Memory Improvement Through Nicotine Dosing (MIND) Study (MIND)

Long-Term Nicotine Treatment of Mild Cognitive Impairment

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Mild Cognitive Impairment
• Intervention / Treatment: Drug: Nicotine Transdermal Patch; Drug: Placebo Patch

• Study Type: Interventional
• Enrollment (Estimated): 380
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85254
      • Perseverance Research Center
  • Arkansas
    • North Little Rock, Arkansas, United States, 72205
      • Central Arkansas Veterans Healthcare System
  • California
    • Downey, California, United States, 90242
      • USC Rancho Los Amigos
    • San Diego, California, United States, 92123
      • Sharp Neurocognitive Research Center
    • Santa Ana, California, United States, 92705
      • Syrentis Clinical Research
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Nuvance Health Medical Practice Ct, Inc.; Associated Neurologists, PC
  • District of Columbia
    • Washington, District of Columbia, United States, 200072145
      • Georgetown University
  • Florida
    • Atlantis, Florida, United States, 33462
      • Jem Research Institute
    • Delray Beach, Florida, United States, 33445
      • Brain Matters Research
    • Miami, Florida, United States, 33137
      • Miami Jewish Health Systems
    • Stuart, Florida, United States, 34997
      • Brain Matters Research
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University Movement and Memory Disorders
  • Idaho
    • Meridian, Idaho, United States, 83642
      • Velocity Clinical Research - Boise
  • Illinois
    • Chicago, Illinois, United States, 606113010
      • Northwestern University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Massachusetts
    • Plymouth, Massachusetts, United States, 02360
      • Headlands Eastern MA LLC
  • New York
    • Buffalo, New York, United States, 14203
      • University at Buffalo (UBMD)
    • East Syracuse, New York, United States, 13057
      • Velocity Clinical Research - Syracuse
    • New York, New York, United States, 100166055
      • New York University Medical Center
    • New York, New York, United States, 100296552
      • Mount Sinai School of Medicine
    • New York, New York, United States, 11229
      • Integrative Clinical Trials
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Central States Research (formerly Tulsa Clinical Research)
  • Oregon
    • Portland, Oregon, United States, 97225
      • Providence Brain and Spine Institute
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18105
      • LeHigh Valley Hospital
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 294011113
      • Ralph H. Johnson VA Health Care System
  • Tennessee
    • Cordova, Tennessee, United States, 38018
      • Neurology Clinic, P.C.
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Neurological Institute
    • San Antonio, Texas, United States, 78229
      • Glenn Biggs Institute at the University of Texas Health
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Memory and Brain Wellness Center
    • Spokane, Washington, United States, 99202
      • Kingfisher Cooperative, LLC
  • Wisconsin
    • Madison, Wisconsin, United States, 53706
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nicotine Transdermal Patch; 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; 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.
Placebo Comparator: Placebo Patch; 190 participants will wear matching placebo patches during waking hours.	Drug: Placebo Patch; Matching placebo patches worn during waking hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Cerebral Spinal Fluid (CSF) Biomarkers to Month 25	CSF will be performed in approximately 50 participants each	2 years
Change from Baseline of Volumetric Magnetic Resonance Imaging (vMRI) to Month 25		2 years

Collaborators and Investigators

• Sponsor: University of Southern California
• Collaborators: National Institute on Aging (NIA); Alzheimer's Therapeutic Research Institute; Vanderbilt University
• Investigators: Study Director: Paul Aisen, MD, USC Alzheimer's Therapeutic Research Institute (ATRI); Study Director: Paul Newhouse, MD, Vanderbilt University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Alzheimer's Therapeutic Research Institute (ATRI). ATRI is the Coordinating Center for the MIND study.
• MIND study public website

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2017
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: March 22, 2016
• First Submitted That Met QC Criteria: March 22, 2016
• First Posted (Estimated): March 25, 2016

Study Record Updates

• Last Update Posted (Estimated): December 21, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Nicotine; Transdermal Patch
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Ganglionic Stimulants; Nicotinic Agonists; Cholinergic Agonists; Nicotine
• Other Study ID Numbers: ATRI-002-NIC; R01AG047992 (U.S. NIH Grant/Contract); 131918 (Other Identifier: Food and Drug Administration (FDA))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES