Corticolimbic Degeneration and Treatment of Dementia

• ClinicalTrials.gov Identifier: NCT00768261
• Recruitment Status: Completed
• First Posted: October 8, 2008
• Results First Posted: September 11, 2018
• Last Update Posted: September 11, 2018
• Sponsor: Washington University School of Medicine
• Collaborator: Northwestern University
• Information provided by (Responsible Party): Washington University School of Medicine

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Dementia
• Interventions: Drug: Memantine (Namenda®); Drug: Donepezil (Aricept®)
• Enrollment: 39

Participant Flow

Recruitment Details
Pre-assignment Details	39 subjects enrolled in Group3.14 maps have passed inspection for quality and are included in final analysis. Subject data from a previously published study of donepezil(Wang et al.,2010) with 18 very mild dementia of the Alzheimer's type patients treated with donepezil,14 untreated with mild DAT, and 56 cognitively normal individuals are included.

Arm/Group Title	1 Very Mild to Mild DAT Untreated	2 Very Mild to Mild DAT Treated With Donepezil	3 Very Mild to Mild DAT Treated With the Combination	4 Nondemented Comparison Subjects.
Arm/Group Description	Group 1) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are untreated with either cholinesterase inhibitors or memantine	Group 2) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with donepezil. Donepezil (Aricept®): 5mg/day for six weeks and if no serious side-effects increased to 10mg/dy.	Group 3) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with the combination of donepezil and memantine. Memantine (Namenda®): Drug treatment will begin with 5 mg/day of donepezil for six weeks. After six weeks of such treatment, the subjects symptoms will be re-evaluated and any side-effects of treatment assessed and recorded. If no serious side-effects of donepezil are encountered, the dose of donepezil will be increased to 10 mg/day. For subjects prescribed the combination of donepezil and memantine, memantine (20 mg/day) will be added to the drug treatment regimen after the dose of donepezil has been established (i.e., at six weeks). Again, memantine will be initially started at 10 mg/day and increased to its full dose only if no serious side-effects are encountered. Memantine (Namenda®): Initial dose of 10mg/day and increased to full dose of 20mg/day if no serious side-effects	Group 4) nondemented comparison subjects.
Period Title: Overall Study
Started	14	18	39	56
Completed	14	18	14	56
Not Completed	0	0	25	0

Baseline Characteristics

Arm/Group Title		1 Very Mild to Mild DAT Untreated	2 Very Mild to Mild DAT Treated With Donepezil	3 Very Mild to Mild DAT Treated With the Combination	4 Nondemented Comparison Subjects.	Total
Arm/Group Description		Group 1) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are untreated with either cholinesterase inhibitors or memantine	Group 2) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with donepezil. Donepezil (Aricept®): 5mg/day for six weeks and if no serious side-effects increased to 10mg/dy.	Group 3) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with the combination of donepezil and memantine. Memantine (Namenda®): Drug treatment will begin with 5 mg/day of donepezil for six weeks. After six weeks of such treatment, the subjects symptoms will be re-evaluated and any side-effects of treatment assessed and recorded. If no serious side-effects of donepezil are encountered, the dose of donepezil will be increased to 10 mg/day. For subjects prescribed the combination of donepezil and memantine, memantine (20 mg/day) will be added to the drug treatment regimen after the dose of donepezil has been established (i.e., at six weeks). Again, memantine will be initially started at 10 mg/day and increased to its full dose only if no serious side-effects are encountered. Memantine (Namenda®): Initial dose of 10mg/day and increased to full dose of 20mg/day if no serious side-effects	Group 4) nondemented comparison subjects.	Total of all reporting groups
Overall Number of Baseline Participants		14	18	14	56	102
Baseline Analysis Population Description		Group 3; 39 subjects initially included. 8 subjects ineligible at initial assessment. 8 didn't have a follow-up MR scans for reasons; being deceased at the eos, refusal to scan, being unable to complete scanning due to discomfort. 5 subjects excluded due to poor baseline MR quality. 4 more scans excluded due to poor longitudinal mapping quality
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants	18 participants	14 participants	56 participants	102 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	1 7.1%	1 5.6%	0 0.0%	0 0.0%	2 2.0%
	>=65 years	13 92.9%	17 94.4%	14 100.0%	56 100.0%	100 98.0%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants	18 participants	14 participants	56 participants	102 participants
	Female	6 42.9%	8 44.4%	6 42.9%	35 62.5%	55 53.9%
	Male	8 57.1%	10 55.6%	8 57.1%	21 37.5%	47 46.1%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	14 participants	18 participants	14 participants	56 participants	102 participants
		14 100.0%	18 100.0%	14 100.0%	56 100.0%	102 100.0%

