Bexarotene Amyloid Treatment for Alzheimer's Disease

NCT01782742 | Completed Phase 2 Results DMC

• 1 other identifier: CCF-IRB 12-783
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Alzheimer's Disease

Keywords

Mild to Moderate Alzheimer's Disease

Outcome Measures

Primary Outcomes (6)

• Drug-Placebo Difference in Change From Baseline to Week 4 in the Composite Amyloid Burden of the Brain

  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

  Baseline to Week 4

• Primary Outcome by Genotype (ALL SUBJECTS)

  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)

  Baseline to Week 4

• Primary Outcome by Genotype (NON ApoE4 CARRIERS)

  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)

  Baseline to Week 4

• Primary Outcome by Genotype (ApoE4 CARRIERS)

  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)

  Baseline to Week 4

• Primary Outcome by Genotype (HETEROZYGOTE ApoE4 CARRIERS)

  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)

  Baseline to Week 4

• Primary Outcome by Genotype (HOMOZYGOTE ApoE4 CARRIERS)

  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.

  Baseline to Week 4

Secondary Outcomes (9)

• Change in MMSE Score in ALL Subjects From Baseline to Week 4

  Baseline to Week 4

• Change in ADAS-Cog Score in ALL Subjects From Baseline to Week 4

  Baseline to Week 4

• Change in the Global Clinical Dementia Rating Score in ALL Subjects From Baseline to Week 4

  Baseline to Week 4

• Change in NPI Scores in ALL Subjects From Baseline to Week 4

  Baseline to Week 4

• Change in the Activities of Daily Living (ADCS-ADL) Score in ALL Subjects From Baseline to Week 4

  Baseline to Week 4

Study Arms (2)

Bexarotene treatment Arm

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Bexarotene DRUG

Subjects will be randomized 4:1 to receive 4 weeks of double blind treatment of either Bexarotene or Placebo

Also known as: Targretin

Bexarotene treatment Arm

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 50 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• The Cleveland Clinic: lead

Study Sites (1)

Cleveland Clinic Lou Ruvo Center for Brain Health

Las Vegas, Nevada, 89106, United States

Location

Related Publications (1)

• Cummings JL, Zhong K, Kinney JW, Heaney C, Moll-Tudla J, Joshi A, Pontecorvo M, Devous M, Tang A, Bena J. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease. Alzheimers Res Ther. 2016 Jan 29;8:4. doi: 10.1186/s13195-016-0173-2.

  PMID: 26822146 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Bexarotene

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Limitations and Caveats

Sample size of this trial is small. There was 1 participant withdrawal due to adverse event. Primary outcome measures were completed by all 20 participants as anticipated.

Results Point of Contact

• Title: Jeffrey Cummings, MD, ScD
• Organization: Cleveland Clinic Lou Ruvo Center for Brain Health

cumminj@ccf.org

702.483.6029

Study Officials

• Jeffrey L Cummings, MD, ScD

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2013
• First Posted: February 4, 2013
• Study Start: February 1, 2013
• Primary Completion: August 1, 2014
• Study Completion: December 1, 2014
• Last Updated: February 12, 2016
• Results First Posted: February 12, 2016

Record last verified: 2016-02

Locations

US (1)