Bexarotene Amyloid Treatment for Alzheimer's Disease (BEAT-AD)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
The Cleveland Clinic
ClinicalTrials.gov Identifier:
NCT01782742
First received: January 29, 2013
Last updated: February 10, 2016
Last verified: February 2016
  Purpose

Retinoid X receptors (RXR) are nuclear receptors that have been linked to numerous metabolic pathways relevant to Alzheimer's disease (AD) and Aβ (harmful protein) production and removal. The study drug "bexarotene" is an FDA approved anti-cancer agent but is not approved for use in Alzheimer's disease. Bexarotene acts as an RXR agonist that has reduced Aβ (harmful protein) in the brain in experimental models of Alzheimer's disease.

This study aims to determine the safety and effect on abnormal proteins found in the brain (based on brain scans) of 300 mg of "bexarotene" administered for one month compared to placebo (inactive agent).


Condition Intervention Phase
Alzheimer's Disease
Drug: Bexarotene
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Double Blind Placebo Controlled Randomized Study to Evaluate the Efficacy and Safety of Bexarotene in Patients With Mild to Moderate Alzheimer's Disease

Resource links provided by NLM:


Further study details as provided by The Cleveland Clinic:

Primary Outcome Measures:
  • Drug-Placebo Difference in Change From Baseline to Week 4 in the Composite Amyloid Burden of the Brain [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    The primary study endpoint for all subjects is the change from baseline to Week 4 in amyloid burden as measured by standard uptake units regional (SUVr) on amyloid brain imaging obtained through 18F-AV-45 PET

  • Primary Outcome by Genotype (ALL SUBJECTS) [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (E-4 carriers compared to E-4 non-carriers)

  • Primary Outcome by Genotype (NON ApoE4 CARRIERS) [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    Measures changes from baseline on treatment compared to placebo at week 4 on composite and regional Beta Amyloid burden according to ApoE genotype (NON ApoE4 CARRIERS)

  • Primary Outcome by Genotype (ApoE4 CARRIERS) [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (E-4 carriers)

  • Primary Outcome by Genotype (HETEROZYGOTE ApoE4 CARRIERS) [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (HETEROZYGOTE ApoE4 CARRIERS)

  • Primary Outcome by Genotype (HOMOZYGOTE ApoE4 CARRIERS) [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]

    This measures the change from baseline on treatment compared to placebo at week 4 on composite and regional beta amyloid burden according to ApoE genotype (HOMOZYGOTE ApoE4 CARRIERS)

    There are no homozygote ApoE4 carriers on the placebo arm, therefore no data can be presented on this arm.



Secondary Outcome Measures:
  • Change in MMSE Score in ALL Subjects From Baseline to Week 4 [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    The MMSE evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two overlapping pentagons. A lower score indicates more cognitive impairment. The lowest score that any particular person can get is 0 and the highest score is 30.

  • Change in ADAS-Cog Score in ALL Subjects From Baseline to Week 4 [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    The ADAS-Cog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates more impairment. Scores from the original portion of the test range from 0 (best) to 85 (worse). A positive change indicates cognitive worsening.

  • Change in the Global Clinical Dementia Rating Score in ALL Subjects From Baseline to Week 4 [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    The CDR is a clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively). Higher score means more severe dementia rating. The score is based on interviews with the participant and study partner, using a structured interview that assesses six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.

  • Change in NPI Scores in ALL Subjects From Baseline to Week 4 [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    The NPI is a well validated, reliable, multi-item instrument to assess psychopathology in AD based on interview with the study partner. The NPI evaluates both the frequency and severity of 10 neuropsychiatric disturbances. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously) as well as severity (1=mild, 2=moderate, 3=severe). The overall score and the score for each subscale are the product of severity and frequency. Overall score range from 0 meaning no disturbance to 144 meaning severe disturbance

  • Change in the Activities of Daily Living (ADCS-ADL) Score in ALL Subjects From Baseline to Week 4 [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    The ADCS-ADL is an activities-of-daily-living inventory developed by the ADCS to assess functional performance in participants with AD (Galasko et al., 1997). Using a structured interview format, study partners are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. Overall score range from 0 meaning fully independent to 78 meaning fully dependent on assistance for activities of daily living

  • Secondary Outcome Measuring Serum Biomarker Outcome Level Changes From Baseline to Week 4 in Beta amyloid1-40 and Beta amyloid1-42 (ALL SUBJECTS) [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    Change from baseline to week 4 in beta amyloid1-40 and beta amyloid1-42 serum levels comprised in secondary biomarker outcomes

