): A phase 2 proof-of-concept clinical trial using hippocampal volume as a surrogate endpoint

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P8 - Poster Session 8 (11:45 AM-12:45 PM)

Poster/Presentation
Number 7-008

Objective To assess the effect of Allopregnanolone on brain structure and connectivity.

Background

Given that hippocampal volume is a well-established imaging biomarker predictive of cognitive decline although not itself a measure of cognition, we propose its use as a surrogate endpoint to test the efficacy of allopregnanolone as a regenerative therapeutic for mild AD.

Design/Methods A multi-center, double-blind, randomized-controlled clinical trial. A total of 200 participants with mild AD, 100 participants per treatment arm, will be enrolled. Eligible participants are male or female, age 55-80 years, diagnosed with probable AD, an MMSE of 20–26 and APOE ε4 carriers. Study intervention is allopregnanolone 4 mg (administered intravenously over 30 minutes, once-per-week) or matching placebo, 1:1 allocation, for a 12-month period. After 12 months, all participants in the placebo group will be crossed-over to receive allopregnanolone for the 6-month open-label phase. Brain imaging to evaluate the primary endpoint will be conducted at baseline, 6 and 12 months. All imaging sites participating in the trial will be thoroughly assessed and must have adequate capabilities of performing both basic and advanced MRI sequences required in the protocol.

Results Primary endpoint is mean rate of change in hippocampal volume at 12 months. Secondary endpoints include mean rate of change in cognitive outcomes (CANTAB-PAL, ADAS-Cog11), functional (ADCS-iADL) and safety outcomes at 12 months. Exploratory endpoints include 1) regional brain volumes, white matter fiber tract diffusion measures, average intrinsic connectivity, and cerebral blood flow; 2) blood-based biomarkers of target engagement; 3) other clinical outcomes (CDR-SB, ADAS-Cog14, MMSE, NPI-Q, EQ-5D-5L health-related quality of life scale, QoL-AD, Zarit Burden Interview Questionnaire at 12 and 18 months; 4) change from baseline in open-label treatment participants for all endpoints.

Conclusions Outcomes from this study will validate previous findings indicating that allopregnanolone may exert both regenerative and neuroprotective effects on structure and connectivity in the Alzheimer’s brain.

Authors/Disclosures
Gerson D. Hernandez Rivera, MD, MPH (Center for Innovation in Brain Science / University of Arizona) PRESENTER	Dr. Hernandez Rivera has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuTherapeutics. The institution of Dr. Hernandez Rivera has received research support from National Institute on Aging. The institution of Dr. Hernandez Rivera has received research support from National Institute on Aging.
Claudia Lopez (University of Arizona)	Mrs. Lopez has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Lon Schneider, MD (USC School of Medicine)	Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AC Immue. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biovie. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Athira. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alpha-cognition. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Corium. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cortexyme. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurim Ltd. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novo Nordisk. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Otsuka. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. The institution of Dr. Schneider has received research support from NIH. The institution of Dr. Schneider has received research support from Eli Lilly. The institution of Dr. Schneider has received research support from Biogen. The institution of Dr. Schneider has received research support from Biohaven.
Roberta Diaz Brinton, PhD (University of Arizona)	Roberta Diaz Brinton, PhD has nothing to disclose.

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