Olfactory Deficits in MCI as Predictor of Improved Cognition on Donepezil

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
United States Department of Defense
Information provided by (Responsible Party):
New York State Psychiatric Institute
ClinicalTrials.gov Identifier:
NCT01845636
First received: April 26, 2013
Last updated: August 27, 2015
Last verified: August 2015
  Purpose
Odor identification deficits, which are a result of early Alzheimer's Disease (AD) pathology in the olfactory bulb and tract as well as olfactory projection areas in the medial temporal lobe (entorhinal and piriform cortex and hippocampus), lateral and central orbitofrontal cortex and several other regions, occur in AD and strongly predict mild cognitive impairment (MCI) conversion to AD. Our pilot data, along with converging findings in the literature, suggests that odor identification deficits, both incremental change over time and change in response to an anticholinergic challenge, may be clinically simple, relatively inexpensive, predictors of cognitive improvement with acetylcholinesterase inhibitor (ACheI) treatment with potential clinical implications for predicting improvement and monitoring ACheI therapy.

Condition Intervention Phase
Mild Cognitive Impairment
Drug: Donepezil
Drug: Atropine
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Olfactory Deficits in Mild Cognitive Impairment as a Predictor of Improved Cognition on Donepezil

Resource links provided by NLM:


Further study details as provided by New York State Psychiatric Institute:

Primary Outcome Measures:
  • Selective Reminding Test (SRT) [ Time Frame: Week 0, Week 8, Week 26, Week 52 ] [ Designated as safety issue: No ]
    The 12-item, 6-trial SRT is a memory measure used to assess verbal list learning and memory. The total number of words learned over six trials (total immediate recall), and delayed recall (after a 15-minute delay) will be obtained.


Secondary Outcome Measures:
  • Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) [ Time Frame: Week 0, Week 8, Week 26, Week 52 ] [ Designated as safety issue: No ]
    The modified ADAS-Cog is a cognitive battery that assesses learning, memory, language production, language comprehension, constructional praxis, ideational praxis, and orientation.

  • Pfeffer Functional Activities Questionnaire (FAQ) [ Time Frame: Week 0, Week 4, Week 8, Week 26, Week 52 ] [ Designated as safety issue: No ]
    FAQ is a widely used 10-item instrument that takes 3 minutes to administer and focuses on instrumental, social and cognitive functioning.

  • Measurement of Everyday Cognition (Ecog) [ Time Frame: Week 0, Week 4, Week 8, Week 26, Week 52 ] [ Designated as safety issue: No ]
    This instrument has 40 items, takes 20 minutes to administer, and focuses on functional correlates of cognitive deficits.

  • Clinician's Interview Based Impression of Change plus Caregiver Input (CIBIC-plus) [ Time Frame: Week 0, Week 2, Week 4, Week 8, Week 26, Week 52 ] [ Designated as safety issue: No ]
    The CIBIC-plus is a well-validated, reliable and widely used measure (range 1-7) of global improvement used in AD and MCI trials.


Other Outcome Measures:
  • Mini-Mental State Examination - MMSE [ Time Frame: Week 0, Week 26, Week 52 ] [ Designated as safety issue: No ]
  • Trail Making Test (Parts A and B) [ Time Frame: Week 0, Week 52 ] [ Designated as safety issue: No ]
    Parts A and B are composed of 25 circles. Patients are asked to scan the entire page and identify the next number or letter in a sequence.

  • Wechsler Adult Intelligence Scale (WAIS) -III Digit Symbol Subtest [ Time Frame: Week 0, Week 52 ] [ Designated as safety issue: No ]
  • Controlled Word Association (CFL) [ Time Frame: Week 0, Week 52 ] [ Designated as safety issue: No ]
  • Boston Naming Test (BNT) [ Time Frame: Week 0, Week 52 ] [ Designated as safety issue: No ]
  • Wechsler Memory Scale (WMS)-R Digit Span [ Time Frame: Week 0, Week 52 ] [ Designated as safety issue: No ]
  • Treatment Emergent Symptom Scale (TESS) [ Time Frame: Week 0, Week 4, Week 8, Week 26, Week 52 ] [ Designated as safety issue: No ]
    TESS is widely used to evaluate somatic side effects. For each item, a rating is made on a 3-point scale, with an additional rating on the likelihood that the medication caused the side effect.


