Clinical trial NCT01951118: Olfactory Deficits and Donepezil Treatment in Cognitively Impaired Elderly
Official title: Olfactory Deficits and Donepezil Treatment in Cognitively Impaired Elderly
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Alzheimer Disease
Mild Cognitive Impairment
Delirium, Dementia, Amnestic, Cognitive Disorders
Keywords: Smell
Olfaction Disorders
Atropine
Donepezil
Cholinesterase Inhibitors
Cognition Disorders
Lead sponsor: New York State Psychiatric Institute
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute on Aging (NIA)
First posted: 2013-09-26
Enrollment: 121
Sex: ALL
Minimum age (years): 55
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Change Over Time in Selective Reminding Test (SRT) Scores
timeFrame: Week 0, Week 8, Week 26, Week 52
Secondary outcomes:
measure: Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog)
timeFrame: Week 0, Week 8, Week 26, Week 52
measure: Clinician's Interview Based Impression (CIBIC-plus)
timeFrame: Week 8, Week 26, Week 52
measure: Pfeffer Functional Activities Questionnaire (FAQ)
timeFrame: Week 0, Week 8, Week 26, Week 52
measure: Measurement of Everyday Cognition (Ecog)
timeFrame: Week 0, Week 8, Week 26, Week 52
Other outcomes:
measure: Mini-Mental State Examination - MMSE
timeFrame: Week 0, Week 26, Week 52
measure: Trail Making Test (Parts A and B)
timeFrame: Week 0, Week 52
measure: Wechsler Adult Intelligence Scale (WAIS) -III Digit Symbol Subtest
timeFrame: Week 0, Week 52
measure: Controlled Word Association (CFL)
timeFrame: Week 0, Week 52
measure: Boston Naming Test (BNT)
timeFrame: Week 0, Week 52
measure: Wechsler Memory Scale (WMS)-R Digit Span
timeFrame: Week 0, Week 52.
measure: Treatment Emergent Symptom Scale (TESS)
timeFrame: Week 0, Week 8, Week 26, Week 52
Locations:
city: New York
country: United States
facility: New York State Psychiatric Institute
state: New York
Study officials:
affiliation: Columbia University
name: Davangere Devanand, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.