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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Alzheimer Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Drug: Placebo
* Drug: Eligard 22.5Mg Suspension for Injection


Participation Criteria
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Eligibility Criteria
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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 Ever treated with active or passive immunization for AD (e.g. Lecanemab) due to unknown alterations in systemic and brain inflammation, which may confound results

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 |