Clinical trial NCT03649724: The LUCINDA Trial: LeUprolide Plus Cholinesterase Inhibition to Reduce Neurological Decline in Alzheimer's
Official title: The LUCINDA Trial: LeUprolide Plus Cholinesterase Inhibition to Reduce Neurological Decline in Alzheimer's
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Alzheimer Disease
Mild Cognitive Impairment
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: Tolmar Pharmaceuticals
First posted: 2018-08-28
Enrollment: 180
Sex: FEMALE
Minimum age (years): 60
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percent change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog-11)
timeFrame: Baseline, 48 Weeks
Secondary outcomes:
measure: Percent change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
timeFrame: Baseline, 48 Weeks
measure: Alzheimer Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC+)
timeFrame: Baseline, 48 Weeks
measure: Percent change in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
timeFrame: Baseline, 48 Weeks
measure: Percent change in Burden Inventory
timeFrame: Baseline, 48 Weeks
measure: Percent change in Neuropsychiatric Inventory (NPI)
timeFrame: Baseline, 48 Weeks
measure: Change in Brain Magnetic Resonance Imaging (MRI) biomarkers
timeFrame: Baseline, 48 Weeks
Other outcomes:
Locations:
city: Boca Raton
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Madison
country: United States
facility: University of Wisconsin - Madison
state: Wisconsin
Study officials:
affiliation: Weill Medical College of Cornell University
name: Tracy A Butler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Miami
name: James E Galvin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Craig S Atwood, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.