Outcome Measures

1. Primary Outcome

Title	Rate of Change of Hippocampal Volume Slope
Description	[Not Specified]
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1 Very Mild to Mild DAT Untreated	2 Very Mild to Mild DAT Treated With Donepezil	3 Very Mild to Mild DAT Treated With the Combination	4 Nondemented Comparison Subjects.
Arm/Group Description:	Group 1) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are untreated with either cholinesterase inhibitors or memantine	Group 2) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with donepezil. Donepezil (Aricept®): 5mg/day for six weeks and if no serious side-effects increased to 10mg/dy.	Group 3) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with the combination of donepezil and memantine. Memantine (Namenda®): Drug treatment will begin with 5 mg/day of donepezil for six weeks. After six weeks of such treatment, the subjects symptoms will be re-evaluated and any side-effects of treatment assessed and recorded. If no serious side-effects of donepezil are encountered, the dose of donepezil will be increased to 10 mg/day. For subjects prescribed the combination of donepezil and memantine, memantine (20 mg/day) will be added to the drug treatment regimen after the dose of donepezil has been established (i.e., at six weeks). Again, memantine will be initially started at 10 mg/day and increased to its full dose only if no serious side-effects are encountered. Memantine (Namenda®): Initial dose of 10mg/day and increased to full dose of 20mg/day if no serious side-effects	Group 4) nondemented comparison subjects.
Overall Number of Participants Analyzed	14	18	14	56
Mean (Standard Deviation); Unit of Measure: mm^3/year
left hippocampal volume slope	-70.2418748 (31.4801034)	-88.4738591 (52.2621175)	-94.0768115 (48.349487)	-46.9484805 (83.5825530)
right hippocampal volume slope	-99.9437062 (65.1619838)	-94.3258652 (44.7959659)	-125.0687876 (72.5509442)	-80.0840066 (130.3453711)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 Very Mild to Mild DAT Untreated, 2 Very Mild to Mild DAT Treated With Donepezil, 3 Very Mild to Mild DAT Treated With the Combination, 4 Nondemented Comparison Subjects.
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.095
	Comments	[Not Specified]
	Method	ANOVA
	Comments	df= 3,92

2. Secondary Outcome

Title	Comparison of Combined DAT Patients' Mean (SD) Hippocampal Volume Slope (mm^3/Year) Rate of Change
Description	The ADAS-Cog evaluates cognition and differentiates normal from impaired cognitive functioning. The total score is the summed number of errors in each task. The greater the impairment, the greater the score. We combined the dementia of the Alzheimer's type patients receiving all treatments together and grouped them into 3 subgroups according to the rates of change(roc) of their ADAS-Cog scores. To determine trends in hippocampal volume atrophy over time we compared the patients showing most negative ADAS-Cog rate of change (improving), patients with most positive ADAS-cog roc (worsening), patients with intermediate, near-zero ADAS-Cog roc (stable) .
Time Frame	two years

Outcome Measure Data

Analysis Population Description

We combined the DAT patients who received any treatment (donepezil or combined) & used the annual roc in ADAS-Cog to equally separate them into 3 subgroups; improving (1/3 negative ADAS-Cog roc), stable (1/3 near-zero ADAS-Cog change) & worsening (1/3 positive ADAS-Cog change).

Arm/Group Title	Improved	Worsening	Stable
Arm/Group Description:	Response group by ADAS-Cog rates	Response group by ADAS-Cog rates	Response group by ADAS-Cog rates
Overall Number of Participants Analyzed	10	11	11
Mean (Standard Deviation); Unit of Measure: (mm^3/year)
left hippocampal volume slope	-70 (56)	-106 (55)	-100 (37)
right hippocampal volume slope	-77 (51)	-141 (78)	-105 (34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Improved, Stable
	Comments	There would be a treatment effect on the changes of hippocampal measures over time. Repeated measures ANOVA on hippocampal volume slopes with hemisphere as a within-subject repeated factor, and treatment group as the main effect.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.066
	Comments	[Not Specified]
	Method	ANOVA
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Improved, Worsening
	Comments	There would be a treatment effect on the changes of hippocampal measures over time. Repeated measures ANOVA on hippocampal volume slopes with hemisphere as a within-subject repeated factor, and treatment group as the main effect.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.009
	Comments	[Not Specified]
	Method	ANOVA
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Worsening, Stable
	Comments	There would be a treatment effect on the changes of hippocampal measures over time. Repeated measures ANOVA on hippocampal volume slopes with hemisphere as a within-subject repeated factor, and treatment group as the main effect.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.30
	Comments	[Not Specified]
	Method	ANOVA
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Improved, Worsening, Stable
	Comments	RM-ANOVA on hippocampal volume slope
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0288
	Comments	[Not Specified]
	Method	Repeated Measures ANOVA
	Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	1 Very Mild to Mild DAT Untreated	2 Very Mild to Mild DAT Treated With Donepezil	3 Very Mild to Mild DAT Treated With the Combination	4 Nondemented Comparison Subjects.
Arm/Group Description	Group 1) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are untreated with either cholinesterase inhibitors or memantine	Group 2) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with donepezil. Donepezil (Aricept®): 5mg/day for six weeks and if no serious side-effects increased to 10mg/dy.	Group 3) subjects with very mild (CDR 0.5) to mild (CDR 1) DAT that are treated with the combination of donepezil and memantine. Memantine (Namenda®): Drug treatment will begin with 5 mg/day of donepezil for six weeks. After six weeks of such treatment, the subjects symptoms will be re-evaluated and any side-effects of treatment assessed and recorded. If no serious side-effects of donepezil are encountered, the dose of donepezil will be increased to 10 mg/day. For subjects prescribed the combination of donepezil and memantine, memantine (20 mg/day) will be added to the drug treatment regimen after the dose of donepezil has been established (i.e., at six weeks). Again, memantine will be initially started at 10 mg/day and increased to its full dose only if no serious side-effects are encountered. Memantine (Namenda®): Initial dose of 10mg/day and increased to full dose of 20mg/day if no serious side-effects	Group 4) nondemented comparison subjects.
All-Cause Mortality
	1 Very Mild to Mild DAT Untreated	2 Very Mild to Mild DAT Treated With Donepezil	3 Very Mild to Mild DAT Treated With the Combination	4 Nondemented Comparison Subjects.
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--
Serious Adverse Events
	1 Very Mild to Mild DAT Untreated	2 Very Mild to Mild DAT Treated With Donepezil	3 Very Mild to Mild DAT Treated With the Combination	4 Nondemented Comparison Subjects.
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/14 (0.00%)	0/18 (0.00%)	0/14 (0.00%)	0/56 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	1 Very Mild to Mild DAT Untreated	2 Very Mild to Mild DAT Treated With Donepezil	3 Very Mild to Mild DAT Treated With the Combination	4 Nondemented Comparison Subjects.
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/14 (0.00%)	0/18 (0.00%)	0/14 (0.00%)	0/56 (0.00%)

Limitations and Caveats

Interpretation of results limited to evaluating overall effects in naturalistic groups undergoing 2 drug treatments;Insufficient subjects to determine possible existence of DAT patient subgroups showing drug-specific slowing of disease progression

More Information

Certain Agreements

Principal Investigators are NOT 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.

Results Point of Contact

• Name/Title: John G. Csernansky, MD
• Organization: Washington University
• Phone: (312) 926-2323
• EMail: jgc@northwestern.edu

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT00768261
• Other Study ID Numbers: 5R01MH060883-06 ( U.S. NIH Grant/Contract )
• First Submitted: October 7, 2008
• First Posted: October 8, 2008
• Results First Submitted: April 24, 2018
• Results First Posted: September 11, 2018
• Last Update Posted: September 11, 2018