Clinical trial NCT01782742: Bexarotene Amyloid Treatment for Alzheimer's Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Keywords: Mild to Moderate Alzheimer's Disease
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
First posted: 2013-02-04
Enrollment: 20
Sex: ALL
Minimum age (years): 50
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility 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.

Primary outcomes:
measure: Drug-Placebo Difference in Change From Baseline to Week 4 in the Composite Amyloid Burden of the Brain
timeFrame: Baseline to Week 4
measure: Primary Outcome by Genotype (ALL SUBJECTS)
timeFrame: Baseline to Week 4
measure: Primary Outcome by Genotype (NON ApoE4 CARRIERS)
timeFrame: Baseline to Week 4
measure: Primary Outcome by Genotype (ApoE4 CARRIERS)
timeFrame: Baseline to Week 4
measure: Primary Outcome by Genotype (HETEROZYGOTE ApoE4 CARRIERS)
timeFrame: Baseline to Week 4
measure: Primary Outcome by Genotype (HOMOZYGOTE ApoE4 CARRIERS)
timeFrame: Baseline to Week 4
Secondary outcomes:
measure: Change in MMSE Score in ALL Subjects From Baseline to Week 4
timeFrame: Baseline to Week 4
measure: Change in ADAS-Cog Score in ALL Subjects From Baseline to Week 4
timeFrame: Baseline to Week 4
measure: Change in the Global Clinical Dementia Rating Score in ALL Subjects From Baseline to Week 4
timeFrame: Baseline to Week 4
measure: Change in NPI Scores in ALL Subjects From Baseline to Week 4
timeFrame: Baseline to Week 4
measure: Change in the Activities of Daily Living (ADCS-ADL) Score in ALL Subjects From Baseline to Week 4
timeFrame: Baseline to Week 4
measure: Secondary Outcome Measuring Serum Biomarker Outcome Level Changes From Baseline to Week 4 in Beta amyloid1-40 and Beta amyloid1-42 (ALL SUBJECTS)
timeFrame: Baseline to Week 4
measure: Serum Biomarker Outcome Level Changes From Baseline to Week 4 in Beta amyloid1-40 and Beta amyloid1-42 (Non ApoE4 Carriers)
timeFrame: Baseline to Week 4
measure: Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in All Subjects
timeFrame: Baseline to Week 4
measure: Change in the Ratio of Beta Amyloid 42 to Beta Amyloid 40 in Non ApoE4 Carriers
timeFrame: Baseline to Week 4
Other outcomes:
Locations:
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health
state: Nevada
Study officials:
affiliation: The Cleveland Clinic
name: Jeffrey L Cummings, MD, ScD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.