A Phase Ib Multiple Ascending Dose Study of the Safety, Tolerability, and CNS Availability of AZD0530 in Alzheimer's Disease
Overview
- Phase
- Phase 1
- Intervention
- saracatinib
- Conditions
- Alzheimer's Disease
- Sponsor
- Stephen M. Strittmatter
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Number of Participants with Adverse Events on AZD0530
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
Alzheimer's disease is a devastating neurodegenerative disorder, for which there is currently no effective treatment to slow or halt progression. Beta amyloid peptide accumulates in the brains of those with Alzheimer's, and is thought to play a major role in triggering the dementia. The investigators recently characterized a molecular pathway by which ß-amyloid damages neurons, and showed that the protein termed Fyn kinase is crucial. Our data suggest that blocking Fyn will have a significant therapeutic benefit for Alzheimer's. Astra Zeneca has developed a blocker of Fyn and related kinases (AZD0530) for the treatment of cancer. Chronic AZD0530 administration is well tolerated in humans, and the investigators propose to test its potential as a novel Alzheimer's disease modifying therapy. This study will assess the safety and tolerability of AZD0530 in patients with Alzheimer's disease.
Investigators
Stephen M. Strittmatter
Professor of Neurology and Neurobiology
Yale University
Eligibility Criteria
Inclusion Criteria
- •NIA-Alzheimer's Association core clinical criteria for probable AD
- •Age between 50-90 (inclusive).
- •MMSE score between 16 and 26 (inclusive)
- •Clinical Dementia Rating = 0.5, 1.0, or 2
- •Stability of permitted medications for 4 weeks. In particular, subjects may:
- •Take stable doses of antidepressants (if they are not currently depressed or do not have a history of major depression within the past 1 year).
- •Washout from psychoactive medication for at least 4 weeks prior to screening.
- •Cholinesterase inhibitors are allowable if stable for 12 weeks prior to screen.
- •Geriatric Depression Scale less than
- •Study partner is available who has frequent contact with the subject (e.g. an average of 8 hours per week or more), and can accompany the subject to all clinic visits for the duration of the protocol.
Exclusion Criteria
- •Any significant neurologic disease other than AD, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities
- •Screening/baseline MRI scan with evidence of infection, infarction, or other focal lesions. Subjects with multiple lacunes or lacunes in a critical memory structure are excluded.
- •Subjects that have any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker will be excluded from the study.
- •Major depression, bipolar disorder as described in DSM-IV within the past 1 year. Psychotic features, agitation or behavioral problems within 3 months, which could lead to difficulty complying with the protocol.
- •History of schizophrenia (DSM IV criteria).
- •History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).
- •Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol.
- •Clinically significant abnormalities in B12 or TFTs that might interfere with the study.
- •Residence in skilled nursing facility.
- •Current use (within 30 days of screening) of specific psychoactive medications (e.g., typical neuroleptics, narcotic analgesics, antiparkinsonian medications, systemic corticosteroids, or medications with significant central anticholinergic activity, etc.). Current use of warfarin.
Arms & Interventions
Saracatinib group 3
Group 3 will receive saracatinib at a dose determined by the response to 50mg P.O. daily, as well as dose given to group 2. Duration is 4 weeks.
Intervention: saracatinib
Saracatinib group 1
This group will receive AZD0530 (saracatinib) experimental oral drug , once daily, for a duration of 4 weeks. Dosage is 50mg per day.
Intervention: saracatinib
Saracatinib group 2
Group 2 will receive saracatinib at a daily oral dose determined by the response to 50mg P.O. daily. Duration is 4 weeks.
Intervention: saracatinib
Placebo group 1-3
Subjects receiving saracatinib in groups 1-3 will be compared to subjects receiving daily, oral, placebo drug.
Intervention: Placebo
Outcomes
Primary Outcomes
Number of Participants with Adverse Events on AZD0530
Time Frame: up to 4 weeks
Patients will be followed closely for any adverse events. These include laboratory measurements, such as complete blood cell counts, basic metabolic panel, including renal function and electrolyte levels, coagulations factors, and liver function tests. These measures will be assessed weekly. Patients will have cognitive testing weekly, to ensure the absence of a prominent decline in function while on study drug. General daily function will be assessed, and any clinical symptoms, such as dizziness, headache or other symptoms will be addressed. All measures will be compared to baseline testing before drug therapy is started.
CNS availability of AZD0530 after oral dosing
Time Frame: 4 weeks
Cerebrospinal fluid will be obtained at the end of the study to measure drug level. CSF will be obtained by a lumbar puncture.
Secondary Outcomes
- Effects of AZD0530 on cognitive function in patients with Alzheimer's disease(4 weeks)
- Effect of AZD0530 on brain glucose metabolism in patients with Alzheimer's disease(4 weeks)