Alzheimer's Disease
Conditions
Keywords
Memory problems, Alzheimer's Disease
Brief summary
This is a 6-month pilot randomized double-blind placebo-controlled trial of carvedilol, with the primary objective being to determine whether carvedilol treatment is associated with improvement in Alzheimer's Disease (AD) as compared to placebo treatment. Secondary objectives are to monitor changes in cerebrospinal fluid amyloid levels and whether this dose will be safe and well-tolerated in AD patients. Clinical assessments will be performed at baseline, 3 months, and 6 months, while cerebrospinal fluid and blood samples will be obtained at baseline and 6 months.
Detailed description
The purpose of the study is to measure decline in episodic memory in participants with early AD taking carvedilol compared to placebo treatment as evidenced by the Hopkins Verbal Learning Test (HVLT). cerebrospinal fluid levels of Aβ oligomers in early AD, will be measured in participants receiving carvedilol treatment when compared to placebo treatment. Adverse effects will be monitored in participants receiving carvedilol when compared to placebo. To assess adverse events, routine chemistry and hematology studies, vital signs, and electrocardiographic parameters before and after 6 months randomized placebo-controlled double-blind treatment with carvedilol at a target dose of 25 mg daily, comparing 25 early AD participants taking carvedilol vs. 25 early AD participants taking placebo.
Interventions
DRUGCarvedilol
target dose of 25 mg daily which is half the maximum dose used in clinical practice
DRUGPlacebo
a pill that will look like the active drug but will not contain any carvedilol
Sponsors
Icahn School of Medicine at Mount Sinai
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 100 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of AD by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria * Mini-Mental State Exam (MMSE) 16-26. This range corresponds roughly to mild AD as rated by CDR below, and provides a rapid test for efficient screening of potential participants. * Clinical Dementia Rating (CDR) \< 1 (mild dementia). This corresponds with early AD. Participants will be eligible if they have AD diagnosis and CDR of 0.5 or 1.0. The category of CDR 0.5 AD is particularly important to include as these participants are in the earliest stage that can be diagnosed as dementia (as opposed to mild cognitive impairment) and thus are in the earliest clinical stage of AD. * Patients will be allowed to remain on current FDA-approved Alzheimer's treatments including cholinesterase inhibitors and memantine, so long as the dose has been stable for \>= 3 months. These medications lack any notable effects on amyloid synthesis or metabolism and thus there is no reason to exclude them. The rationale behind requiring a stable dose is so that change in the trial can be attributed to the study intervention rather than recent changes of other medications affecting cognition. * Patients will be allowed to remain on antidepressant and antipsychotics medications so long as the dose has been stable for \>= 3 months. The rationale is the same as above. * Knowledgeable informant available for all study visits. This is standard practice in AD research because many standard instruments and questionnaires in this trial require a knowledgeable informant.
Exclusion criteria
* Evidence of non-AD dementias including Huntington's disease, Parkinson's disease, or frontotemporal dementia. 2.Current Diagnostic and Statistical Manual Diploma in Social Medicine (DSM)-IV Axis I diagnoses other than dementia, including major depression, bipolar disorder, schizophrenia, anxiety disorders, alcohol abuse, or other substance abuse. These diagnoses would merit their own treatment plans and changes in these conditions could significantly affect cognitive and functional outcomes, confounding our efforts to study the efficacy of the study intervention. * Any clinically significant medical condition that could interfere with the subject's ability to safely participate in the study or to be followed. * Current use of Beta-blocking agents. * Contraindications to use of Beta-blocking agents, to be determined in consultation with the patient's primary care physician or (if appropriate) cardiologist. * Clinically significant hepatic or renal insufficiency.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | Baseline, 3 months, and 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | 6 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carvedilol 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 | 14 |
| Placebo Non active substance
Placebo: a pill that will look like the active drug but will not contain any carvedilol | 15 |
| Total | 29 |
Baseline characteristics
| Characteristic | Carvedilol | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 9 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 6 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 14 Participants | 25 Participants |
| Sex: Female, Male Female | 10 Participants | 6 Participants | 16 Participants |
| Sex: Female, Male Male | 4 Participants | 9 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 14 | 12 / 15 |
| serious Total, serious adverse events | 2 / 14 | 1 / 15 |
