Olfactory Deficits and Donepezil Treatment in Cognitively Impaired Elderly

• ClinicalTrials.gov Identifier: NCT01951118
• Recruitment Status: Completed
• First Posted: September 26, 2013
• Results First Posted: July 13, 2020
• Last Update Posted: July 13, 2020
• Sponsor: New York State Psychiatric Institute
• Collaborators: National Institutes of Health (NIH); National Institute on Aging (NIA)
• Information provided by (Responsible Party): Davangere P. Devanand, New York State Psychiatric Institute

Tracking Information

• First Submitted Date: September 18, 2013
• First Posted Date: September 26, 2013
• Results First Submitted Date: May 29, 2020
• Results First Posted Date: July 13, 2020
• Last Update Posted Date: July 13, 2020
• Actual Study Start Date: October 2013
• Actual Primary Completion Date: May 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 10, 2020)

Change Over Time in Selective Reminding Test (SRT) Scores [ Time Frame: Week 0, Week 8, Week 26, Week 52 ]

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.

Original Primary Outcome Measures (submitted: September 23, 2013)

Change over time in Selective Reminding Test (SRT) Scores [ Time Frame: Week 0, Week 8, Week 26, Week 52 ]

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.

Current Secondary Outcome Measures (submitted: July 10, 2020)

• Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) [ Time Frame: Week 0, Week 8, Week 26, Week 52 ]
  The modified Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) is a cognitive battery that assesses learning, memory, language production, language comprehension, constructional praxis, ideational praxis, and orientation. The ADAS-Cog is not a timed test and the participant's score does not depend on how rapidly the test is completed. The ADAS-Cog total score is based on the total number of errors made in the test by the participant. Therefore, a lower total score indicates a higher cognitive performance. The total score ranges from 0 to 95 and is determined by summing the errors from 12 subscales. The total score, indicating number of errors made, is the number that is reported at each timeframe.
• Clinician's Interview Based Impression (CIBIC-plus) [ Time Frame: Week 8, Week 26, Week 52 ]
  The CIBIC-plus is a well-validated, reliable and widely used measure (range 1-7) of global improvement used in AD and MCI trials. This is a measure of change based on clinician impression. Higher values represent a worse outcome.
• Pfeffer Functional Activities Questionnaire (FAQ) [ Time Frame: Week 0, Week 8, Week 26, Week 52 ]
  FAQ is a widely used 10-item instrument that takes 3 minutes to administer and focuses on instrumental, social and cognitive functioning. The assessment is completed by a study informant - typically a caregiver able to report best on the patient's current ability. The instrument assesses the patient's current ability, at the point of testing and through the past month, in these various domains. The total score is described as the cumulative scores of each item, ranging from "0 - No help needed" to "3 - No, unable to do." More impairment is indicated by higher scores. The reported total score range is from 0 (no impairment score) to 30 (maximum impairment score).
• Measurement of Everyday Cognition (Ecog) [ Time Frame: Week 0, Week 8, Week 26, Week 52 ]
  This instrument has 40 items, takes 20 minutes to administer, and focuses on functional correlates of cognitive deficits. This assessment asks the study informant to rate the participant's ability to perform certain tasks with the domains of Memory, Language, Visual-spatial and Perceptual Abilities, Executive Functioning: Planning, Executive Functioning: Organization, and Executive Functioning: Divided Attention. The informant is asked to compare functioning from 10 years prior to the time of testing. The Everyday Cognition measure uses the sum score of all of the subscales, and the items are reverse coded (i.e., 1= "Better or no change", 2="Questionable/occasionally worse", 3="Consistently a little worse", 4="Consistently much worse"), meaning that lower scores are better. Reported total scores range from 39 (Better or no change) to 156 (Consistently much worse).

Original Secondary Outcome Measures (submitted: September 23, 2013)

• Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) [ Time Frame: Week 0, Week 8, Week 26, Week 52 ]
  The modified ADAS-Cog is a cognitive battery that assesses learning, memory, language production, language comprehension, constructional praxis, ideational praxis, and orientation.
• Clinician's Interview Based Impression (CIBIC-plus) [ Time Frame: Week 0, Week 2, Week 4, Week 8, Week 26, Week 52 ]
  The CIBIC-plus is a well-validated, reliable and widely used measure (range 1-7) of global improvement in AD and MCI trials.
• Pfeffer Functional Activities Questionnaire (FAQ) [ Time Frame: Week 0, Week 4, Week 8, Week 26, Week 52 ]
  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 ]
  This instrument has 40 items, takes 20 minutes to administer, and focuses on functional correlates of cognitive deficits.

