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

Tracking Information

• First Submitted Date: May 9, 2011
• First Posted Date: May 16, 2011
• Results First Submitted Date: October 26, 2017
• Results First Posted Date: February 6, 2018
• Last Update Posted Date: February 6, 2018
• Actual Study Start Date: June 2011
• Actual Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 8, 2018)

Hopkins Verbal Learning Test (HVLT) Scores at Baseline, 3, and 6 Months [ Time Frame: 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.

Original Primary Outcome Measures (submitted: May 13, 2011)

To determine whether carvedilol treatment has a beneficial effect on episodic recall [ Time Frame: 6 months ]

We will measure 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, comparing changes in HVLT Immediate and Delayed Recall score in 25 AD participants taking carvedilol vs. 25 AD participants taking placebo.

Current Secondary Outcome Measures (submitted: January 8, 2018)

• Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers [ Time Frame: 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.
• Effect of Carvedilol Treatment in Cerebrospinal Fluid (CSF) Levels of Amyloid-beta Oligomers [ Time Frame: 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).

Original Secondary Outcome Measures (submitted: May 13, 2011)

To determine whether carvedilol treatment is associated with decrease in CSF levels of amyloid-beta oligomers [ Time Frame: 6 months ]

We 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 25 AD participants taking carvedilol vs. 25 AD participants taking placebo.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Trial of Carvedilol in Alzheimer's Disease
• Official Title: Pilot Trial of Carvedilol in 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.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Alzheimer's Disease

Intervention

• Drug: Carvedilol
  target dose of 25 mg daily which is half the maximum dose used in clinical practice
• Drug: Placebo
  a pill that will look like the active drug but will not contain any carvedilol

Study Arms

• Active Comparator: 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.
  Intervention: Drug: Carvedilol
• Placebo Comparator: Placebo
  Non active substance
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 8, 2018): 29
• Original Estimated Enrollment (submitted: May 13, 2011): 50
• Actual Study Completion Date: January 2017
• Actual Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 100 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01354444
• Other Study ID Numbers: NA_00035546
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Johns Hopkins University
• Original Responsible Party: Paul Rosenberg, M.D., Johns Hopkins University School of Medicine
• Current Study Sponsor: Johns Hopkins University
• Original Study Sponsor: Same as current
• Collaborators: Icahn School of Medicine at Mount Sinai

Investigators

• Principal Investigator: Paul B. Rosenberg, M.D.; Johns Hopkins University

• PRS Account: Johns Hopkins University
• Verification Date: January 2018