Outcome results
Primary
Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HVLT Score in Placebo Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at 6 months (delayed recall) | 1 Scores on a scale | Standard Deviation 2 |
| HVLT Score in Placebo Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at Baseline (immediate recall) | 13 Scores on a scale | Standard Deviation 4 |
| HVLT Score in Placebo Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at 3 months (immediate recall) | 12 Scores on a scale | Standard Deviation 5 |
| HVLT Score in Placebo Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at 6 months (immediate recall) | 12 Scores on a scale | Standard Deviation 5 |
| HVLT Score in Placebo Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at Baseline (delayed recall) | 1 Scores on a scale | Standard Deviation 2 |
| HVLT Score in Placebo Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at 3 months (delayed recall) | 1 Scores on a scale | Standard Deviation 2 |
| HVLT Score in Treatment Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at 3 months (immediate recall) | 13 Scores on a scale | Standard Deviation 4 |
| HVLT Score in Treatment Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at Baseline (delayed recall) | 1 Scores on a scale | Standard Deviation 1 |
| HVLT Score in Treatment Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at 6 months (delayed recall) | 0 Scores on a scale | Standard Deviation 0 |
| HVLT Score in Treatment Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at 6 months (immediate recall) | 13 Scores on a scale | Standard Deviation 6 |
| HVLT Score in Treatment Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at Baseline (immediate recall) | 12 Scores on a scale | Standard Deviation 6 |
| HVLT Score in Treatment Group | Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months | HVLT score at 3 months (delayed recall) | 1 Scores on a scale | Standard Deviation 2 |
Comparison: This analysis compares immediate recall before and after 6 months between the treatment and placebo group.p-value: 0.56595% CI: [-3.796, 6.761]Regression, Linear
Secondary
Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HVLT Score in Placebo Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Baseline Tau (pg/mL) | 169.476 pg/mL | Standard Deviation 93.931 |
| HVLT Score in Placebo Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Six month P tau (pg/mL) | 56.003 pg/mL | Standard Deviation 23.984 |
| HVLT Score in Placebo Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Baseline ABeta42 (pg/mL) | 396.985 pg/mL | Standard Deviation 212.411 |
| HVLT Score in Placebo Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Baseline P tau (pg/mL) | 42.666 pg/mL | Standard Deviation 10.176 |
| HVLT Score in Placebo Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Six month Tau (pg/mL) | 222.461 pg/mL | Standard Deviation 139.839 |
| HVLT Score in Placebo Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Six month ABeta42 (pg/mL) | 499.325 pg/mL | Standard Deviation 174.308 |
| HVLT Score in Treatment Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Six month Tau (pg/mL) | 171.757 pg/mL | Standard Deviation 53.72 |
| HVLT Score in Treatment Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Baseline Tau (pg/mL) | 169.484 pg/mL | Standard Deviation 48.386 |
| HVLT Score in Treatment Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Six month ABeta42 (pg/mL) | 361.563 pg/mL | Standard Deviation 89.044 |
| HVLT Score in Treatment Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Baseline P tau (pg/mL) | 66.133 pg/mL | Standard Deviation 24.503 |
| HVLT Score in Treatment Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Six month P tau (pg/mL) | 64.331 pg/mL | Standard Deviation 25.766 |
| HVLT Score in Treatment Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Baseline ABeta42 (pg/mL) | 379.406 pg/mL | Standard Deviation 100.892 |
Comparison: This analysis compares the change in total Tau between the treatment and placebo group from baseline to 6 months later.p-value: 0.481Rank sum test
Comparison: This analysis compares the change in Abeta42 between the treatment and placebo group from baseline to 6 months later.p-value: 0.0562Rank sum test
Comparison: This analysis compares the change in p-tau between the treatment and placebo group from baseline to 6 months later.p-value: 0.314Rank sum test
Comparison: This analysis compares the change in oligomeric Abeta between the treatment and placebo group from baseline to 6 months later.p-value: 0.438Rank sum test
Secondary
Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HVLT Score in Placebo Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Baseline Oligomeric ABeta (ng/mL) | 3.83 ng/mL | Standard Deviation 3.314 |
| HVLT Score in Placebo Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Six month oligomeric ABeta (ng/mL) | 3.895 ng/mL | Standard Deviation 3.376 |
| HVLT Score in Treatment Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Baseline Oligomeric ABeta (ng/mL) | 0.129 ng/mL | Standard Deviation 0.034 |
| HVLT Score in Treatment Group | Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers | Six month oligomeric ABeta (ng/mL) | 0.117 ng/mL | Standard Deviation 0.101 |