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

NCT02167256 | Completed Phase 2 Results DMC

• 2 other identifiers: 14040138304UH3TR000967-02
• Study Type: interventional
• Target: 159
• Locations: 2 countries
• Sites: 22

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.

Conditions

Alzheimer's Disease

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (4)

• The Effect of Treatment With AZD0530 on Cognitive and Behavioral Function

  12 months

• Percent Change in Brain Volume Before and After Treatment

  12 months

• Cerebrospinal Fluid Levels of Total Tau, Phospho-tau (p-Tau), and Amyloid-beta 1-42 (Abeta 1-42)

  12 months

• Change in Brain Glucose Uptake Measured Using 18F-FDG PET Imaging

  12 months

Study Arms (2)

AZD0530 100mg daily

EXPERIMENTAL

Patients in the experimental group (50%) will be started on this dose. After 2 weeks, patients with a plasma drug level of \<100ng/ml will receive 125mg AZD0530 daily and remain in the same experimental group as patient receiving 100mg daily.

Drug: AZD0530 100mg daily; Drug: AZD0530 125mg daily

AZD0530 Placebo

PLACEBO COMPARATOR

50% of patients will receive placebo treatment for the duration of the study,

Drug: Placebo

Interventions

AZD0530 100mg daily DRUG

All patients in experimental group (50%) will be started on 100mg AZD0530 daily

Also known as: saracatinib

AZD0530 100mg daily

AZD0530 125mg daily DRUG

Patients with plasma drug level \<100ng/ml after 2 weeks of 100mg AZD0530 daily will receive 125mg daily of AZD0530.

Also known as: saracatinib

AZD0530 100mg daily

Placebo DRUG

50% of patients will receive placebo treatment for the duration of the study.

Also known as: saracatinib

AZD0530 Placebo

Eligibility Criteria

• Age: 55 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• NIA-Alzheimer's Association core clinical criteria for probable AD
• F-Florbetapir scan with evidence of elevated Aβ (based on central review)
• Age between 55-85 (inclusive)
• MMSE score between 18 and 26 (inclusive)
• 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
• Geriatric Depression Scale less than 6 \[Note: a score ≥6 on this screening scale may be permissible, if the subject is examined by a site clinician and judged not to be depressed.\]
• 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
• Visual and auditory acuity adequate for neuropsychological testing
• Good general health with no disease expected to interfere with the study
• Subject is not pregnant, lactating, or of childbearing potential (i.e., women must be two years post-menopausal or surgically sterile)
• Modified Hachinski less than or equal to 4
• Completed six grades of education or has a good work history
• Must speak English or Spanish fluently

You may not qualify if:

• 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 or multiple lacunes or lacunes in a critical memory structure
• Subjects that have any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker
• 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
• History of schizophrenia (DSM V criteria)
• History of alcohol or substance abuse or dependence within the past 2 years (DSM V criteria)
• 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.
• 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
• Residence in skilled nursing facility.
• Use of any excluded medication as described in study protocol
• 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.
• Neutropenia defined as absolute neutrophils count of \<1,800/microliter
• Thrombocytopenia defined as platelet count \<120x103/microliter
• For CSF sub-study participants, a current blood clotting or bleeding disorder, or significantly abnormal PT or PTT at screening
• Clinically significant abnormalities in screening laboratories, including:

Sponsors & Collaborators

• Yale University: lead
• Alzheimer's Therapeutic Research Institute: collaborator

Study Sites (22)

Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

Banner Sun Health Research Institute

Sun City, Arizona, 85351, United States

Location

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

Yale Alzheimer's Disease Research Unit

New Haven, Connecticut, 06510, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20057, United States

Location

Wien Center for Clinical Research/Mount Sinai Medical Center

Miami Beach, Florida, 33140, United States

Location

University of South Florida - Health Byrd Alzheimer Institute

Tampa, Florida, 33613, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Kentucky

Lexington, Kentucky, 40504, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan, Ann Arbor

Ann Arbor, Michigan, 48105-2945, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

University of Rochester Medical Center

Rochester, New York, 14620, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

University of Pittsburgh, Alzheimer's Disease Research Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Roper St. Francis Hospital

Charleston, South Carolina, 29401, United States

Location

University of Washington

Seattle, Washington, 98108, United States

Location

University of British Columbia, Clinic for AD & Related Disorders

Vancouver, British Columbia, V6T 1Z3, Canada

Location

Related Publications (2)

• Donohue MC, Langford O, Insel PS, van Dyck CH, Petersen RC, Craft S, Sethuraman G, Raman R, Aisen PS; Alzheimer's Disease Neuroimaging Initiative. Natural cubic splines for the analysis of Alzheimer's clinical trials. Pharm Stat. 2023 May-Jun;22(3):508-519. doi: 10.1002/pst.2285. Epub 2023 Jan 10.

  PMID: 36627206 DERIVED

• 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.

  PMID: 31329216 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

saracatinib

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Stephen Strittmatter
• Organization: Yale University

stephen.strittmatter@yale.edu

2037854878

Study Officials

• Christopher H van Dyck, MD

  Yale University

  STUDY DIRECTOR

• Paul Aisen, MD, PhD

  USC Alzheimer's Therapeutic Research Institute (ATRI)

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology and Neurobiology

Study Record Dates

• First Submitted: June 12, 2014
• First Posted: June 19, 2014
• Study Start: December 1, 2014
• Primary Completion: February 27, 2018
• Study Completion: February 27, 2018
• Last Updated: August 14, 2019
• Results First Posted: August 14, 2019

Record last verified: 2019-07

Locations

US (21); CA (1)