The LUCINDA Trial: LeUprolide Plus Cholinesterase Inhibition to Reduce Neurological Decline in Alzheimer's (LUCINDA)

The LUCINDA Trial is a three-site, phase II, randomized, double-blind, placebo-controlled study of leuprolide acetate (Eligard) in women with Mild Cognitive Impairment or Alzheimer's Disease taking a stable dose of a cholinesterase inhibitor medication like donepezil. Its objective is to assess the efficacy of a 48-week regimen of leuprolide (22.5 mg per 12 weeks) compared to placebo on cognitive function, global function and plasma and neuroimaging biomarkers.

Study Overview

• Status: Active, not recruiting
• Conditions: Alzheimer Disease; Mild Cognitive Impairment
• Intervention / Treatment: Drug: Placebo; Drug: Eligard 22.5Mg Suspension for Injection

Detailed Description

This project aims to re-purpose the safe and well-tolerated gonadotropin-releasing hormone (GnRH) analogue Leuprolide Acetate for use in Alzheimer's Disease (AD). Leuprolide Acetate is currently used in adults for prostate cancer, endometriosis, uterine fibroids and in preparation for in-vitro fertilization, and in children for central precocious puberty. The purpose of this study to confirm and extend results from a prior phase II study (Bowen et al, 2015) which demonstrated that Leuprolide halted cognitive and functional decline in a subgroup of women with mild-moderate AD who were also taking the acetylcholinesterase inhibitor donepezil. Objectives are to replicate, in the same subgroup, Leuprolide's clinical EFFICACY in this prior trial and to add neuroimaging and plasma BIOMARKERS that will help elucidate Leuprolide's likely multiple mechanisms of action in AD. These mechanisms include decreasing levels of Luteinizing Hormone (LH) based on extensive preclinical evidence that decreasing LH preserves cognition and decreases amyloid deposition and tau phosphorylation in animal models of AD, as well as new evidence that GnRH analogues may have anti-inflammatory effects.

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Boca Raton, Florida, United States, 33433
      • University of Miami Miller School of Medicine
  • New York
    • New York, New York, United States, 10021
      • Weill Medical College of Cornell University
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin - Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female, post-menopausal
• Probable AD or MCI due to AD according to NIA-AA criteria
• Taking a stable dose of a cholinesterase inhibitor such as donepezil/Aricept and dosage likely to remain stable throughout the trial
• MOCA > 11 or blind MOCA > 8 (inclusive) at screening visit
• Hachinski score <5 supporting clinical judgment that dementia is not of vascular origin
• Fluent in English
• has a study partner / caregiver who interacts with the subject for at least 5 hours per week on average and can participate in evaluations

Exclusion Criteria:

• Presence based on exam, history or MRI of significant brain disease other than AD such as schizophrenia, epilepsy, Parkinson's disease or large territory stroke
• Current substance abuse in accord with DSM V criteria
• Significantly depressed (Geriatric Depression Scale > 10)
• Physical or psychological MRI contraindications, or likely unable to tolerate neuroimaging
• Taking other medications known to affect serum sex hormone or gonadotropin concentrations such as estrogen and/or progesterone for hormone replacement therapy, goserelin or danazol
• Presence of significant systemic illness likely to interfere with participation in or completion of the study or to affect study results such as cancer within 5 years (other than non-melanoma skin cancer), autoimmune disease, recent myocardial infarction, signs/symptoms of organ failure based on history, ECG, screening laboratory and/or physical exams
• Receiving other investigational drugs within 30 days or 5 half-lives prior to randomization, whichever is longer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 0.25 ml of sterile normal saline administered subcutaneously / 12 weeks	Drug: Placebo; Placebo (0.25 ml normal saline) will be administered subcutaneously once every twelve weeks for 48 weeks.
Experimental: Leuprolide; Eligard 22.5mg administered subcutaneously / 12 weeks	Drug: Eligard 22.5Mg Suspension for Injection; Eligard 22.5Mg Suspension for Injection will be administered subcutaneously, in accord with manufacturer's direction, once every twelve weeks for 48 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog-11)	The ADAS-cog-11 consists of 11 tasks measuring the disturbances of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of Alzheimer's Disease.	Baseline, 48 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)	The ADCS-ADL assesses a subject's ability to perform activities of daily living such as eating, walking and bathing.	Baseline, 48 Weeks
Alzheimer Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC+)	The ADCS-CGIC+ uses structured interviews with the subject and his or her caregiver to determine whether there has been a change in the subject's overall level of functioning.	Baseline, 48 Weeks
Percent change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)	The RBANS is a set of tests that measures thinking abilities including memory, language and attention.	Baseline, 48 Weeks
Percent change in Burden Inventory	The Burden Inventory is a questionnaire that assesses how people sometimes feel when they are taking care of another person.	Baseline, 48 Weeks
Percent change in Neuropsychiatric Inventory (NPI)	The NPI measures behavioral and emotional symptoms of Alzheimer's Disease.	Baseline, 48 Weeks
Change in Brain Magnetic Resonance Imaging (MRI) biomarkers	Percent change in volume of AD-related brain regions (hippocampi, ventricles) and hippocampal perfusion measured with Arterial Spin Labeling (ASL) will be assessed.	Baseline, 48 Weeks

