Safety and Tolerability of AZD0530 (Saracatinib) in Alzheimer's Disease

NCT01864655 | Completed Phase 1 DMC

• 3 other identifiers: 13030116641UH2TR000967-011R01NS084911-01
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Alzheimer's Disease

Outcome Measures

Primary Outcomes (2)

• Number of Participants with Adverse Events on AZD0530

  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.

  up to 4 weeks

• CNS availability of AZD0530 after oral dosing

  Cerebrospinal fluid will be obtained at the end of the study to measure drug level. CSF will be obtained by a lumbar puncture.

  4 weeks

Secondary Outcomes (2)

• 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

Study Arms (4)

Saracatinib group 1

EXPERIMENTAL

This group will receive AZD0530 (saracatinib) experimental oral drug , once daily, for a duration of 4 weeks. Dosage is 50mg per day.

Drug: saracatinib

Saracatinib group 2

EXPERIMENTAL

Group 2 will receive saracatinib at a daily oral dose determined by the response to 50mg P.O. daily. Duration is 4 weeks.

Drug: saracatinib

Saracatinib group 3

EXPERIMENTAL

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.

Drug: saracatinib

Placebo group 1-3

PLACEBO COMPARATOR

Subjects receiving saracatinib in groups 1-3 will be compared to subjects receiving daily, oral, placebo drug.

Drug: Placebo

Interventions

saracatinib DRUG

oral drug given to experimental group

Also known as: AZD0530

Saracatinib group 1; Saracatinib group 2; Saracatinib group 3

Placebo DRUG

Placebo given to placebo group

Placebo group 1-3

Eligibility Criteria

• Age: 50 Years - 90 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 2. Age between 50-90 (inclusive). 3. MMSE score between 16 and 26 (inclusive) 4. Clinical Dementia Rating = 0.5, 1.0, or 2 5. 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. 6. Geriatric Depression Scale less than 6. 7. 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.
• \. Visual and auditory acuity adequate for neuropsychological testing. 9. Good general health with no diseases 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).
• \. Modified Hachinski less than or equal to 4. 12. Completed six grades of education or has a good work history (sufficient to exclude mental retardation).
• \. 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. 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.
• Investigational amyloid lowering therapies are prohibited two months prior to screening and for the duration of the trial. Other investigational agents are prohibited one month prior to screening and for the duration of the trial.
• 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.
• \. 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 patient at risk because of participation in the study, or influence the results, or the patient's ability to participate in the study.
• \. Clinically significant abnormalities in B12 or TFTs that might interfere with the study.
• \. Residence in skilled nursing facility. 10. 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.

Sponsors & Collaborators

• Stephen M. Strittmatter: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

Yale Alzheimer's Disease Research Unit

New Haven, Connecticut, 06510, United States

Location

Related Publications (1)

• Nygaard HB, Wagner AF, Bowen GS, Good SP, MacAvoy MG, Strittmatter KA, Kaufman AC, Rosenberg BJ, Sekine-Konno T, Varma P, Chen K, Koleske AJ, Reiman EM, Strittmatter SM, van Dyck CH. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease. Alzheimers Res Ther. 2015 Apr 14;7(1):35. doi: 10.1186/s13195-015-0119-0. eCollection 2015.

  PMID: 25874001 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

Study Officials

• Haakon B Nygaard, MD, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

• Christopher van Dyck, MD

  Yale University

  PRINCIPAL INVESTIGATOR

• Stephen M Strittmatter, MD, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Neurology and Neurobiology

Study Record Dates

• First Submitted: May 8, 2013
• First Posted: May 29, 2013
• Study Start: July 1, 2013
• Primary Completion: March 1, 2014
• Study Completion: November 6, 2014
• Last Updated: April 23, 2021

Record last verified: 2021-04

Locations

US (1)