Delaying the Progression of Driving Impairment in Individuals With Mild Alzheimer's Disease

• Sponsor: Florida Atlantic University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00476008
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 60
• Location: 1
• Arms: 2
• Duration (Months): 63
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The purpose of the study is to determine whether memantine delays the progression of driving impairment in patients with mild Alzheimer's Disease (AD).

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Memantine; Drug: Placebo	Phase 4

Detailed Description

It is well known, and of great concern to both patients and families, that individuals with Alzheimer's disease (AD) eventually become driving impaired. Drivers with dementia are estimated to be 2-8 times more likely to be involved in an automobile crash as unimpaired peers. Approximately half of individuals with mild AD have the skills needed to drive safely. Formal driver evaluation may be necessary to make this distinction. Some reviews in the literature have suggested that individuals identified as high risk, such as those with AD, be advised by their physicians to cease driving altogether. Other studies suggest that these individuals may continue to drive for up to 4 years following diagnosis. Memantine may be effective in delaying the progression of driving impairment in individuals with mild AD. If the investigators can demonstrate a significant delay in the decline in the driving ability, this could extend their driving time and therefore be of immense benefit to patients and their caregivers.

Comparison(s): Subjects treated with memantine over a period of 12 months, compared to subjects on placebo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Delaying the Progression of Driving Impairment in Individuals With Mild Alzheimer's Disease
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo One tablet placebo morning and evening (BID) for 12 months	Drug: Placebo; One tablet placebo morning and evening (BID) for 12 months
Active Comparator: Memantine One tablet memantine (Namenda)10mg morning and evening (BID) for 12 months.	Drug: Memantine; One tablet memantine (Namenda)10mg morning and evening (BID) for 12 months; Other Names: Namenda

Outcome Measures

Primary Outcome Measures

1. The Primary Outcome Measure is the Number of Subjects in Each Group Who Are Able to Pass the DriveABLE On-Road Test at Month 12 (Endpoint). [Baseline and 12 months]

   The DriveABLE On-Road Test utilizes a standardized road course and standardized scoring procedures designed to identify driving errors indicative of decline in competence scores. This road test takes approximately 30-45 minutes and covers a distance of approximately 9 miles.

Secondary Outcome Measures

1. Fuld Object Memory Evaluation [baseline and 12 months]

   Ten common objects in a bag were presented to determine whether the subject could identify objects by touch. The subject was not told that memory of this event would be tested. The subject names each object and then pulls it out of the bag to see if he is correct. After distracting the subject, by asking the patient to say words rapidly from a single category (rapid verbal retrieval), the subject is asked to recall the objects from the bag. The subject was then offered two more chances to learn and recall them (store and retrieve) by reminding the subject of omitted items after each recall, with rapid verbal retrieval preventing rehearsal before each recall opportunity. Retrieval scores were summed over the three trials with the range of possible scores being 0-30. Lower scores indicate more severe impairment.

2. Rey Complex Figure Test [baseline and 12 months]

   This is a measure of visual-spatial and constructional ability as well as higher order cognitive processes including planning, organizing, and problem solving. Subjects are asked to copy a complicated drawing. 18 elements are scored from 0-2 depending on accuracy/distortion and location of the reproduction. The maximum score is 36 points. Lower scores indicate more severe impairment

3. Trail Making Test - Part A [baseline and 12 months]

   A simple test of visual tracking. The score is the time in seconds required to complete. Higher scores indicate lower functioning.

4. Trail Making Test - Part B [baseline and 12 months]

   This tests cognitive flexibility and set-shifting. It is considered to be a test of executive functioning and has been shown to correlate with on-road driving ability. The score is the time in seconds required to complete each part. Higher scores indicate decreased functioning.

5. Mini Mental Status Exam [baseline and 12 months]

   Scores range from 0-30 with lower scores indicating decreased functioning.

6. Useful Field of View [baseline and 12 months]

   The Useful Field of View is a computer-administered test that measures higher order processing skills such as divided attention and visual processing speed. Scores can be predictive of ability to perform many everyday activities, such as driving a vehicle. Speed of visual processing is measured as the examinee identifies a target, but must also localize a simultaneously presented target displayed in the periphery of the computer monitor. Scores range from 1 to 4 with 1 being no impairment, 2= mild, 3= moderate and 4=serious impairment.

7. Motor Free Visual Perception Test - Visual Closure Subtest [baseline and 12 months]

   This is an 11 item multiple choice test of visual perception. Scores range from 0-11. This test measures visual perception deficits separate from motor skill abilities. Higher scores indicate more severe impairment.

8. Cognitive Dementia Rating Scale [baseline and 12 months]

   This scale is used to stage severity of dementia. Scores are on a five-point scale in which 0 indicates no cognitive impairment, .5 = very mild dementia,1 = mild, 2 = moderate and 3= severe.

9. Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) [baseline and 12 months]

   The ADAS-Cog is a performance based test that measures specific cognitive and behavioral dysfunctions in patients with Alzheimer's disease. The cognitive subscale comprises 11 items which measure word recall (0-10), ability to follow single and multi-step commands (0-5), constructional praxis (0-5), ideational praxis (0-5), naming objects(0-5), word recognition (0-12), orientation (0-8), comprehension of spoken language (0-5), word finding difficulty(0-5) and ability to remember test instructions (0-5). 0 = no impairment with higher scores indicating more severe impairment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women ages 60 years of age and older

• Subjects must either be previously diagnosed with mild Alzheimer's Disease (AD) by a neurologist, psychiatrist, geriatrician, or be evaluated at a Memory Disorders Center prior to entry into the study

• Subjects must have a score of ≥ 23 on the Mini-Mental State Examination (MMSE) at the Screening Visit

• Subjects must receive a passing score on the DriveABLE test

• Female subjects must be at least 2 years post-menopausal or surgically sterile

• Written informed consent must be obtained from the subject prior to the initiation of any study specific procedures

Exclusion Criteria:

• Subjects who have been treated with a depot neuroleptic within six (6) months of the Screening Visit

• Subjects who fail the OPTEC vision test at the screening visit

• Subjects who score > 7 on the Hachinski Test at the screening visit

• Subjects with evidence of clinically significant and active pulmonary, gastrointestinal, renal, hepatic, endocrine or cardiovascular system disease (subjects with controlled hypertension, right bundle branch block [complete or partial] and pacemakers may be included in the study). Subjects with thyroid disease may also be included in the study, provided they are euthyroid on treatment. Subjects with controlled diabetes may also be included

• Recent (< 2years) B12 or folate deficiency that was considered clinically significant

• Subjects with evidence of other psychiatric/neurologic disorders including, but not limited to, stroke, Vascular Dementia, Lewy-Body Disease, Parkinson's Disease, seizure disorder, head injury with loss of consciousness within the past 5 years, any psychotic disorder, or bipolar disorder

• Subjects who are taking, or have taken, amantadine, ketamine, dextromethorphan that cannot be discontinued or switched to an allowable alternative medication prior to the minimum allowable interval before Baseline

• Subjects who have been in an investigational drug study or who have received treatment with an investigational drug within 30 days (or 5 half-lives, whichever is longer) of the Screening Visit

• Any condition, which would make the subject, in the opinion of the investigator, unsuitable for the study

• If subjects are taking Acetylcholinesterase inhibitors (AChEls), they must be on a stable dose for > 3 months prior to baseline. No initiation of AChEls is permitted; discontinuation and dose reduction are permitted

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Charles E. Schmidt College of Medicine, Florida Atlantic University	Boca Raton	Florida	United States	33431

Sponsors and Collaborators

• Florida Atlantic University
• Forest Laboratories

Investigators

• Principal Investigator: Peter J Holland, MD, Charles E, Schmidt College of Medicine at Florida Atlantic University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Florida Atlantic University
• ClinicalTrials.gov Identifier: NCT00476008
• Other Study ID Numbers: NAM-MD-49
• First Posted: May 21, 2007
• Last Update Posted: Aug 11, 2014
• Last Verified: Aug 1, 2014

• Keywords provided by Florida Atlantic University: Alzheimer's Disease; Mild Alzheimer's Disease; Driving; Driving Impairment
• Additional relevant MeSH terms: Alzheimer Disease; Memantine

Study Results

Participant Flow

Recruitment Details	Recruitment dates July 2007 - September 2011 Newspaper print ads, physician referral, subject referral, press releases
Pre-assignment Detail	Prior to randomization, subjects completed a screening visit to discuss/sign informed consent and determine study eligibility. Of the 60 subjects screened, 17 were excluded due to not passing the screening visit driving test, scoring out of the inclusion criteria range on screening visit assessments or meeting an exclusion criteria.

Arm/Group Title	Memantine	Placebo
Arm/Group Description	Memantine : Memantine (Namenda)10mg BID for 12 months	Placebo : Placebo BID for 12 months
Period Title: Overall Study
STARTED	22	21
6 Month Testing	15	14
COMPLETED	13	13
NOT COMPLETED	9	8

Baseline Characteristics

Arm/Group Title	Memantine	Placebo	Total
Arm/Group Description	Memantine : Memantine (Namenda)10mg BID for 12 months	Placebo : Placebo BID for 12 months	Total of all reporting groups
Overall Participants	22	21	43
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	1 4.5%	0 0%	1 2.3%
>=65 years	21 95.5%	21 100%	42 97.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	78.13 (6.38)	80.47 (5.92)	79.28 (6.21)
Sex: Female, Male (Count of Participants)
Female	10 45.5%	5 23.8%	15 34.9%
Male	12 54.5%	16 76.2%	28 65.1%
Region of Enrollment (participants) [Number]
United States	22 100%	21 100%	43 100%

Outcome Measures

1. Primary Outcome

Title	The Primary Outcome Measure is the Number of Subjects in Each Group Who Are Able to Pass the DriveABLE On-Road Test at Month 12 (Endpoint).
Description	The DriveABLE On-Road Test utilizes a standardized road course and standardized scoring procedures designed to identify driving errors indicative of decline in competence scores. This road test takes approximately 30-45 minutes and covers a distance of approximately 9 miles.
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

One subject in the placebo group could not complete the driving test at 12 months due to his vision being below the legal limit to drive.

Arm/Group Title	Memantine	Placebo
Arm/Group Description	Memantine : Memantine (Namenda)10mg BID for 12 months	Placebo : Placebo BID for 12 months
Measure Participants	13	12
DriveABLE passed	13 (0) 59.1%	10 47.6%
DriveABLE same or improved	13 59.1%	9 42.9%

2. Secondary Outcome

Title	Fuld Object Memory Evaluation
Description	Ten common objects in a bag were presented to determine whether the subject could identify objects by touch. The subject was not told that memory of this event would be tested. The subject names each object and then pulls it out of the bag to see if he is correct. After distracting the subject, by asking the patient to say words rapidly from a single category (rapid verbal retrieval), the subject is asked to recall the objects from the bag. The subject was then offered two more chances to learn and recall them (store and retrieve) by reminding the subject of omitted items after each recall, with rapid verbal retrieval preventing rehearsal before each recall opportunity. Retrieval scores were summed over the three trials with the range of possible scores being 0-30. Lower scores indicate more severe impairment.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Placebo : Placebo BID for 12 months	Memantine : Memantine (Namenda)10mg BID for 12 months
Measure Participants	13	13
Baseline Sum of Retrieval Score	18.87 (5.00)	18.38 (8.76)
12 month Sum of Retrieval Score	19.08 (8.47)	17.94 (5.85)

3. Secondary Outcome

Title	Rey Complex Figure Test
Description	This is a measure of visual-spatial and constructional ability as well as higher order cognitive processes including planning, organizing, and problem solving. Subjects are asked to copy a complicated drawing. 18 elements are scored from 0-2 depending on accuracy/distortion and location of the reproduction. The maximum score is 36 points. Lower scores indicate more severe impairment
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Placebo: One tablet placebo morning and evening (BID) for 12 months	Memantine: One tablet memantine (Namenda)10mg morning and evening (BID) for 12 months
Measure Participants	13	13
Baseline	27.53 (6.05)	29.30 (5.10)
12 Months	29.96 (4.54)	27.85 (5.75)

4. Secondary Outcome

Title	Trail Making Test - Part A
Description	A simple test of visual tracking. The score is the time in seconds required to complete. Higher scores indicate lower functioning.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Placebo : Placebo BID for 12 months	Memantine : Memantine (Namenda)10mg BID for 12 months
Measure Participants	13	13
Baseline	50.33 (17.2)	39.63 (12.37)
12 months	53.46 (22.00)	38.54 (16.32)

5. Secondary Outcome

Title	Trail Making Test - Part B
Description	This tests cognitive flexibility and set-shifting. It is considered to be a test of executive functioning and has been shown to correlate with on-road driving ability. The score is the time in seconds required to complete each part. Higher scores indicate decreased functioning.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Placebo : Placebo BID for 12 months	Memantine : Memantine (Namenda)10mg BID for 12 months
Measure Participants	13	13
Baseline	195.33 (128.58)	117.75 (43.03)
12 months	233.15 (159.49)	170.92 (145.33)

6. Secondary Outcome

Title	Mini Mental Status Exam
Description	Scores range from 0-30 with lower scores indicating decreased functioning.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Placebo : Placebo BID for 12 months	Memantine : Memantine (Namenda)10mg BID for 12 months
Measure Participants	13	13
Baseline	27.67 (1.63)	28.13 (2.00)
12 Months	26.00 (3.56)	27.15 (2.34)

7. Secondary Outcome

Title	Useful Field of View
Description	The Useful Field of View is a computer-administered test that measures higher order processing skills such as divided attention and visual processing speed. Scores can be predictive of ability to perform many everyday activities, such as driving a vehicle. Speed of visual processing is measured as the examinee identifies a target, but must also localize a simultaneously presented target displayed in the periphery of the computer monitor. Scores range from 1 to 4 with 1 being no impairment, 2= mild, 3= moderate and 4=serious impairment.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Placebo : Placebo BID for 12 months	Memantine : Memantine (Namenda)10mg BID for 12 months
Measure Participants	13	13
Baseline	3.00 (1.31)	2.44 (1.50)
12 months	2.54 (1.45)	2.08 (1.38)

8. Secondary Outcome

Title	Motor Free Visual Perception Test - Visual Closure Subtest
Description	This is an 11 item multiple choice test of visual perception. Scores range from 0-11. This test measures visual perception deficits separate from motor skill abilities. Higher scores indicate more severe impairment.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Placebo : Placebo BID for 12 months	Memantine : Memantine (Namenda)10mg BID for 12 months
Measure Participants	13	13
Baseline	2.93 (2.52)	2.00 (2.19)
12 months	3.23 (2.83)	2.69 (2.53)

9. Secondary Outcome

Title	Cognitive Dementia Rating Scale
Description	This scale is used to stage severity of dementia. Scores are on a five-point scale in which 0 indicates no cognitive impairment, .5 = very mild dementia,1 = mild, 2 = moderate and 3= severe.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Placebo : Placebo BID for 12 months	Memantine : Memantine (Namenda)10mg BID for 12 months
Measure Participants	13	13
Baseline	2.30 (1.31)	2.41 (1.11)
12 Months	2.31 (2.71)	1.81 (1.61)