Estimated Enrollment: 60
Study Start Date: August 2012
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Donepezil Treatment & Atropine Challenge
Atropine nasal spray is administered at baseline for the atropine challenge which involves administration of the 40-item University of Pennsylvania Smell Identification Test (UPSIT) immediately before and 45 minutes after atropine administration. Immediately after the atropine challenge, donepezil treatment is started and continues for 52 weeks.
Drug: Donepezil
Donepezil 5mg will be given for 4 weeks and if tolerated, the dose will be increased to 10 mg per day. The dose range of 5 to 10 mg of donepezil per day will be continued for the study duration, and this is the recommended dose for donepezil in the treatment of mild to moderate Alzheimer's disease.
Other Name: Aricept
Drug: Atropine
A single acute dose of 1 mg of atropine nasal spray is administered to the nostril. The dose chosen reflects clinical doses typically used by Ear, Nose, and Throat (ENT) physicians.
Other Name: Atropine sulfate ophthalmic solution 1%

Detailed Description:

In this clinical trial, the investigators will evaluate, treat and follow a broad sample of 60 adult patients with amnestic MCI at New York State Psychiatric Institute/Columbia University Medical Center. Recruitment will be from clinics and/or advertisements. In the protocol, all 60 amnestic MCI patients will receive baseline memory and olfactory assessments and begin treatment with donepezil. Patients will be followed for a total of 1 year. During this time, patients will be monitored closely by the study physician and will receive memory and olfactory assessments at weeks 8, 26, and 52. In addition, an olfactory challenge test will be done at baseline.

This project will be of value in the selection of patients with mild cognitive impairment for treatment based on the evaluation of olfaction tests to predict response to donepezil and other ACheI. Since mild cognitive impairment is widespread and Alzheimer's disease represents a major public health problem, this study has considerable public purpose and significance.

  Eligibility

Ages Eligible for Study:   55 Years to 95 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Of either sex, age 55-95 years old
  • Patients who meet criteria for amnestic mild cognitive impairment by meeting all of the following:

    (i) subjective memory complaints (ii) Wechsler Memory Scale-R Logical Memory combined Story A + B immediate recall score or combined Story A + B delayed recall score or Free and Cued Selective Reminding Test immediate recall or delayed recall score greater than 1.5 Standard Deviation (SD) below norms or Selective Reminding Test immediate recall or delayed recall score greater than 1.5 SD below norms iii) no functional impairment consistent with dementia

  • Folstein Mini Mental State (MMSE) score ≥ 23 out of 30
  • Clinical Dementia Rating (CDR) of 0.5 (questionable dementia)
  • Availability of informant

Exclusion Criteria:

  • Meets Criteria for dementia by Diagnostic and Statistical Manual IV (DSM-IV) criteria or probable Alzheimer's disease
  • Meets DSM IV criteria for:

    (i)schizophrenia, schizoaffective disorder, other psychosis, or bipolar I disorder (ii)alcohol or substance dependence or abuse (current or within past 6 months)

  • Current untreated major depression or suicidality
  • Parkinson's disease, Lewy body disease, multiple sclerosis, central nervous system infection, Huntington's disease, amyotrophic lateral sclerosis, other major neurological disorder.
  • Mental Retardation
  • Clinical stroke with residual neurological deficits. MRI findings of cerebrovascular disease (small infarcts, lacunes, periventricular disease) in the absence of clinical stroke with residual neurological deficits will not lead to exclusion.
  • Patients receiving cholinesterase inhibitors (donepezil, rivastigmine, galantamine) or memantine will be excluded.
  • Acute, severe, unstable medical illness. For cancer, patients with active illness or metastases will be excluded, but past history of successfully treated cancer will not lead to exclusion.
  • Medical contraindication to donepezil treatment or prior history of intolerability to donepezil treatment.
  • Medications with anticholinergic effects that have been shown to adversely impact cognition will not be permitted. Benzodiazepines in lorazepam equivalents greater than or equal to 2 mg daily and narcotics will also not be permitted.
  • Exclusion criterion for olfaction: history of anosmia due to any cause (e.g. traumatic or congenital) verified by UPSIT score of <11 out of 40; head trauma with loss of consciousness; nasal sinus disease, current upper respiratory infection; severe allergies to odors; current smoker > 1 pack daily.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01845636

Locations
United States, New York
New York State Psychiatric Institute
New York, New York, United States, 10032
Sponsors and Collaborators
New York State Psychiatric Institute
United States Department of Defense
Investigators
Principal Investigator: Davangere Devanand, M.D. Columbia University
Study Director: Gregory Pelton, M.D. Columbia University
  More Information

Responsible Party: New York State Psychiatric Institute
ClinicalTrials.gov Identifier: NCT01845636     History of Changes
Other Study ID Numbers: 6577  W81XWH-12-0142 
Study First Received: April 26, 2013
Last Updated: August 27, 2015
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
United States: Federal Government

Keywords provided by New York State Psychiatric Institute:
Olfaction
Donepezil
Alzheimer's Disease
Mild Cognitive Impairment
Memory

Additional relevant MeSH terms:
Cognition Disorders
Mild Cognitive Impairment
Neurocognitive Disorders
Mental Disorders
Ophthalmic Solutions
Donepezil
Atropine
Pharmaceutical Solutions
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Nootropic Agents
Adjuvants, Anesthesia
Anti-Arrhythmia Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Mydriatics
Parasympatholytics
Muscarinic Antagonists
Cholinergic Antagonists

ClinicalTrials.gov processed this record on August 25, 2016