Nicotine Treatment of Cognitive Decline in Down Syndrome

Nicotinic Treatment of Age-Related Cognitive Decline in Down Syndrome: An Open Label Pilot Trial

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01778946

Enrollment

Registered

2013-01-29

Start date

2013-04-30

Completion date

2021-02-28

Last updated

2022-05-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Down Syndrome, Mild Cognitive Impairment

Keywords

Nicotine, Down Syndrome, Mild Cognitive Impairment, Event Related Potential, Memory, Attention, Trisomy 21, Neuroprotection, Cognitive Enhancement, Alzheimer's Disease, Dementia, APOE

Brief summary

This study will ascertain whether nicotine is safe and tolerable in DS patients, help with dose-ranging of nicotine in DS, look for evidence of enhancements in cognitive functioning, and establish evidence for biological and behavioral correlates of nicotinic stimulation effects. The knowledge gained from the translational aspects of this project may also guide the application of new nicotinic drugs in DS and generate, for the first time, data on the importance of nicotinic receptor changes in the development of cognitive impairment in DS adults. Hypotheses: * Transdermal nicotine treatment will be well tolerated out to one month by non-smoking DS patients without significant adverse effects. * Nicotine will enhance cognitive performance by one month compared to baseline and post-treatment testing. * Nicotine will enhance functioning detectable by clinician and/or informant ratings (pre-post).

Detailed description

Over 50% of adults with Down Syndrome (DS) develop Alzheimer's disease (AD) by the age of 60 (Nadel 2003), and life expectancy in DS is now 50-60 years. Thus, age-associated cognitive impairment and dementia in older adults with DS is an urgent public health concern. The investigators propose that nicotinic stimulation is a promising strategy to stabilize or improve cognitive functioning in adults with DS, possibly with additional neuroprotective effects. The investigators have extensive experience investigating the role of nicotinic receptors on human cognition and impairment. This application takes advantage of new insights into treating Mild Cognitive Impairment (MCI-the precursor condition to Alzheimer's Disease (AD) in typically developing individuals) with nicotine to propose an open label pilot study of transdermal nicotine in middle-aged non-smoking DS patients who show early cognitive and/or behavioral changes consistent with MCI/dementia. The goal of this study is to establish preliminary evidence for safety, gain preliminary evidence as to whether nicotine enhances cognitive functioning in DS adults, and examine electrophysiological, biological, and behavioral correlates of nicotinic stimulation effects. The investigators propose that positive results on cognitive or functional indices that would lead to a larger and longer double-blind trial to test more definitively whether nicotinic stimulation may be cognitively and/or functionally enhancing for DS patients. The knowledge gained from the translational aspects of this project will guide the development of potentially new nicotinic drugs in DS and generate, for the first time, data on the importance of nicotinic receptor changes in the development of cognitive impairment in DS adults. This work also represents the first time that cutting-edge advances in treating MCI/AD in the general population are immediately and rigorously applied to those with DS.

Interventions

DRUGLow Dose Nicotine (7mg)

DRUGModerate Dose Nicotine (14mg)

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

25 Years to No maximum

Healthy volunteers

Inclusion criteria

* Cognitive complaints and/or memory difficulties which are verified as new onset by an informant. * Cognitive Global Rating consistent with mild impairment or deterioration from premorbid baseline. * General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease/dementia cannot be made by the physician at the time of the screening visit. * No significant cerebrovascular disease: Modified Hachinski score of less than or equal to 4. * Age 25+. * Stable medications for at least 1 month prior to screening. Central nervous system (CNS) medications should be stable for 3 months. * No evidence of major depression. * Informant is available who has frequent contact with the subject (e.g. an average of 10 hours per week or more). * Adequate visual and auditory acuity to allow neuropsychological testing. * Good general health with no additional diseases expected to interfere with the study. * Normal B12, rapid plasma reagin (RPR), and Thyroid Function Tests or without any clinically significant abnormalities that would be expected to interfere with the study. * ECG without clinically significant abnormalities that would be expected to interfere with the study. * Subject is not pregnant, lactating. * Subjects will be taking no drugs with cholinergic properties (e.g donepezil). * Agreement not to take other vitamin or supplements other than multivitamins. * Negative urine pregnancy test in females.

Exclusion criteria

* Any significant neurologic disease such as Alzheimer's disease, 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. * Active Major depression or another major psychiatric disorder as described in DSM-IV. * History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria). * Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol including: * History of myocardial infarction in the past year or unstable or severe cardiovascular disease including angina or congestive heart failure (CHF) with symptoms at rest. * Clinically significant obstructive pulmonary disease or asthma. * Clinically significant and unstable gastrointestinal disorder such as ulcer disease or a history of active or occult gastrointestinal bleeding within two years. * Clinically significant laboratory test abnormalities on the battery of screening tests (hematology, chemistry, urinalysis, ECG). * Insulin-requiring diabetes or uncontrolled diabetes mellitus. * Uncontrolled hypertension (systolic BP\> 170 or diastolic BP\> 100). * Use of any investigational drugs within 30 days or 5 half-lives, whichever is longer, prior to screening.

