Mild Cognitive Impairment
Conditions
Keywords
Alzheimer's Disease, Nicotine, Transdermal Patch
Brief summary
The purpose of the study is to see if daily transdermal nicotine is able to produce a significant cognitive, clinical and functional improvement in participants with MCI. Neuronal nicotinic receptors have long been known to play a critical role in memory function in preclinical studies, with nicotine improving attention, learning, and memory function. The study will enroll 380 participants for a 2 year period. Participants will be randomized (50:50) to either the transdermal nicotine, beginning at 7mg/day, and increasing to 21mg/day, or placebo skin patch.
Interventions
21mg Nicotine transdermal patches worn during waking hours. Active dose will titrate up from 3.5mg to 21mg in the first 5 weeks of treatment, remain at 21mg up to month 24, and then taper down for three weeks.
DRUGPlacebo Patch
Matching placebo patches worn during waking hours.
Sponsors
University of Southern California
National Institute on Aging (NIA)
Vanderbilt University
Alzheimer's Therapeutic Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Participant must have a subjective memory concern as reported by participant, study partner, or clinician 2. Abnormal memory function documented by scoring within the education adjusted ranges on the Logical Memory II subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale - Revised: * less than or equal to 11 for 16 or more years of education * less than or equal to 9 for 8 - 15 years of education * less than or equal to 6 for 0 - 7 years of education 3. Mini-Mental State Exam score between 24 and 30, inclusive 4. Clinical Dementia Rating (CDR) Global = 0.5. Memory Box score must be at least 0.5 5. General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease dementia cannot be made by the site physician at the time of the screening visit 6. Age 55-90 (inclusive) 7. Stable permitted medications for 4 weeks or longer as specified in Section 6, including: • Memantine and cholinesterase inhibitors are allowable if stable for 12 weeks prior to screen 8. Geriatric Depression Scale score of less than or equal to 14 9. Study Partner is available who has frequent contact with the participant (e.g. an average of 10 hours per week or more), and can accompany the participant to most visits to answer questions about the participant 10. Adequate visual and auditory acuity to allow neuropsychological testing 11. Good general health with no additional diseases/disorders expected to interfere with the study 12. Participant is not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile) 13. Completed six grades of education or has a good work history 14. Fluent in English or Spanish
Exclusion criteria
1. Regular use of tobacco products within the past year, such as smoking (cigarettes, pipes, cigars, etc.) or use of other nicotine products (chewing tobacco, e-cigarettes, nicotine patches, gum, sprays, etc.). 2. Any significant neurologic disease such as Alzheimer's disease dementia, Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities. 3. Major depression, bipolar disorder as described in DSM-V within the past 1 year or psychotic features, agitation or behavioral problems within 3 months, which could lead to difficulty complying with the protocol 4. History of schizophrenia (DSM V criteria) 5. History of alcohol or substance abuse or dependence within the past 2 years (DSM V criteria) 6. Clinically significant or unstable medical condition, including uncontrolled hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic disease in the opinion of the Investigator, may either put the participant at risk because of participation in the study, or influence the results, or the participant's ability to participate in the study. 7. Has had a history within the last 5 years of a primary or recurrent malignant disease with the exception of non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate-specific antigen post-treatment 8. Clinically significant abnormalities in B12 or TFTs (Thyroid Function Tests) that might interfere with the study. A low B12 is exclusionary, unless the required follow-up labs (homocysteine (HC) and methylmalonic acid (MMA)) indicate that it is not physiologically significant. 9. Clinically significant abnormalities in screening laboratories or ECG. 10. Residence in skilled nursing facility. 11. Use of any excluded medication as described in the protocol, including: * Use of centrally acting anti-cholinergic drugs * Use of any investigational drugs within 30 days or 5 half-lives, whichever is longer, prior to screening. 12. For CSF sub-study participants, a current blood clotting or bleeding disorder, or significantly abnormal PT or PTT (partial thromboplastin time) at screening 13. For MRI sub-study participants, contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker. 14. Patients whom the Site PI deems to be otherwise ineligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cogstate Battery International Shopping List Test - Total Immediate Recall (ISLT-TIR) | From Baseline to month 24 | The ISLT - TIR represents the number of correct responses made when remembering the twelve word shopping list on three consecutive trials. The unit of the variable is correct responses count and higher score is better performance. Scores range from 0 to 36. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mild Cognitive Impairment - Clinical Global Impression of Change (MCI-CGIC) to Month 24 | From Baseline to month 24 | The MCI-CGIC is the MCI version of the clinician's global impression of change. In this trial it will measure change in the participant's condition between the baseline visit and subsequent visits. |