10. Secondary Outcome

Title	Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)
Description	The ADAS-Cog is a performance based test that measures specific cognitive and behavioral dysfunctions in patients with Alzheimer's disease. The cognitive subscale comprises 11 items which measure word recall (0-10), ability to follow single and multi-step commands (0-5), constructional praxis (0-5), ideational praxis (0-5), naming objects(0-5), word recognition (0-12), orientation (0-8), comprehension of spoken language (0-5), word finding difficulty(0-5) and ability to remember test instructions (0-5). 0 = no impairment with higher scores indicating more severe impairment.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Memantine
Arm/Group Description	Placebo : Placebo BID for 12 months	Memantine : Memantine (Namenda)10mg BID for 12 months
Measure Participants	13	13
1) Word Recall - Baseline	4.33 (1.28)	4.00 (1.26)
1) Word Recall - 12 Months	4.56 (1.97)	4.13 (1.31)
2) Commands - Baseline	.40 (.51)	0 (0)
2) Commands - 12 Months	.23 (.60)	.85 (2.76)
3) Constructional Praxis - Baseline	3.40 (.51)	3.44 (.63)
3) Constructional Praxis - 12 Months	3.54 (.52)	3.46 (.52)
4) Ideational Praxis - Baseline	5.00 (0)	5.00 (0)
4) Ideational Praxis - 12 months	4.92 (.28)	5.00 (0)
5) Naming - Baseline	1.80 (1.70)	2.38 (3.93)
5) Naming - 12 months	1.31 (1.38)	1.77 (1.69)
6) Orientation - Baseline	.80 (1.01)	.44 (1.09)
6) Orientation - 12 Months	.85 (1.34)	.46 (.88)
7) Word Recognition - Baseline	9.60 (6.07)	7.27 (5.42)
7) Word Recognition - 12 Months	8.10 (8.39)	9.31 (4.91)
8) Remember Test Instructions - Baseline	0.00 (0)	0.00 (0)
8) Remember Test Instructions - 12 Months	0.00 (0)	0.00 (0)
9) Spoken Language - Baseline	.20 (.77)	0.00 (0)
9) Spoken Language - 12 Months	.23 (.83)	0 (1.00)
10) Word Finding - Baseline	.13 (.52)	0.00 (0)
10) Word Finding - 12 Months	.15 (.55)	.08 (.28)
11) Comprehension - Baseline	.07 (.26)	.06 (.25)
11) Comprehension - 12 Months	.31 (.63)	.15 (.38)

Adverse Events

Arm/Group Title	Memantine		Placebo
Arm/Group Description	Memantine : Memantine (Namenda)10mg BID for 12 months		Placebo : Placebo BID for 12 months
All Cause Mortality
	Memantine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Memantine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/22 (9.1%)		3/21 (14.3%)
Cardiac disorders
Myocardial Infarction	1/22 (4.5%)	1	0/21 (0%)	0
General disorders
Generalized Weakness	0/22 (0%)	0	1/21 (4.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Mouth Cancer	1/22 (4.5%)	1	0/21 (0%)	0
Rectal carcinoma	0/22 (0%)	0	1/21 (4.8%)	1
Vascular disorders
Stroke	0/22 (0%)	0	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	Memantine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/22 (27.3%)		9/21 (42.9%)
Endocrine disorders
Hypothyroidism	0/22 (0%)	0	2/21 (9.5%)	2
Gastrointestinal disorders
Decreased Appetite	2/22 (9.1%)	2	0/21 (0%)	0
Nausea	0/22 (0%)	0	3/21 (14.3%)	3
Constipation	0/22 (0%)	0	3/21 (14.3%)	3
General disorders
Dizziness	2/22 (9.1%)	2	0/21 (0%)	0
Fatigue	4/22 (18.2%)	4	3/21 (14.3%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	0/22 (0%)	0	2/21 (9.5%)	2
Nervous system disorders
Headache	2/22 (9.1%)	2	0/21 (0%)	0
Insomnia	2/22 (9.1%)	2	0/21 (0%)	0
Psychiatric disorders
Depression	0/22 (0%)	0	2/21 (9.5%)	2
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/22 (0%)	0	2/21 (9.5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.