A Phase IIa Multi-Center Study of 18F-FDG PET, Safety, and Tolerability of AZD0530 in Mild Alzheimer's Disease

Alzheimer's Disease Clinical Trial

Official title:

A Phase IIa Multi-Center Study of 18F-FDG PET, Safety, and Tolerability of AZD0530 in Mild Alzheimer's Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02167256
• Other study ID #: 1404013830
• Secondary ID: 4UH3TR000967-02
• Status: Completed
• Phase: Phase 2
• Start date: December 2014
• Est. completion date: February 27, 2018

Study information

• Verified date: July 2019
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 159
• Est. completion date: February 27, 2018
• Est. primary completion date: February 27, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years to 85 Years

Eligibility

Inclusion Criteria

1. NIA-Alzheimer's Association core clinical criteria for probable AD

2. 18F-Florbetapir scan with evidence of elevated Aß (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

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

Drug:
• AZD0530 100mg daily
All patients in experimental group (50%) will be started on 100mg AZD0530 daily
• AZD0530 125mg daily
Patients with plasma drug level <100ng/ml after 2 weeks of 100mg AZD0530 daily will receive 125mg daily of AZD0530.
• Placebo
50% of patients will receive placebo treatment for the duration of the study.

Locations

Country	Name	City	State
Canada	University of British Columbia, Clinic for AD & Related Disorders	Vancouver	British Columbia
United States	University of Michigan, Ann Arbor	Ann Arbor	Michigan
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Roper St. Francis Hospital	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	University of Kentucky	Lexington	Kentucky
United States	University of California, Los Angeles	Los Angeles	California
United States	Wien Center for Clinical Research/Mount Sinai Medical Center	Miami Beach	Florida
United States	Yale Alzheimer's Disease Research Unit	New Haven	Connecticut
United States	Mount Sinai School of Medicine	New York	New York
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	University of Pittsburgh, Alzheimer's Disease Research Center	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	University of Rochester Medical Center	Rochester	New York
United States	University of Washington	Seattle	Washington
United States	Banner Sun Health Research Institute	Sun City	Arizona
United States	University of South Florida - Health Byrd Alzheimer Institute	Tampa	Florida
United States	Georgetown University	Washington	District of Columbia
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Yale University	Alzheimer's Therapeutic Research Institute

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Brain Glucose Uptake Measured Using 18F-FDG PET Imaging	Composite measure of brain glucose uptake using F18-FDG PET in a pre-defined set of brain regions, between baseline and 12 months.	12 months
Primary	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.	Assessment of any adverse effects between drug and placebo-treated subjects	12 months
Secondary	The Effect of Treatment With AZD0530 on Cognitive and Behavioral Function	The change in cognitive function between baseline and 12 months will be measured by the following tests: Alzheimer Disease Assessment Scale - Cognitive 11 (ADAS-cog11). Measures: Cognitive function Maximum score: 70; Minimum score: 0. Higher score equals worse cognitive function; Mini-Mental State Examination (MMSE) Measures: Cognitive Function Maximum score: 30; Minimum score: 0. Higher score equal better cognitive function; Alzheimer Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) Measures: Ability to perform routine daily activities Maximum score: 78; Minimum score: 0. Higher score equals better ability to perform activities of daily living; Clinical Dementia Rating Sum of Boxes (CDR-SO) Measures: Dementia severity Maximum score: 18; Minimum score: 0. Higher score equals more severe dementia.	12 months
Secondary	Percent Change in Brain Volume Before and After Treatment	Change in volume of pre-defined brain regions between baseline and 12 months of treatment.	12 months
Secondary	Cerebrospinal Fluid Levels of Total Tau, Phospho-tau (p-Tau), and Amyloid-beta 1-42 (Abeta 1-42)	Measure concentration of Tau and Amyloid-beta 1-42 biomarkers in the cerebrospinal fluid between baseline and 12 months of treatment	12 months
Secondary	Change in Brain Glucose Uptake Measured Using 18F-FDG PET Imaging	The results from the primary outcome with brain FDG-PET imaging was analyzed by ApoE genotype. Composite measure of brain glucose uptake using F18-FDG PET in a pre-defined set of brain regions, between baseline and 12 months.	12 months