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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02167256
Recruitment Status : Completed
First Posted : June 19, 2014
Results First Posted : August 14, 2019
Last Update Posted : August 14, 2019
Sponsor:
Collaborator:
Alzheimer's Therapeutic Research Institute
Information provided by (Responsible Party):
Stephen M. Strittmatter, Yale University

Tracking Information
First Submitted Date  ICMJE June 12, 2014
First Posted Date  ICMJE June 19, 2014
Results First Submitted Date  ICMJE June 19, 2019
Results First Posted Date  ICMJE August 14, 2019
Last Update Posted Date August 14, 2019
Actual Study Start Date  ICMJE December 2014
Actual Primary Completion Date February 27, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 25, 2019)
  • Change in Brain Glucose Uptake Measured Using 18F-FDG PET Imaging [ Time Frame: 12 months ]
    Composite measure of brain glucose uptake using F18-FDG PET in a pre-defined set of brain regions, between baseline and 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. [ Time Frame: 12 months ]
    Assessment of any adverse effects between drug and placebo-treated subjects
Original Primary Outcome Measures  ICMJE
 (submitted: June 16, 2014)
  • The effect of treatment with AZD0530 on 6-month reductions in 18F-FDG PET measurements of the cerebral metabolic rate for glucose (CMRgl) using statistical parametric mapping (SPM) statistical region of in [ Time Frame: 6 months ]
  • Safety and tolerability of treatment with AZD0530 over a 6-month period in subjects with mild AD as assessed by analysis of adverse events, including symptoms, and abnormal findings on physical examinations, neurological examinations, standard laboratory [ Time Frame: 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 25, 2019)
  • The Effect of Treatment With AZD0530 on Cognitive and Behavioral Function [ Time Frame: 12 months ]
    The change in cognitive function between baseline and 12 months will be measured by the following tests:
    1. Alzheimer Disease Assessment Scale - Cognitive 11 (ADAS-cog11). Measures: Cognitive function Maximum score: 70; Minimum score: 0. Higher score equals worse cognitive function
    2. Mini-Mental State Examination (MMSE) Measures: Cognitive Function Maximum score: 30; Minimum score: 0. Higher score equal better cognitive function
    3. 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
    4. Clinical Dementia Rating Sum of Boxes (CDR-SO) Measures: Dementia severity Maximum score: 18; Minimum score: 0. Higher score equals more severe dementia.
  • Percent Change in Brain Volume Before and After Treatment [ Time Frame: 12 months ]
    Change in volume of pre-defined brain regions between baseline and 12 months of treatment.
  • Cerebrospinal Fluid Levels of Total Tau, Phospho-tau (p-Tau), and Amyloid-beta 1-42 (Abeta 1-42) [ Time Frame: 12 months ]
    Measure concentration of Tau and Amyloid-beta 1-42 biomarkers in the cerebrospinal fluid between baseline and 12 months of treatment
  • Change in Brain Glucose Uptake Measured Using 18F-FDG PET Imaging [ Time Frame: 12 months ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2014)
  • The effect of treatment with AZD0530 on cognitive and behavioral function in participants with mild AD. [ Time Frame: 6 months ]
    The change in cognitive deficit will be measured by ADAS-cog, MMSE, ADCS-ADL, and CDR-SO.
  • To assess the effect of treatment with AZD0530 on the rate of brain atrophy using volumetric magnetic resonance imaging (MRI). [ Time Frame: 6 months ]
  • To assess the effect of treatment with AZD0530 on CSF biomarkers of AD (particularly CSF total Tau and CSF pTau). [ Time Frame: 6 months ]
  • To assess the influence of APOE genotype on the effects of treatment with AZD0530. [ Time Frame: 6 months ]
    The results from the primary outcome with FDG-PET will be segregated in this secondary analysis by ApoE genotype.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase IIa Multi-Center Study of 18F-FDG PET, Safety, and Tolerability of AZD0530 in Mild Alzheimer's Disease
Official Title  ICMJE A Phase IIa Multi-Center Study of 18F-FDG PET, Safety, and Tolerability of AZD0530 in Mild Alzheimer's Disease
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Alzheimer's Disease
Intervention  ICMJE
  • Drug: AZD0530 100mg daily
    All patients in experimental group (50%) will be started on 100mg AZD0530 daily
    Other Name: saracatinib
  • Drug: AZD0530 125mg daily
    Patients with plasma drug level <100ng/ml after 2 weeks of 100mg AZD0530 daily will receive 125mg daily of AZD0530.
    Other Name: saracatinib
  • Drug: Placebo
    50% of patients will receive placebo treatment for the duration of the study.
    Other Name: saracatinib
Study Arms  ICMJE
  • Experimental: AZD0530 100mg daily
    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.
    Interventions:
    • Drug: AZD0530 100mg daily
    • Drug: AZD0530 125mg daily
  • Placebo Comparator: AZD0530 Placebo
    50% of patients will receive placebo treatment for the duration of the study,
    Intervention: Drug: Placebo
Publications * 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 Jul 22. doi: 10.1001/jamaneurol.2019.2050. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 1, 2016)
159
Original Estimated Enrollment  ICMJE
 (submitted: June 16, 2014)
152
Actual Study Completion Date  ICMJE February 27, 2018
Actual Primary Completion Date February 27, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 55 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02167256
Other Study ID Numbers  ICMJE 1404013830
4UH3TR000967-02 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Stephen M. Strittmatter, Yale University
Study Sponsor  ICMJE Yale University
Collaborators  ICMJE Alzheimer's Therapeutic Research Institute
Investigators  ICMJE
Study Director: Christopher H van Dyck, MD Yale University
Study Director: Paul Aisen, MD, PhD USC Alzheimer's Therapeutic Research Institute (ATRI)
PRS Account Yale University
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP