Trial of Carvedilol in Alzheimer's Disease

• ClinicalTrials.gov Identifier: NCT01354444
• Recruitment Status: Completed
• First Posted: May 16, 2011
• Results First Posted: February 6, 2018
• Last Update Posted: February 6, 2018
• Sponsor: Johns Hopkins University
• Collaborator: Icahn School of Medicine at Mount Sinai
• Information provided by (Responsible Party): Johns Hopkins University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Alzheimer's Disease
• Interventions: Drug: Carvedilol; Drug: Placebo
• Enrollment: 29

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Carvedilol	Placebo
Arm/Group Description	Carvedilol is a is a beta-blocker. Beta-blockers are generally used to reduce the workload on the heart and help it to beat more regularly. Carvedilol: target dose of 25 mg daily which is half the maximum dose used in clinical practice	Non active substance Placebo: a pill that will look like the active drug but will not contain any carvedilol
Period Title: Overall Study
Started	14	15
Completed	6	11
Not Completed	8	4

Baseline Characteristics

Arm/Group Title		Carvedilol	Placebo	Total
Arm/Group Description		Carvedilol is a is a beta-blocker. Beta-blockers are generally used to reduce the workload on the heart and help it to beat more regularly. Carvedilol: target dose of 25 mg daily which is half the maximum dose used in clinical practice	Non active substance Placebo: a pill that will look like the active drug but will not contain any carvedilol	Total of all reporting groups
Overall Number of Baseline Participants		14	15	29
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants	15 participants	29 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	5 35.7%	6 40.0%	11 37.9%
	>=65 years	9 64.3%	9 60.0%	18 62.1%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants	15 participants	29 participants
	Female	10 71.4%	6 40.0%	16 55.2%
	Male	4 28.6%	9 60.0%	13 44.8%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants	15 participants	29 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	3 21.4%	1 6.7%	4 13.8%
	White	11 78.6%	14 93.3%	25 86.2%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months
Description	The investigators measured episodic memory (as evidence by the Hopkins Verbal Learning Test (HVLT)) before and after 6 months randomized placebo-controlled double-blind treatment with carvedilol at a target dose of 25 mg daily. Changes in HVLT Immediate and Delayed Recall score in 14 Alzheimer's Disease (AD) participants taking carvedilol vs. 15 AD participants taking placebo were compared. HVLT test score ranges are as follows: immediate recall (0-24) delayed recall (0-12). Higher scores indicate better episodic memory recall.
Time Frame	Baseline, 3 months, and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HVLT Score in Placebo Group	HVLT Score in Treatment Group
Arm/Group Description:	Descriptive statistics for immediate recall in the Hopkins Verbal Learning Test in the placebo group	Descriptive statistics for immediate recall in the Hopkins Verbal Learning Test in the treatment group
Overall Number of Participants Analyzed	15	14
Mean (Standard Deviation); Unit of Measure: Scores on a scale
HVLT score at Baseline (immediate recall)	13 (4)	12 (6)
HVLT score at 3 months (immediate recall)	12 (5)	13 (4)
HVLT score at 6 months (immediate recall)	12 (5)	13 (6)
HVLT score at Baseline (delayed recall)	1 (2)	1 (1)
HVLT score at 3 months (delayed recall)	1 (2)	1 (2)
HVLT score at 6 months (delayed recall)	1 (2)	0 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HVLT Score in Placebo Group, HVLT Score in Treatment Group
	Comments	This analysis compares immediate recall before and after 6 months between the treatment and placebo group.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.565
	Comments	[Not Specified]
	Method	Regression, Linear
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Coefficient
	Estimated Value	1.48
	Confidence Interval	(2-Sided) 95%; -3.796 to 6.761
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers
Description	The investigators will measure CSF Abeta oligomer levels before and after 6 months randomized placebo-controlled double-blind treatment with carvedilol at a target dose of 25 mg daily, comparing the change in levels in 6 AD participants taking carvedilol vs. 10 AD participants taking placebo. These 16 participants had both baseline and 6 month CSF collected (of the entire study population). CSF was collected at the baseline visit and 6 months later.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carvedilol	Placebo
Arm/Group Description:	Carvedilol is a is a beta-blocker. Beta-blockers are generally used to reduce the workload on the heart and help it to beat more regularly. Carvedilol: target dose of 25 mg daily which is half the maximum dose used in clinical practice	Non active substance Placebo: a pill that will look like the active drug but will not contain any carvedilol
Overall Number of Participants Analyzed	6	10
Mean (Standard Deviation); Unit of Measure: pg/mL
Baseline Tau (pg/mL)	169.476 (93.931)	169.484 (48.386)
Baseline ABeta42 (pg/mL)	396.985 (212.411)	379.406 (100.892)
Baseline P tau (pg/mL)	42.666 (10.176)	66.133 (24.503)
Six month Tau (pg/mL)	222.461 (139.839)	171.757 (53.72)
Six month ABeta42 (pg/mL)	499.325 (174.308)	361.563 (89.044)
Six month P tau (pg/mL)	56.003 (23.984)	64.331 (25.766)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Carvedilol, Placebo
	Comments	This analysis compares the change in total Tau between the treatment and placebo group from baseline to 6 months later.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.481
	Comments	[Not Specified]
	Method	Rank sum test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Carvedilol, Placebo
	Comments	This analysis compares the change in Abeta42 between the treatment and placebo group from baseline to 6 months later.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0562
	Comments	[Not Specified]
	Method	Rank sum test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Carvedilol, Placebo
	Comments	This analysis compares the change in p-tau between the treatment and placebo group from baseline to 6 months later.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.314
	Comments	[Not Specified]
	Method	Rank sum test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Carvedilol, Placebo
	Comments	This analysis compares the change in oligomeric Abeta between the treatment and placebo group from baseline to 6 months later.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.438
	Comments	[Not Specified]
	Method	Rank sum test
	Comments	[Not Specified]

