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

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ClinicalTrials.gov Identifier: NCT03274817
Recruitment Status : Recruiting
First Posted : September 7, 2017
Last Update Posted : October 22, 2018
Sponsor:
Information provided by (Responsible Party):
New York University School of Medicine

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Alzheimer Disease Drug: Escitalopram Pill Drug: Venlafaxine Pill Drug: Placebo Oral Tablet Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 31 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Prevention
Official Title: A Proof of Concept Study of the Prevention of Mild Cognitive Impairment and Eventual Alzheimer's Disease Using F18 Flutemetamol
Actual Study Start Date : July 11, 2017
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2019


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 Name: 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 Name: 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.




Primary Outcome Measures :
  1. Z-score for the hippocampal region of interest in the theta band [ Time Frame: 24 Months ]
    responders show will less increase in score with treatment compared with baseline, in comparison with placebo treated subjects.

  2. Multivariate Z score for overall theta abnormality in the frontal and parieto-temporal regions; [ Time Frame: 24 Months ]
    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.

  3. Probability of deterioration from logistic regression predictive of future decline; [ Time Frame: 24 Months ]
  4. Z-score coherence (synchrony) between right central and parietal regions across all bands; [ Time Frame: 24 Months ]
    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.

  5. Mean frequency across the total EEG brain spectrum. [ Time Frame: 24 Months ]
  6. Metabolic reduction in the hippocampal formation (a region including the hippocampal subiculum and the entorhinal cortex) assessed bilaterally. [ Time Frame: 24 Months ]

Secondary Outcome Measures :
  1. Brief Cognitive Rating Scale Axes I to V total scores [ Time Frame: 24 Months ]
  2. The Mini-Mental State Examination (MMSE) total scores [ Time Frame: 24 Months ]
    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.

  3. MAC-Q total score [ Time Frame: 24 Months ]
    brief index of memory complaint.



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Ages Eligible for Study:   60 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03274817


Contacts
Contact: Anaztasia Ulysse (212)-263-0771 Anaztasia.Ulysse@nyumc.org

Locations
United States, New York
New York University School of Medicine Recruiting
New York, New York, United States, 10016
Contact: Anaztasia Ulysse    212-263-0771    Anaztasia.Ulysse@nyumc.org   
Principal Investigator: Barry Reisberg, MD         
Sponsors and Collaborators
New York University School of Medicine
Investigators
Principal Investigator: Barry Reisberg New York University School of Medicine

Responsible Party: New York University School of Medicine
ClinicalTrials.gov Identifier: NCT03274817     History of Changes
Other Study ID Numbers: 09-0228
First Posted: September 7, 2017    Key Record Dates
Last Update Posted: October 22, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by New York University School of Medicine:
Alzheimer's Disease
Depression
Escitalopram
Venlafaxine

Additional relevant MeSH terms:
Alzheimer Disease
Cognitive Dysfunction
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Citalopram
Venlafaxine Hydrochloride
Dexetimide
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists