Olfactory Deficits and Donepezil Treatment in Cognitively Impaired Elderly

NCT01951118 | Completed Phase 4 Results DMC

• 2 other identifiers: 66551R01AG041795
• Study Type: interventional
• Target: 121
• Locations: 1 country
• Sites: 1

Brief Summary

Olfactory identification deficits occur in patients with Alzheimer's disease (AD), are associated with disease severity, predict conversion from mild cognitive impairment (MCI) to AD and are associated with healthy elderly subjects developing MCI. Odor (olfactory) identification deficits may reflect degeneration of cholinergic inputs to the olfactory bulb and other olfactory brain regions. Acetylcholinesterase inhibitors (ACheI) like donepezil show modest effects in improving cognition but can be associated with adverse effects and increased burden and costs because of the need for prolonged, often lifelong, treatment. Converging findings on odor identification test performance (UPSIT, scratch and sniff 40-item test) from four pilot studies, including two of our own, suggest that acute change in the UPSIT in response to an anticholinergic challenge (atropine nasal spray), incremental change over 8 weeks, and even the baseline UPSIT score by itself, may predict cognitive improvement with ACheI treatment in MCI and AD. If change in odor identification deficits can help to identify which patients should receive ACheI treatment, this simple inexpensive approach will advance the goal of improving personalized treatment, improve selection and monitoring of patients for ACheI treatment, reduce needless ACheI exposure with risk of side effects, and decrease health care costs.

Conditions

Alzheimer Disease; Mild Cognitive Impairment; Delirium, Dementia, Amnestic, Cognitive Disorders

Keywords

Smell; Olfaction Disorders; Atropine; Donepezil; Cholinesterase Inhibitors; Cognition Disorders

Outcome Measures

Primary Outcomes (1)

• Change Over Time in Selective Reminding Test (SRT) Scores

  The Selective Reminding Test (SRT) is a 12-item test of verbal learning and memory. To administer, the researcher will read aloud a list of 12 words. The participant repeats each word aloud to ensure that the word was heard correctly. Immediately following the reading of all 12 words, the participant is asked to recall as many words as possible within the one minute time limit. The participant is then reminded of the words they did not say and asked to recall the list again. This process is repeated for 6 trials. The total immediate recall is the total number of words recalled by the participant from all 6 trials. This is the number that is reported. Lower scores indicate fewer words recalled and a poorer performance.

  Week 0, Week 8, Week 26, Week 52

Secondary Outcomes (4)

• Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog)

  Week 0, Week 8, Week 26, Week 52

• Clinician's Interview Based Impression (CIBIC-plus)

  Week 8, Week 26, Week 52

• Pfeffer Functional Activities Questionnaire (FAQ)

  Week 0, Week 8, Week 26, Week 52

• Measurement of Everyday Cognition (Ecog)

  Week 0, Week 8, Week 26, Week 52

Other Outcomes (7)

• Mini-Mental State Examination - MMSE

  Week 0, Week 26, Week 52

• Trail Making Test (Parts A and B)

  Week 0, Week 52

• Wechsler Adult Intelligence Scale (WAIS) -III Digit Symbol Subtest

  Week 0, Week 52

Study Arms (1)

Donepezil Treatment & Atropine Challenge

EXPERIMENTAL

Atropine nasal spray is administered at baseline for the atropine challenge which involves administration of the 40-item 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

Interventions

Donepezil DRUG

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. For patients who do not tolerate donepezil or have a history of intolerance to donepezil or cannot take donepezil for other reasons, treatment with other cholinesterase inhibitors (galantamine or rivastigmine) is permitted at any stage of the protocol. Data will be analyzed in two ways: for donepezil alone, and for any cholinesterase inhibitor (donepezil or rivastigmine or galantamine) as the intervention.

Also known as: Aricept

Donepezil Treatment & Atropine Challenge

Eligibility Criteria

• Age: 55 Years - 95 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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-III 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
• Retains capacity to consent

You may not qualify if:

• 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 less than or equal to 2 mg daily and narcotics will also not be permitted.
• Meets criteria for dementia by Diagnostic and Statistical Manual IV (DSM-IV) or probable Alzheimer's disease by National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA)
• Meets Diagnostic and Statistical Manual IV Text Revision (DSM IV TR) 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
• Cystic Fibrosis
• Patients receiving cholinesterase inhibitors (donepezil, rivastigmine, galantamine) or memantine will be excluded. Patients already receiving one of these medications at screening who undergo a 2-week washout before starting all study procedures will not be excluded.
• Study 2
• Of either sex, age 55-95 years old
• Diagnosis of probable Alzheimer's disease (NINCDS-ADRDA criteria) and the diagnosis of "Probable AD dementia: core clinical diagnosis with amnestic or nonamnestic initial presentation".
• Folstein Mini Mental State (MMSE) score 18-27 out of 30
• Availability of informant
• Retains capacity to consent

Sponsors & Collaborators

• New York State Psychiatric Institute: lead
• National Institutes of Health (NIH): collaborator
• National Institute on Aging (NIA): collaborator

Study Sites (1)

New York State Psychiatric Institute

New York, New York, 10032, United States

Location

Related Publications (1)

• Devanand DP, Liu X, Chunga RE, Cohen H, Andrews H, Schofield PW, Stern Y, Huey ED, Choi J, Pelton GH. Odor Identification Impairment and Change with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment. J Alzheimers Dis. 2020;75(3):845-854. doi: 10.3233/JAD-200021.

  PMID: 32333591 DERIVED

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction; Neurocognitive Disorders; Anosmia; Olfaction Disorders; Cognition Disorders

Interventions

Donepezil

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Mental Disorders; Sensation Disorders; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Indans; Indenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Davangere Devanand
• Organization: New York State Psychiatric Institute

dpd3@cumc.columbia.edu

646-774-8658

Study Officials

• Davangere Devanand, M.D.

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Clinical Psychiatry and Neurology

Study Record Dates

• First Submitted: September 18, 2013
• First Posted: September 26, 2013
• Study Start: October 1, 2013
• Primary Completion: May 1, 2019
• Study Completion: May 1, 2019
• Last Updated: July 13, 2020
• Results First Posted: July 13, 2020

Record last verified: 2020-07

Locations

US (1)