3. Secondary Outcome

Title	Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers
Description	The investigators will measure CSF Abeta oligomer levels before and after 6 months randomized placebo-controlled double-blind treatment with carvedilol at a target dose of 25 mg daily, comparing the change in levels in 6 AD participants taking carvedilol vs. 10 AD participants taking placebo. These 16 participants had both baseline and 6 month CSF collected (of the entire study population).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carvedilol	Placebo
Arm/Group Description:	Carvedilol is a is a beta-blocker. Beta-blockers are generally used to reduce the workload on the heart and help it to beat more regularly. Carvedilol: target dose of 25 mg daily which is half the maximum dose used in clinical practice	Non active substance Placebo: a pill that will look like the active drug but will not contain any carvedilol
Overall Number of Participants Analyzed	6	10
Mean (Standard Deviation); Unit of Measure: ng/mL
Baseline Oligomeric ABeta (ng/mL)	3.83 (3.314)	0.129 (0.034)
Six month oligomeric ABeta (ng/mL)	3.895 (3.376)	0.117 (0.101)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	Adverse Events are presented without regard to the specific Adverse Event Term.
Arm/Group Title	Carvedilol		Placebo
Arm/Group Description	Carvedilol is a is a beta-blocker. Beta-blockers are generally used to reduce the workload on the heart and help it to beat more regularly. Carvedilol: target dose of 25 mg daily which is half the maximum dose used in clinical practice		Non active substance Placebo: a pill that will look like the active drug but will not contain any carvedilol
All-Cause Mortality
	Carvedilol		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Carvedilol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/14 (14.29%)		1/15 (6.67%)
Blood and lymphatic system disorders
HEME	1/14 (7.14%)	1	0/15 (0.00%)	0
Gastrointestinal disorders
GI	0/14 (0.00%)	0	1/15 (6.67%)	1
Nervous system disorders
Neurologic	1/14 (7.14%)	1	0/15 (0.00%)	0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Carvedilol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/14 (85.71%)		12/15 (80.00%)
Blood and lymphatic system disorders
HEME	1/14 (7.14%)	1	1/15 (6.67%)	1
Cardiac disorders
Cardiac	10/14 (71.43%)	10	10/15 (66.67%)	10
Gastrointestinal disorders
GI	2/14 (14.29%)	2	3/15 (20.00%)	3
Immune system disorders
Oncology	1/14 (7.14%)	1	0/15 (0.00%)	0
Infections and infestations
Infectious disease	1/14 (7.14%)	1	1/15 (6.67%)	1
Musculoskeletal and connective tissue disorders
Arthritis	0/14 (0.00%)	0	4/15 (26.67%)	4
Nervous system disorders
Systemic	2/14 (14.29%)	2	4/15 (26.67%)	4
Neurologic	2/14 (14.29%)	2	2/15 (13.33%)	2
Psychiatric disorders
Psychiatric	1/14 (7.14%)	1	5/15 (33.33%)	5
Skin and subcutaneous tissue disorders
Dermatologic	0/14 (0.00%)	0	1/15 (6.67%)	1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

Results Point of Contact

• Name/Title: Paul Rosenberg, MD
• Organization: Johns Hopkins University
• Phone: 410-550-9883
• EMail: prosenb9@jhmi.edu

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT01354444
• Other Study ID Numbers: NA_00035546
• First Submitted: May 9, 2011
• First Posted: May 16, 2011
• Results First Submitted: October 26, 2017
• Results First Posted: February 6, 2018
• Last Update Posted: February 6, 2018