A Proof of Concept Study of the Prevention of Mild Cognitive Impairment and Eventual Alzheimer's Disease Using F18 Flutemetamol

This is an investigator-initiated study comparing two types of FDA-approved anti-depressants, Escitalopram and Venlafaxine, to placebo, in order to determine if these medications have positive effects on cognition and memory in those who are between the ages of 50 to 89 years old, who are cognitively normal, and who have subjective memory concerns. Research has shown that those who are cognitively normal but report subjective cognitive impairment are more likely to progress to mild cognitive impairment and Alzheimer's disease in the future. Anti-depressants such as Escitalopram and Venlafaxine have been shown to stimulate production of neurons in memory-sensitive areas such as the hippocampus. Therefore, the investigator is researching whether these drugs would help cognition in those with subjective cognitive impairment, and would help to prevent cognitive decline and eventual Alzheimer's disease.

Study Overview

• Status: Terminated
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Escitalopram Pill; Drug: Venlafaxine Pill; Drug: Placebo Oral Tablet

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • New York University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects must have subjective cognitive impairment (SCI) and be free of objective evidence of cognitive impairment. Operationally, this will be defined as subjects with Global Deterioration Scale (GDS) score of stage 2.4
• Subjects must be between 60 and 80 years of age.
• Subjects must have a knowledgeable informant (study partner) who can accompany them to the evaluations, or, when necessary, be available for telephone contact.
• Subjects must be otherwise healthy and fulfill all of the inclusion criteria for participation in the NYU ADC. Exclusion criteria are enumerated below.
• Subjects must be in a position to comply with all of the study procedures described herein.
• Subjects must have a minimum of 12 years of education.
• Subjects must be fluent in English.
• Subjects original language at birth and/or, in childhood, must have been English, alone, or in conjunction with other languages.

Exclusion Criteria:

• Subjects who have normal brain aging, who are free of subjective cognitive impairment (SCI), and are therefore categorized at GDS stage 1, will be excluded.
• Subjects with MCI or dementia and are therefore categorized as being at GDS stage 3 or greater, will be excluded.
• Subjects with a mini mental status examination (MMSE) score61 of ≤ 27 will be excluded.
• Subjects with a Hamilton Depression Scale (HDS) score ≥ 16,62 signifying the presence of notable depressive symptomatology which warrants treatment, will be excluded.
• Subjects with a primary diagnosis of depression or with a major depression diagnosis will be excluded.
• Subjects with a significant medical, neurologic, or psychiatric condition, including depression or anxiety disorder, that might interfere with cognition will be excluded.
• Subjects with a history of adverse reactions to escitalopram and/or venlaflaxine will be excluded.
• Subjects, who are judged to have had adverse reactions to selective serotonin reuptake inhibitor medications as a class, will be excluded.
• Subjects taking the antibiotic Zyvox (linezolid) or methylene blue therapy or who are planning to have a diagnostic procedure utilizing methylene blue dye, will be excluded.
• Subjects who are on psychoactive or cognitively active medications or who have received such medications in the prior 8 weeks, will be excluded. These excluded medications encompass antidepressant medications, antipsychotic medications, anxiolytic medications, cholinesterase inhibitors, memantine, antiseizure medications, antiparkinsonian medication and other CNS acting medications.
• Subjects who are receiving other medications or substances with reported neurogenic enhancer or neurogenic inhibitor effects will not be excluded. The reason for this inclusionary approach is that just as the effects of neurogenic enhancers on Alzheimer's disease appears to be complex (specifically, likely useful in prevention, possibly not useful effects on disease progression), the same complexity apparently applies to substances with reported neurogenic enhancer or inhibitor effects. For example, the angiotensin II receptor antagonist losartan has been reported to suppress running enhanced neurogenesis in the rat.63 This same medication and medication class has also been reported to be useful in improving memory64 and in the prevention of Alzheimer's disease, possibly by other mechanisms.65

• Subjects with a history of significant cerebrovascular disease will be excluded. This will be identified by one of the following:

  i. history of stroke. ii. Any focal signs of significant neuropathology from the neurological examination.

iii. A score of ≥ 4 on the Rosen modification of the Hachinski Ischemia Scale.66 iv. Focal pathology on the MRI scan, indicative of history of infarction. l. Past history of brain damage, seizure, mental retardation or serious neurological disorders.

• Significant history of alcoholism or drug abuse.
• Previous history of schizophrenia, mania, or major depression.
• Severe cardiac, pulmonary, vascular, metabolic, or hematologic conditions.
• Presence of a cardiac pacemaker.
• Presence of any metallic device or implant which would contraindicate an MRI (magnetic resonance imaging) scan of the brain.
• Physical impairment of such severity as to adversely affect the validity of psychological testing.
• Hostility or refusal to cooperate.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Escitalopram; Escitalopram (lexapro) is presently the most widely used selective serotonin reuptake inhibitor (SSRI) antidepressant.	Drug: Escitalopram Pill; Subjects randomized to group A will receive Lexapro (escitalopram), in an initial, baseline dosage of 5 mg daily.; Other Names: Lexapro
Active Comparator: Venlafaxine; Venlafaxine is a norepinephrine, serotonin and dopamine reuptake inhibitor antidepressant.The specific form of venlafaxine which will be employed is Effexor XR (venlafaxine hydrochloride extended release capsules)	Drug: Venlafaxine Pill; Subjects randomized to group B will receive Effexor XR (venlafaxine extended release capsules), in an initial baseline dosage of 37.5 mg daily.; Other Names: Effexor XR
Placebo Comparator: Placebo; Subjects randomized to group C will receive placebo tablets, which will be matched to the Lexapro and the Effexor XR as far as possible, and will also be administered on a once daily schedule at baseline.	Drug: Placebo Oral Tablet; Subjects randomized to group C will receive placebo tablets, which will be matched to the Lexapro and the Effexor XR as far as possible, and will also be administered on a once daily schedule at baseline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Z-score for the hippocampal region of interest in the theta band	responders show will less increase in score with treatment compared with baseline, in comparison with placebo treated subjects.	24 Months
Multivariate Z score for overall theta abnormality in the frontal and parieto-temporal regions;	Each subject can serve as their own control, z-transformed relative to initial values accessed for each of the endpoints. In addition, each subject can be evaluated relative to age-expected normal values.	24 Months
Probability of deterioration from logistic regression predictive of future decline;		24 Months
Z-score coherence (synchrony) between right central and parietal regions across all bands;	Each subject can serve as their own control, z-transformed relative to initial values accessed for each of the endpoints. In addition, each subject can be evaluated relative to age-expected normal values.	24 Months
Mean frequency across the total EEG brain spectrum.		24 Months
Metabolic reduction in the hippocampal formation (a region including the hippocampal subiculum and the entorhinal cortex) assessed bilaterally.		24 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brief Cognitive Rating Scale Axes I to V total scores		24 Months
The Mini-Mental State Examination (MMSE) total scores	30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It is commonly used in medicine and allied health to screen for dementia.	24 Months
MAC-Q total score	brief index of memory complaint.	24 Months

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Investigators: Principal Investigator: Barry Reisberg, NYU Langone Health

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2009
• Primary Completion (Actual): September 25, 2019
• Study Completion (Actual): September 25, 2019

Study Registration Dates

• First Submitted: September 5, 2017
• First Submitted That Met QC Criteria: September 5, 2017
• First Posted (Actual): September 7, 2017

Study Record Updates

• Last Update Posted (Actual): June 2, 2020
• Last Update Submitted That Met QC Criteria: May 29, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Depression; Alzheimer's Disease; Venlafaxine; Escitalopram
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Citalopram; Venlafaxine Hydrochloride
• Other Study ID Numbers: 09-0228

Plan for Individual participant data (IPD)

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

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