Clinical trial NCT02167256: A Phase IIa Multi-Center Study of 18F-FDG PET, Safety, and Tolerability of AZD0530 in Mild Alzheimer's Disease
Official title: A Phase IIa Multi-Center Study of 18F-FDG PET, Safety, and Tolerability of AZD0530 in Mild Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: Alzheimer's Therapeutic Research Institute
First posted: 2014-06-19
Enrollment: 159
Sex: ALL
Minimum age (years): 55
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: AZD0530 is an inhibitor of Src and Abl family kinases1. It has been developed as treatment for malignancies because these kinases play a role in tumor invasion and proliferation. However, the Src family kinases (SFKs) are highly expressed in brain and have major effects on synaptic plasticity2. Moreover, the investigators have recently shown that a specific SFK, namely Fyn, is aberrantly activated by specific conformations of the Amyloid Beta (Aß) peptide from Alzheimer's disease (AD). Genetic deletion of Fyn rescues AD deficits in preclinical models. This clinical trial will test the potential benefit of AZD0530 for Alzheimer's disease modification.


Eligibility criteria: Inclusion Criteria

1. NIA-Alzheimer's Association core clinical criteria for probable AD
2. 18F-Florbetapir scan with evidence of elevated Aβ (based on central review)
3. Age between 55-85 (inclusive)
4. MMSE score between 18 and 26 (inclusive)
5. Stability of permitted medications for 4 weeks. In particular:

   * Stable doses of antidepressants lacking significant anticholinergic side effects (if they are not currently depressed and do not have a history of major depression within the past 1 year)
   * Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to screen
6. Geriatric Depression Scale less than 6 \[Note: a score ≥6 on this screening scale may be permissible, if the subject is examined by a site clinician and judged not to be depressed.\]
7. Study partner is available who has frequent contact with the subject (e.g., average of 10 hours per week or more), and can accompany the subject to most visits to answer questions about the subject
8. Visual and auditory acuity adequate for neuropsychological testing
9. Good general health with no disease expected to interfere with the study
10. Subject is not pregnant, lactating, or of childbearing potential (i.e., women must be two years post-menopausal or surgically sterile)
11. Modified Hachinski less than or equal to 4
12. Completed six grades of education or has a good work history
13. Must speak English or Spanish fluently

Exclusion Criteria

1. 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
2. Screening/baseline MRI scan with evidence of infection, infarction, or other focal lesions or multiple lacunes or lacunes in a critical memory structure
3. Subjects that have any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker
4. Major depression, bipolar disorder as described in DSM-IV within the past 1 year or psychotic features, agitation or behavioral problems within 3 months, which could lead to difficulty complying with the protocol
5. History of schizophrenia (DSM V criteria)
6. History of alcohol or substance abuse or dependence within the past 2 years (DSM V criteria)
7. Clinically significant or unstable medical condition, including uncontrolled hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal, hepatic, endocrine, or other systemic disease in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results, or the subject's ability to participate in the study.
8. Has had a history within the last 5 years of a primary or recurrent malignant disease with the exception of non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate-specific antigen post-treatment
9. Clinically significant abnormalities in B12 or TFTs that might interfere with the study. A low B12 is exclusionary, unless follow-up labs (homocysteine (HC) and methylmalonic acid (MMA)) indicate that it is not physiologically significant.
10. Residence in skilled nursing facility.
11. Use of any excluded medication as described in study protocol
12. Current or recent participation in any procedures involving radioactive agents, including current, past, or anticipated exposure to radiation in the workplace, such that the total radiation dose exposure to the subject in a given year would exceed the limits of annual and total dose commitment set forth in the US Code of Federal Regulations (CFR) Title 21 Section 361.1. This guideline is an effective dose of 5 rem received per year.
13. Neutropenia defined as absolute neutrophils count of \<1,800/microliter
14. Thrombocytopenia defined as platelet count \<120x103/microliter
15. For CSF sub-study participants, a current blood clotting or bleeding disorder, or significantly abnormal PT or PTT at screening
16. Clinically significant abnormalities in screening laboratories, including:

    * Aspartate aminotransferase (AST) \>1.5 times ULN
    * Alanine aminotransferase (ALT) \> 1.5 times ULN
    * Total bilirubin \>1.5 times ULN
    * Serum creatinine \>2.0 times ULN
17. History of interstitial lung disease
18. Patients whom the PI deems to be otherwise ineligible

Primary outcomes:
measure: Change in Brain Glucose Uptake Measured Using 18F-FDG PET Imaging
timeFrame: 12 months
measure: Number of Participants With One or More Serious/Other Adverse Events Subjects With Mild AD as Assessed by Analysis of Adverse Events, Including Symptoms, and Abnormal Findings on Physical and Neurological Examinations, and Standard Labs.
timeFrame: 12 months
Secondary outcomes:
measure: The Effect of Treatment With AZD0530 on Cognitive and Behavioral Function
timeFrame: 12 months
measure: Percent Change in Brain Volume Before and After Treatment
timeFrame: 12 months
measure: Cerebrospinal Fluid Levels of Total Tau, Phospho-tau (p-Tau), and Amyloid-beta 1-42 (Abeta 1-42)
timeFrame: 12 months
measure: Change in Brain Glucose Uptake Measured Using 18F-FDG PET Imaging
timeFrame: 12 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: New Haven
country: United States
facility: Yale Alzheimer's Disease Research Unit
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Miami Beach
country: United States
facility: Wien Center for Clinical Research/Mount Sinai Medical Center
state: Florida
city: Tampa
country: United States
facility: University of South Florida - Health Byrd Alzheimer Institute
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan, Ann Arbor
state: Michigan
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh, Alzheimer's Disease Research Center
state: Pennsylvania
city: Charleston
country: United States
facility: Roper St. Francis Hospital
state: South Carolina
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Vancouver
country: Canada
facility: University of British Columbia, Clinic for AD & Related Disorders
state: British Columbia
Study officials:
affiliation: Yale University
name: Christopher H van Dyck, MD
role: STUDY_DIRECTOR
affiliation: USC Alzheimer's Therapeutic Research Institute (ATRI)
name: Paul Aisen, MD, PhD
role: STUDY_DIRECTOR
References:
citation: van Dyck CH, Nygaard HB, Chen K, Donohue MC, Raman R, Rissman RA, Brewer JB, Koeppe RA, Chow TW, Rafii MS, Gessert D, Choi J, Turner RS, Kaye JA, Gale SA, Reiman EM, Aisen PS, Strittmatter SM. Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol. 2019 Oct 1;76(10):1219-1229. doi: 10.1001/jamaneurol.2019.2050.