  • Serum Biomarker Outcome Level Changes From Baseline to Week 4 in Beta amyloid1-40 and Beta amyloid1-42 (Non ApoE4 Carriers) [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    Change from baseline to week 4 in beta amyloid1-40 and beta amyloid1-42 serum levels comprised in secondary biomarker outcomes (non ApoE4 carriers)

  • Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in All Subjects [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    This measures the change in the ratio of Beta Amyloid 42 to Beta Amyloid 40 from baseline to week 4 in all subjects

  • Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in Non ApoE4 Carriers [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]
    This measures the change in the ratio of Beta Amyloid 42 to Beta Amyloid 40 from baseline to week 4 in non ApoE4 Carriers


Enrollment: 20
Study Start Date: February 2013
Study Completion Date: December 2014
Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Bexarotene treatment Arm

75 mg of Bexarotene BID for week 1, then increasing to 150 mg BID for weeks 2 to 4.

Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks)

Drug: Bexarotene
Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo
Other Name: Targretin
Placebo Comparator: Placebo

1 placebo capsule BID for week 1, then increasing to 2 placebo capsules BID for weeks 2 to 4.

Weeks 5 to 8 is Open-label phase (150 mg BID for 4 weeks)

Drug: Placebo

  Eligibility

Ages Eligible for Study:   50 Years to 90 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males or females 50 to 90 of age inclusive.
  • Diagnosis of probable AD according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria.
  • Willing and able to provide informed consent by either the subject or subject's legal representative.
  • Willing and able to comply with study visits, treatment plan, laboratory tests, brain imaging and other procedures.
  • Subjects must have a positive 18f-AV-45 PET scan as determined by a qualified rater.
  • Mini-Mental State Examinations (MMSE) score between 10-20 inclusive.
  • Must have a study partner who is able and willing to comply with all required study procedures.
  • Females must be postmenopausal.
  • Have at least eight years of education and should have previously (in pre-AD condition) been capable of reading, writing, and communicating effectively with others in English.
  • If receiving therapy with a cholinesterase inhibitor and/or memantine, the dose of these agents has been stable for at least 4 weeks prior to randomization
  • Normal laboratory findings at baseline including CBC, chemistry panel, serum lipids, liver functions, TSH, and vitamin B12.
  • Must consent to ApoE genotyping

Exclusion Criteria:

  • Any clinically relevant neurological disorder capable of producing a dementia syndrome including Parkinson's disease, stroke, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and others.
  • 4 or more micro-hemorrhages (amyloid-related imaging abnormalities - hemorrhage type (ARIA-H) on baseline MRI or any evidence of amyloid-related imaging abnormalities - effusion type (ARIA-E) (Sperling et al, 2011).
  • History of malignancy within the past five years with the exception of basal cell or squamous cell cancer, in-situ cervical cancer, or localized prostate cancer.
  • History of seizure in the past three years prior to randomization
  • Any contraindication of having brain MRI
  • Any contraindication of having PET (inability to lie flat and still for the duration of the scan, intolerance to previous PET such as hypersensitivity reaction to PET ligand or imaging agent)
  • The subject has any unstable medical illness including hypertension, congestive heart failure, chronic obstructive pulmonary disease, renal failure, liver failure or other organ compromise.
  • Other clinically important abnormality on vital signs, physical examination, neurologic examination, laboratory results, or electrocardiogram (ECG) examination (e.g. Atrial fibrillation) that could compromise the study or be detrimental to the subject.
  • The subject has received bexarotene previously.
  • The subject has an allergy to bexarotene.
  • Has had a PET scan in the past 12 months.
  • Has had radiotherapy in the past year.
  • Have participated in an investigational drug or device study within 30 days prior to Visit 2.
  • Have been treated with immunomodulators to treat AD (vaccines, antibodies etc) within 6 months prior to visit 2
  • Unable to swallow uncrushed oral medication in capsule form
  • Have any condition or reason that, in the opinion of the investigator, which could interfere with the ability of the patients to participate or complete the trials, or places the patient at undue risk or complicates the interpretation of safety or efficacy data.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01782742

Locations
United States, Nevada
Cleveland Clinic Lou Ruvo Center for Brain Health
Las Vegas, Nevada, United States, 89106
Sponsors and Collaborators
The Cleveland Clinic
Investigators
Principal Investigator: Jeffrey L Cummings, MD, ScD The Cleveland Clinic
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT01782742     History of Changes
Other Study ID Numbers: CCF-IRB 12-783 
Study First Received: January 29, 2013
Results First Received: February 10, 2016
Last Updated: February 10, 2016
Health Authority: United States: Institutional Review Board

Keywords provided by The Cleveland Clinic:
Mild to Moderate Alzheimer's Disease

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Bexarotene
Anticarcinogenic Agents
Protective Agents
Physiological Effects of Drugs
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 27, 2016