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: National Institute on Aging (NIA); Tolmar Pharmaceuticals
• Investigators: Principal Investigator: Tracy A Butler, MD, Weill Medical College of Cornell University; Principal Investigator: James E Galvin, MD, University of Miami; Principal Investigator: Craig S Atwood, PhD, University of Wisconsin, Madison

Publications and helpful links

General Publications

• Butler T, Goldberg JD, Galvin JE, Maloney T, Ravdin L, Glodzik L, de Leon MJ, Hochman T, Bowen RL, Atwood CS. Rationale, study design and implementation of the LUCINDA Trial: Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer's. Contemp Clin Trials. 2021 Aug;107:106488. doi: 10.1016/j.cct.2021.106488. Epub 2021 Jun 22.
• Butler T, Glodzik L, Wang XH, Xi K, Li Y, Pan H, Zhou L, Chiang GC, Morim S, Wickramasuriya N, Tanzi E, Maloney T, Harvey P, Mao X, Razlighi QR, Rusinek H, Shungu DC, de Leon M, Atwood CS, Mozley PD. Positron Emission Tomography reveals age-associated hypothalamic microglial activation in women. Sci Rep. 2022 Aug 3;12(1):13351. doi: 10.1038/s41598-022-17315-8.
• Wickramasuriya N, Hawkins R, Atwood C, Butler T. The roles of GnRH in the human central nervous system. Horm Behav. 2022 Sep;145:105230. doi: 10.1016/j.yhbeh.2022.105230. Epub 2022 Jul 6.
• Butler T, Tey SR, Galvin JE, Perry G, Bowen RL, Atwood CS. Endocrine Dyscrasia in the Etiology and Therapy of Alzheimer's Disease. J Alzheimers Dis. 2024;101(3):705-713. doi: 10.3233/JAD-240334.

Helpful Links

• LUCINDA website

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2020
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: August 22, 2018
• First Submitted That Met QC Criteria: August 22, 2018
• First Posted (Actual): August 28, 2018

Study Record Updates

• Last Update Posted (Actual): August 1, 2025
• Last Update Submitted That Met QC Criteria: July 29, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Cognitive Dysfunction; Alzheimer Disease; Antineoplastic Agents; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Leuprolide
• Other Study ID Numbers: 19-05020209; R01AG057681-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The data and resources sharing plan for this project is in accordance with both Weill Cornell and NIH Data Sharing Policies. All raw clinical, genetic, and imaging data from this project will be available upon written request. Deidentified neuroimaging data may be uploaded to one or more of several available data sharing sites designed for this purpose. The final data will be available in acceptable formats such as presentations and publications.

Research data and results that document and support the study aims will be available after the final results are accepted for publication. The data to be shared will be anonymized and there will be no fees or other restrictions.

• IPD Sharing Time Frame: Research data and results that document and support the study aims will be available after the final results are accepted for publication.
• IPD Sharing Access Criteria: Approval from PI
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No