Clinical trial NCT01560585: Open Label Study of Isotretinoin in Mild to Moderate Alzheimer's Disease
Official title: Open Label Study of Isotretinoin in Mild to Moderate Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Alzheimer's Disease
Keywords: Isotretinoin
Alzheimer's disease
Dementia
Retinoid
Lead sponsor: University Hospitals Cleveland Medical Center
Sponsor class: OTHER
First posted: 2012-03-22
Enrollment: 3
Sex: ALL
Minimum age (years): 50
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an open label study of isotretinoin, a medication which is FDA approved for treatment of other conditions to determine initial safety in Alzheimer's disease.

Detailed description: Retinoids have some relevant characteristics that could be considered useful in treating AlZheimer's disease. These include anti-inflammatory properties, possible anti-amyloid formation proeprties and inhibition of cell cycle properties

Eligibility criteria: Inclusion Criteria:

* Probable AD by DSM IV and NINCDS-ADRDA criteria
* Females must be surgically sterile (bilateral tubal ligation, both ovaries removed or hysterectomy) or post-menopausal for at least 2 years.
* \> 50 years of age
* Residing in the community at baseline (includes assisted living facilities, long-term care nursing facilities)
* Mini Mental State Examination at screen of 12-26 (inclusive)
* No medical contraindications to study participation
* Fluent in English at least 8 years of education.
* Supervision available for study medication. Caregiver/study partner to accompany participant to all visits. Study partner must have direct contact with the participant \> 2 days/week
* Able to ingest oral medication.
* Neuroimaging (CT or MRI or PET) consistent with the diagnosis of AD at some time after the onset of the memory decline.
* Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the investigator
* Stable use of cholinesterase inhibitors and memantine is permitted if doses are stable for 3 months prior to enrollment. Dose should be stable throughout the study unless it is clinically necessary to adjust the medication.
* Stable use of anti-depressants is permitted if doses are stable for 3 months prior to enrollment. Dose should be stable throughout the study unless it is clinically necessary to adjust the medication.

Exclusion Criteria:

* Dementia not due to probable Alzheimer's disease
* Pregnancy, breastfeeding. The rationale is that retinoids are teratogenic and are excreted in breast milk.
* History of clinically significant stroke
* Modified Hachinski Ischemia score ≥ 4
* Current evidence or history in past two years of epilepsy, seizure, focal brain lesion, head injury with loss of consciousness or DSM IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, severe alcohol or substance abuse.
* Sensory impairment which would prevent subject from participating in or cooperating with the protocol.
* Use of another investigational agent within two months.
* Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving an investigational new drug including clinically significant or unstable hematologic, hepatic, cardiovascular (including history of ventricular fibrillation or ventricular tachycardia), pulmonary, gastrointestinal, endocrine, metabolic, renal, or other systemic disease or laboratory abnormality. Abnormal liver function test, including AST, ALT, total bilirubin, or prothrombin time. The rationale is that retinoids can be hepatotoxic.
* Participants receiving behavioral medications (including antidepressants, antipsychotics and anxiolytics) must be on stable doses for at least 4 weeks prior to randomization.
* Active neoplastic disease and any medical conditions requiring concurrent immunosuppression.
* Hypertriglyceridemia greater than 500 mg/dL despite statin/fibrate therapy. The rationale is that retinoids can increase lipids, particularly triglyceride and this can lead to pancreatitis.
* Any medical conditions requiring concurrent use of tetracycline, minocycline, or doxycycline. The rationale is due to enhanced risk of increased intracranial pressure.
* Hypersensitivity to retinoids.
* Presence of psychosis or hallucinations at baseline as determined by Neuropsychiatric inventory or Geriatric Depression Scale-short form greater than or equal to five
* Presence of any unstable cardiovascular disease, uncontrolled diabetes, chronic inflammatory or infectious conditions. Retinoids have been associated with chest pain of unclear etiology, increased serum glucose, myelosuppression and increased risk of infection.
* Use of Drugs and supplements such as: Vitamin A supplements beyond 100% RDA, other immunosuppressants (corticosteroids, chemotherapeutic agents, etc.), Warfarin , Fish Oil (DHA)
* Any other disease or medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this clinical trial.

Primary outcomes:
measure: Change From Baseline to Six Month Timepoint in the Score on the Alzheimer's Disease Assessment Scale- Cognitive Subscale
timeFrame: 6 months from baseline
Secondary outcomes:
measure: Number of Adverse Effects
timeFrame: 28 weeks
Other outcomes:
Locations:
city: Beachwood
country: United States
facility: Parkway Medical Building
state: Ohio
Study officials:
affiliation: University Hospitals Cleveland Medical Center
name: Alan J Lerner, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lee HP, Casadesus G, Zhu X, Lee HG, Perry G, Smith MA, Gustaw-Rothenberg K, Lerner A. All-trans retinoic acid as a novel therapeutic strategy for Alzheimer's disease. Expert Rev Neurother. 2009 Nov;9(11):1615-21. doi: 10.1586/ern.09.86.