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Alzheimer DiseasePhase 4NCT01951118

Olfactory Deficits and Donepezil Treatment in Cognitively Impaired Elderly

A Phase 4 study testing Donepezil in people with Alzheimer Disease and Mild Cognitive Impairment, run by New York State Psychiatric Institute at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 55 to 95 years
What is being tested?
Donepezil
Could I receive a placebo?
No, everyone receives an active treatment
How many people
121 participants
Where
1 siteUnited States
Study dates
Oct 2013to May 2019
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 55 to 95 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

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

Who cannot join

  • 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.
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  • 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
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site
  • New York State Psychiatric Institute

    New York, New York, 10032

Other trials in United States

About this study

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.

Read the 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.

Being tested
Donepezil
Keywords
Smell, Olfaction Disorders, Atropine, Donepezil, Cholinesterase Inhibitors, Cognition Disorders
Medical subject headings
Alzheimer Disease, Cognitive Dysfunction, Neurocognitive Disorders, Anosmia, Olfaction Disorders, Cognition Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DonepezilDrug

    Also called Aricept

    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.

Study groups in NCT01951118
Study groupRoleWhat they receive
Donepezil Treatment & Atropine ChallengeExperimentalAtropine 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.
Receives: Drug: Donepezil

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Week 0, Week 8, Week 26, Week 52

Secondary outcomes (4)
  1. Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog)

    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.

    Measured: Week 0, Week 8, Week 26, Week 52

  2. Clinician's Interview Based Impression (CIBIC-plus)

    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.

    Measured: Week 8, Week 26, Week 52

  3. Pfeffer Functional Activities Questionnaire (FAQ)

    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).

    Measured: Week 0, Week 8, Week 26, Week 52

  4. Measurement of Everyday Cognition (Ecog)

    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).

    Measured: Week 0, Week 8, Week 26, Week 52

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Sep 2013 (estimated)
  2. Study startOct 2013
  3. Primary completionMay 2019
  4. Study completionMay 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Prevention
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
121 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01951118
Sponsor's protocol ID
6655
Other IDs
1R01AG041795
Status last verified
Jul 2020
First submitted
18 Sep 2013
Last updated
13 Jul 2020
Data monitoring committee
Yes

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.

    PubMed 32333591

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Donepezil in people with Alzheimer Disease and Mild Cognitive Impairment, run by New York State Psychiatric Institute at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Jul 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change Over Time in Selective Reminding Test (SRT) Scores (time frame: Week 0, Week 8, Week 26, Week 52). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01951118, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jul 2020.

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