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
Gerson Hernandez Rivera1, Claudia Lopez1, Adam Raikes1, Kathleen Rodgers1, Dawn Matthews2, Lon Schneider3, Roberta Brinton1
1Center for Innovation in Brain Science / University of Arizona, 2ADM diagnostics, 3USC School of Medicine
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.