Memory Improvement Through Nicotine Dosing (MIND) Study

Study Overview
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Brief Summary
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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.

Official Title
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Long-Term Nicotine Treatment of Mild Cognitive Impairment

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Drug: Nicotine Transdermal Patch
* Drug: Placebo Patch


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have a subjective memory concern as reported by participant, study partner, or clinician 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 Mini-Mental State Exam score between 24 and 30, inclusive Clinical Dementia Rating (CDR) Global = 0.5. Memory Box score must be at least 0.5 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 Age 55-90 (inclusive) 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 Geriatric Depression Scale score of less than or equal to 14 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 Adequate visual and auditory acuity to allow neuropsychological testing Good general health with no additional diseases/disorders expected to interfere with the study Participant is not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile) Completed six grades of education or has a good work history Fluent in English or Spanish Exclusion Criteria: 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.). 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. 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 History of schizophrenia (DSM V criteria) History of alcohol or substance abuse or dependence within the past 2 years (DSM V criteria) 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. 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 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. Clinically significant abnormalities in screening laboratories or ECG. Residence in skilled nursing facility. 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. For CSF sub-study participants, a current blood clotting or bleeding disorder, or significantly abnormal PT or PTT (partial thromboplastin time) at screening For MRI sub-study participants, contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker. Patients whom the Site PI deems to be otherwise ineligible.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicotine Transdermal Patch<br>190 participants will wear nicotine transdermal patches during waking hours. Active dose will titrate up from 3.5mg to 21mg in the first 6 weeks of treatment, remain at 21mg for 22.5 months, and then taper down in the final month of treatment | Drug: Nicotine Transdermal Patch<br>* 21mg Nicotine transdermal patches worn during waking hours. Active dose will titrate up from 3.5mg to 21mg in the first 6 weeks of treatment, remain at 21mg for 22.5 months, and then taper down in the final month of treatment.<br>|
| Placebo Comparator: Placebo Patch<br>190 participants will wear matching placebo patches during waking hours. | Drug: Placebo Patch<br>* Matching placebo patches worn during waking hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline of the Conners Continuous Performance Task (CPT) to Month 25 |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Mild Cognitive Impairment - Clinical Global Impression of Change (MCI-CGIC) to Month 25 | 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. | 2 years | 
| Change from Baseline in Cogstate Brief Battery (CBB) to Month 25 | 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. | 2 years | 
| Change in Baseline in New York University (NYU) Paragraph Recall to Month 25 | This test measures immediate and delayed verbal recall of a brief story. | 2 years | 
| Change from Baseline in Clinical Dementia Rating Scale (CDR) - Sum of Boxes (SOB) to Month 25 | The is a clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe. | 2 years | 
| Change in Baseline in Geriatric Depression Scale (GDS) to Month 25 | This is a 30-item self-report assessment used to identify depression in the elderly. | 2 years | 
| Change in Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) to Month 25 | This scale is an inventory developed to assess functional performance in participantss with Alzheimer's disease. | 2 years | 
| Change from Baseline in Older Adult Self Report (OASR) / Older Adult Behavior Checklist (OABCL) to Month 25 | The OASR/OABCL is a general index of psychopathologic symptoms and signs that is specifically relevant to elderly individuals and is developmentally appropriate, covers a wide range of psychopathologic signs and symptoms, and functional measures. It allows multi-informant perspective (both patient and informant). The items are focused on common elderly emotional, functional, or medical problems. The OASR is completed by the participant and the companion OABCL is completed by the informant. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Nicotine, Transdermal Patch