| International Shopping List Test - Delayed Recall (ISRL) | From Baseline to month 24 | This battery will be used for the purpose of assessing the cognitive status of the participants and will assist in documenting multiple domains of cognitive impairment. |
| Identification Task | From Baseline to month 24 | The IDN evaluates attention and is assessed in speed of performance. Lower score is better performance. |
| One Card Learning Task (OCL) | From Baseline to month 24 | The OCL evaluates visual learning and is assessed in accuracy of performance; performance; arcsine square root proportion correct. Higher score is better performance. Ranges from 0 to 1.5708 |
| Detection Task | From Baseline to month 24 | The DET evaluates Psychomotor Function and is assessed in speed of performance; mean of the log10 transformed reaction times for correct responses. Lower score is better performance, ranges from 2.001 to 6. |
| One Back Task (ONB) | From Baseline to month 24 | The ONB evaluates working memory and is assessed in speed of performance; mean of the log10 transformed reaction times for correct responses. Lower score is better performance, ranges from ranges from 2.001 to 6. |
| NYU Immediate Recall (NYU-Immediate) | From Baseline to month 24 | The NYU-Immediate recall evaluates immediate verbal recall. Higher is better performance |
| NYU Delayed Recall (NYU-DELAY) | From Baseline to month 24 | The NY-DELAY evaluates delayed verbal recall. Higher is better performance |
| Clinical Dementia Rating Scale (CDR) - Sum of Boxes (SOB) | From Baseline to month 24 | The is a clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe. |
| Geriatric Depression Scale (GDS) | Month 24 | The Geriatric Depression Scale (GDS) is a 30-item self-report assessment used to identify depression in the elderly. The grid sets a range of 0-9 as "normal", 10-19 as "mildly depressed", and 20-30 as "severely depressed". |
| Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) | From Baseline to month 24 | This scale is an inventory developed to assess functional performance in participantss with Alzheimer's disease. |
Countries
United States
Contacts
STUDY_DIRECTORPaul Aisen, MD
USC Alzheimer's Therapeutic Research Institute (ATRI)
STUDY_DIRECTORPaul Newhouse, MD
Vanderbilt University
Participant flow
Recruitment details
Participants were recruited from 41 sites across USA .The first participant was enrolled on February 22, 2017 and the last participant was enrolled on August 30, 2023.
Pre-assignment details
From 692 screened participants, 348 meet the inclusion criteria and were randomized
Baseline characteristics
| Characteristic | — |
|---|---|
| Activities of Daily Living in people with Mid Cognitive Impairment (ADCS-ADL-MCI) | 43.37 Total score STANDARD_DEVIATION 5.99 |
| Age, Continuous | 73.7 Years STANDARD_DEVIATION 7 |
| APOE ε4 Missing | 3 Participants |
| APOE ε4 No | 107 Participants |
| APOE ε4 Yes | 136 Participants |
| Clinical Dementia Rating Scale Sum of Boxes (CDR- SB) | 1.92 Total score STANDARD_DEVIATION 1.08 |
| Detection task (DET) | 2.67 Speed of performance (log10 msec) STANDARD_DEVIATION 0.11 |
| Hit Reaction Time Standard Error (RT-SE) from the Conners Continuous Performance (CPT) | 7.16 Milliseconds (ms) STANDARD_DEVIATION 2.96 |
| Identification task (IDN) | 2.78 Speed of performance (log10 msec) STANDARD_DEVIATION 0.09 |
| International Shopping List Test - Delayed recall (ISLR) | 5.19 Correct responses (Count) STANDARD_DEVIATION 2.95 |
| International Shopping List Test-Total Immediate Recall (ISLT-TIR) | 18.48 Correct responses (Count) STANDARD_DEVIATION 5.53 |
| Mini-Mental State Examinations (MMSE) | 27.41 total score STANDARD_DEVIATION 1.88 |
| NYU Delayed recall | 4.57 Correct responses (Count) STANDARD_DEVIATION 3.35 |
| NYU Immediate recall | 4.5 Correct responses (Count) STANDARD_DEVIATION 2.43 |
| One Back task (ONB) | 3.01 Speed of performance (log10 msec) STANDARD_DEVIATION 0.12 |
| One Card Learning Task (OCL) | 0.92 Accuracy (arcsin sqrt proportion) STANDARD_DEVIATION 0.12 |
| pTau-217 <0.19 pg/mL | 94 Participants |
| pTau-217 >=0.19 pg/mL | 115 Participants |
| pTau-217 Missing | 9 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 6 Participants |
| Race/Ethnicity, Customized Ethnicity Not hispanic or Latino | 334 Participants |
| Race/Ethnicity, Customized Ethnicity Unknown | 1 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaskan Native | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 5 Participants |
| Race/Ethnicity, Customized Race Black or African American | 12 Participants |
| Race/Ethnicity, Customized Race More than one race | 0 Participants |
| Race/Ethnicity, Customized Race White | 315 Participants |
| Sex: Female, Male Female | 80 Participants |
| Sex: Female, Male Male | 97 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 176 | 1 / 171 |
| other Total, other adverse events | 131 / 176 | 140 / 171 |
| serious Total, serious adverse events | 24 / 176 | 27 / 171 |
Outcome results
None listed