Rationale, study design and implementation of the LUCINDA Trial: Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer's

Abstract

The LUCINDA Trial (Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer's) is a 52 week, randomized, placebo-controlled trial of leuprolide acetate (Eligard) in women with Alzheimer's disease (AD). Leuprolide acetate is a gonadotropin analogue commonly used for hormone-sensitive conditions such as prostate cancer and endometriosis. This repurposed drug demonstrated efficacy in a previous Phase II clinical trial in those women with AD who also received a stable dose of the acetylcholinesterase inhibitor donepezil (Bowen et al., 2015). Basic biological, epidemiological and clinical trial data suggest leuprolide acetate mediates improvement and stabilization of neuropathology and cognitive performance via the modulation of gonadotropin and/or gonadotropin-releasing hormone signaling. LUCINDA will enroll 150 women with mild-moderate AD who are receiving a stable dose of donepezil from three study sites in the United States. Cognition and function are the primary outcome measures as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale. Blood and MRI biomarkers are also measured to assess hormonal, inflammatory and AD biomarker changes. We present the protocol for LUCINDA and discuss trial innovations and challenges including changes necessitated by the covid-19 pandemic and study drug procurement issues.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Leuprolide Acetate Action on Neuronal Cell Cycle.

Model of aberrant cell cycle re-entry initiated by endocrine dyscrasia (low sex hormones but elevated GnRH, LH/FSH and activin signaling) following menopause/andropause. The abortive reactivation of the cell cycle in a post-mitotic, terminally differentiated neuron drives endoreduplication, neuron hypertrophy, amyloid deposition, neurofibrillary tangle formation, autophagy, dendritic spine, synapse and neuron loss, neuron dysfunction, and ultimately cell death. Leuprolide acetate suppresses post-reproductive elevations in GnRH and LH/FSH, and thereby blocks the re-entry of neurons into the cell cycle, preventing neurodegeneration.