Design outcomes

Primary

Measure	Time frame	Description
Tolerability of Nicotine Intervention	1 Month	Maximum transdermal nicotine dosage able to be maintained stably by participants.

Secondary

Measure	Time frame	Description
Cognitive Improvement - Simple Response Time	4 time-points over the 6-week testing period: at baseline, day 14, day 28 (end of treatment), and 2-weeks post-treatment on day 42.	Psychomotor speed was measured by the performance on the CANTAB simple reaction time task
Exploratory - Event-Related Potentials	4 time-points over the 6-week testing period: at baseline, day 14, day 28 (end of treatment), and 2-weeks post-treatment on day 42.	The investigators will measure daily low-moderate dose nicotine treatment's changes to electrophysiological markers of memory performance using an incidental memory task. The incidental memory task consists of presenting participants with a series of 60 complex images, 50 of which are presented once, and 10 which are repeated 5 times each. The task measures the presence of the late positive potential (LPP), a positive deflection over the parietal cortex which is elevated for the repeated compared to the singly presented images. The presence of this potential is indicative of improved recognition memory.
Cognitive Improvement - Continuous Performance Test	4 time-points over the 6-week testing period: at baseline, day 14, day 28 (end of treatment), and 2-weeks post-treatment on day 42.	Performance on the Conners' Continuous Performance Test, which is a measure of sustained attention. The main outcome measure was commission errors, which measures attention failures. The commission errors are calculated as T-scores. Higher T-scores indicate worse performance, lower T-scores indicate better performance. Average performance is a score of 50, with a standard deviation of 10.
Cognitive Improvement - Buschke Selective Reminding Task	4 time-points over the 6-week testing period: at baseline, day 14, day 28 (end of treatment), and 2-weeks post-treatment on day 42.	Episodic memory performance was assessed by the Buschke Selective Reminding Task. The main outcome metric of this test was the total words correctly recalled.
Cognitive Improvement - Critical Flicker Fusion Task	4 time-points over the 6-week testing period: at baseline, day 14, day 28 (end of treatment), and 2-weeks post-treatment on day 42.	Arousal and vigilance were measured by the Critical Flicker Fusion task. The task used at perceptual performance on ascending and descending frequencies of the task.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Nicotine Low Dose Nicotine (7mg) Moderate Dose Nicotine (14mg) All participants in study will begin with the 7mg patch, titrating from 2 hours/day to a full 16 hours/day over the course of the first 7 days (based on individual tolerance). Day 7 - Day 28 of the study, participants will apply a new nicotine patch daily. Depending on tolerance, some participants may increase to the moderate dose (14mg) patch. All participants will apply a new patch daily for a total of 28 days (1 month) Low Dose Nicotine (7mg) Moderate Dose Nicotine (14mg)	7
Total	7

Arm

Count

Nicotine

Low Dose Nicotine (7mg) Moderate Dose Nicotine (14mg) All participants in study will begin with the 7mg patch, titrating from 2 hours/day to a full 16 hours/day over the course of the first 7 days (based on individual tolerance). Day 7 - Day 28 of the study, participants will apply a new nicotine patch daily. Depending on tolerance, some participants may increase to the moderate dose (14mg) patch. All participants will apply a new patch daily for a total of 28 days (1 month) Low Dose Nicotine (7mg) Moderate Dose Nicotine (14mg)

Total

Baseline characteristics

Characteristic	Nicotine
Age, Continuous	40.9 years STANDARD_DEVIATION 11.9
BMI	24.9 Kg/m^2 STANDARD_DEVIATION 3.6
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants
Race (NIH/OMB) White	6 Participants
Region of Enrollment United States	7 participants
Sex: Female, Male Female	1 Participants
Sex: Female, Male Male	6 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 7
other Total, other adverse events	5 / 7
serious Total, serious adverse events	0 / 7

Outcome results

Primary

Tolerability of Nicotine Intervention

Maximum transdermal nicotine dosage able to be maintained stably by participants.

Time frame: 1 Month

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Nicotine	Tolerability of Nicotine Intervention	7 mg	1 Participants
Nicotine	Tolerability of Nicotine Intervention	14 mg	3 Participants

Secondary

Cognitive Improvement - Buschke Selective Reminding Task

Episodic memory performance was assessed by the Buschke Selective Reminding Task. The main outcome metric of this test was the total words correctly recalled.