Current Other Pre-specified Outcome Measures (submitted: July 10, 2020)

• Mini-Mental State Examination - MMSE [ Time Frame: Week 0, Week 26, Week 52 ]
  The Mini Mental State Examination (MMSE) is a widely used 30-item test of cognitive function that includes tests of orientation, attention, memory, language, and visual-spatial skills. Values range from 0-30; a higher value represents a better outcome.
• Trail Making Test (Parts A and B) [ Time Frame: Week 0, Week 52 ]
  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 ]
  The Wechsler Adult Intelligence Scale (WAIS) -III Digit Symbol Subtest is a paper-and-pencil cognitive test presented on a single sheet of paper that requires a subject to match symbols to numbers according to a key located on the top of the page. Values range from 0-93; a higher value represents a better outcome.
• Controlled Word Association (CFL) [ Time Frame: Week 0, Week 52 ]
• Boston Naming Test (BNT) [ Time Frame: Week 0, Week 52 ]
• Wechsler Memory Scale (WMS)-R Digit Span [ Time Frame: Week 0, Week 52. ]
• Treatment Emergent Symptom Scale (TESS) [ Time Frame: Week 0, Week 8, Week 26, Week 52 ]
  The Treatment Emergent Symptom Scale (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. Values range from 0-78; a higher value indicates a worse outcome.

Original Other Pre-specified Outcome Measures (submitted: September 23, 2013)

• Mini-Mental State Examination - MMSE [ Time Frame: Week 0, Week 26, Week 52 ]
• Trail Making Test (Parts A and B) [ Time Frame: Week 0, Week 52 ]
  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 ]
• Controlled Word Association (CFL) [ Time Frame: Week 0, Week 52 ]
• Boston Naming Test (BNT) [ Time Frame: Week 0, Week 52 ]
• Wechsler Memory Scale (WMS)-R Digit Span [ Time Frame: Week 0, Week 52. ]
• Treatment Emergent Symptom Scale (TESS) [ Time Frame: Week 0, Week 4, Week 8, Week 26, Week 52 ]
  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.

Descriptive Information

• Brief Title: Olfactory Deficits and Donepezil Treatment in Cognitively Impaired Elderly
• Official Title: Olfactory Deficits and Donepezil Treatment in Cognitively Impaired Elderly
• 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.

Detailed Description

In this clinical trial, the investigators will evaluate, treat and follow two broad samples of adult patients at New York State Psychiatric Institute/Columbia University Medical Center. Study 1 will include 70 patients with amnestic Mild Cognitive Impairment (MCI). Study 2 will include 100 patients with probable Alzheimer's Disease (AD). Recruitment will be from clinics and/or advertisements. In the protocol, all 170 patients will receive baseline memory and olfactory assessments and are treated 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 0, 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 MCI and AD for treatment based on the evaluation of olfaction tests to predict response to donepezil. Since mild cognitive impairment is widespread and Alzheimer's disease represents a major public health problem, this study has considerable public purpose and significance.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Prevention

Condition

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

Intervention

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. 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.

Other Name: Aricept

Study Arms

Experimental: Donepezil Treatment & Atropine Challenge

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.

Intervention: Drug: Donepezil

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 9, 2019): 121
• Original Estimated Enrollment (submitted: September 23, 2013): 170
• Actual Study Completion Date: May 2019
• Actual Primary Completion Date: May 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Study 1

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-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

Exclusion Criteria:

• 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
• 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. Patients already receiving one of these medications at screening who undergo a 2-week washout before starting all study procedures will not 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.
• 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.
• Exclusion criteria for atropine nasal spray: presence of nasal deformity or disease that makes it difficult to administer the nasal spray reliably. A patient who cannot complete the atropine nasal spray procedure can still participate in the rest of the study.

Study 2

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 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
• 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. Patients already receiving one of these medications at screening who undergo a 2-week washout before starting all study procedures will not 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.
• 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.
• Exclusion criteria for atropine nasal spray: presence of nasal deformity or disease that makes it difficult to administer the nasal spray reliably. A patient who cannot complete the atropine nasal spray procedure can still participate in the rest of the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years to 95 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01951118
• Other Study ID Numbers: 6655; 1R01AG041795 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Davangere P. Devanand, New York State Psychiatric Institute
• Original Responsible Party: New York State Psychiatric Institute
• Current Study Sponsor: New York State Psychiatric Institute
• Original Study Sponsor: Same as current

Collaborators

• National Institutes of Health (NIH)
• National Institute on Aging (NIA)

Investigators

• Principal Investigator: Davangere Devanand, M.D.; Columbia University

• PRS Account: New York State Psychiatric Institute
• Verification Date: July 2020