Clinical trial NCT02720445: Memory Improvement Through Nicotine Dosing (MIND) Study
Official title: Long-Term Nicotine Treatment of Mild Cognitive Impairment
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Mild Cognitive Impairment
Keywords: Alzheimer's Disease
Nicotine
Transdermal Patch
Lead sponsor: University of Southern California
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: Vanderbilt University
name: Alzheimer's Therapeutic Research Institute
First posted: 2016-03-25
Enrollment: 380
Sex: ALL
Minimum age (years): 55
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Cogstate Battery International Shopping List Test - Total Immediate Recall (ISLT-TIR)
timeFrame: 2 years
Secondary outcomes:
measure: Change from Baseline in Mild Cognitive Impairment - Clinical Global Impression of Change (MCI-CGIC) to Month 25
timeFrame: 2 years
measure: Change from Baseline in Cogstate Brief Battery (CBB) to Month 25
timeFrame: 2 years
measure: Change in Baseline in New York University (NYU) Paragraph Recall to Month 25
timeFrame: 2 years
measure: Change from Baseline in Clinical Dementia Rating Scale (CDR) - Sum of Boxes (SOB) to Month 25
timeFrame: 2 years
measure: Change in Baseline in Geriatric Depression Scale (GDS) to Month 25
timeFrame: 2 years
measure: Change in Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) to Month 25
timeFrame: 2 years
measure: Change from Baseline in Older Adult Self Report (OASR) / Older Adult Behavior Checklist (OABCL) to Month 25
timeFrame: 2 years
Other outcomes:
measure: Change from Baseline in Cerebral Spinal Fluid (CSF) Biomarkers to Month 25
timeFrame: 2 years
measure: Change from Baseline of Volumetric Magnetic Resonance Imaging (vMRI) to Month 25
timeFrame: 2 years
Locations:
city: Scottsdale
country: United States
facility: Perseverance Research Center
state: Arizona
city: N. Little Rock
country: United States
facility: Central Arkansas Veterans Healthcare System
state: Arkansas
city: Downey
country: United States
facility: USC Rancho Los Amigos
state: California
city: San Diego
country: United States
facility: Sharp Neurocognitive Research Center
state: California
city: Santa Ana
country: United States
facility: Syrentis Clinical Research
state: California
city: Danbury
country: United States
facility: Nuvance Health Medical Practice Ct, Inc.; Associated Neurologists, PC
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Atlantis
country: United States
facility: JEM Research Institute
state: Florida
city: Delray Beach
country: United States
facility: Brain Matters Research
state: Florida
city: Miami
country: United States
facility: Miami Jewish Health Systems
state: Florida
city: Stuart
country: United States
facility: Brain Matters Research
state: Florida
city: Augusta
country: United States
facility: Augusta University Movement and Memory Disorders
state: Georgia
city: Meridian
country: United States
facility: Velocity Clinical Research - Boise
state: Idaho
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Plymouth
country: United States
facility: Headlands Eastern MA LLC
state: Massachusetts
city: Buffalo
country: United States
facility: University at Buffalo (UBMD)
state: New York
city: East Syracuse
country: United States
facility: Velocity Clinical Research - Syracuse
state: New York
city: New York City
country: United States
facility: Integrative Clinical Trials
state: New York
city: New York
country: United States
facility: New York University Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Tulsa
country: United States
facility: Central States Research (formerly Tulsa Clinical Research)
state: Oklahoma
city: Portland
country: United States
facility: Providence Brain and Spine Institute
state: Oregon
city: Allentown
country: United States
facility: LeHigh Valley Hospital
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Ralph H. Johnson VA Health Care System
state: South Carolina
city: Cordova
country: United States
facility: Neurology Clinic, P.C.
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist Neurological Institute
state: Texas
city: San Antonio
country: United States
facility: Glenn Biggs Institute at the University of Texas Health
state: Texas
city: Seattle
country: United States
facility: University of Washington Memory and Brain Wellness Center
state: Washington
city: Spokane
country: United States
facility: Kingfisher Cooperative, LLC
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: USC Alzheimer's Therapeutic Research Institute (ATRI)
name: Paul Aisen, MD
role: STUDY_DIRECTOR
affiliation: Vanderbilt University
name: Paul Newhouse, MD
role: STUDY_DIRECTOR
References:
citation: Newhouse PA, Potter A, Corwin J, Lenox R. Age-related effects of the nicotinic antagonist mecamylamine on cognition and behavior. Neuropsychopharmacology. 1994 Apr;10(2):93-107. doi: 10.1038/npp.1994.11.
citation: Newhouse P, Kellar K, Aisen P, White H, Wesnes K, Coderre E, Pfaff A, Wilkins H, Howard D, Levin ED. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology. 2012 Jan 10;78(2):91-101. doi: 10.1212/WNL.0b013e31823efcbb.
citation: Dumas J, Hancur-Bucci C, Naylor M, Sites C, Newhouse P. Estrogen treatment effects on anticholinergic-induced cognitive dysfunction in normal postmenopausal women. Neuropsychopharmacology. 2006 Sep;31(9):2065-78. doi: 10.1038/sj.npp.1301042. Epub 2006 Feb 15.
citation: Newhouse PA, Dumas J, Hancur-Bucci C, Naylor M, Sites CK, Benkelfat C, Young SN. Estrogen administration negatively alters mood following monoaminergic depletion and psychosocial stress in postmenopausal women. Neuropsychopharmacology. 2008 Jun;33(7):1514-27. doi: 10.1038/sj.npp.1301530. Epub 2007 Aug 15.
citation: Newhouse PA, Sunderland T, Tariot PN, Blumhardt CL, Weingartner H, Mellow A, Murphy DL. Intravenous nicotine in Alzheimer's disease: a pilot study. Psychopharmacology (Berl). 1988;95(2):171-5. doi: 10.1007/BF00174504.
citation: Joe E, Ringman JM. Cognitive symptoms of Alzheimer's disease: clinical management and prevention. BMJ. 2019 Dec 6;367:l6217. doi: 10.1136/bmj.l6217.