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Multi-Center Development of a Novel Diagnostic Test for Alzheimer's Disease (DTAD)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03560960
Recruitment Status : Recruiting
First Posted : June 19, 2018
Last Update Posted : December 28, 2022
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Boston University

Study Description
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Brief Summary:

In this multi-center study, the investigators plan to develop a simple blood-based test for early detection of Alzheimer's disease (AD). The test is based on a single injection of Pramlintide, an amylin analogue and FDA-approved drug currently used for treatment of diabetes. The investigative team has provided evidence in humans with full-blown AD and AD-relevant mouse models that a single injection of Pramlintide transiently renders the blood brain barrier (BBB) more permeable to Amyloidbeta (Aß) peptides, allowing their efflux from the brain compartment into the blood. This Aß efflux causes a corresponding transient elevation of blood levels of Aß, the magnitude of which the applicants believe is proportional to the brain amyloid load as determined by AV-45 PET. The measured difference in the level of plasma Aß taken just before and a short time after injection should reveal the magnitude of the transient increase in blood Aß levels. Supportive preliminary data comes from later stage (full-blown) AD patients with more in-depth background studies in Tg2576 and 5X Familial Alzheimer's Disease (FAD) mouse models. If successful for use as an early AD (i.e., at the Mild Cognitive Impairment [MCI] stage) biomarker, this could be a game-changer for both early AD diagnostics and clinical trials aimed at identifying and testing the efficacy of drugs useful for treatment of AD at early stages. If Pramlintide is effective in releasing mobile pools of Aß from the brain into the blood, this could also have some therapeutic potential, with the goal of reducing brain amyloid load.

Three groups of particpants will be studied: 1) amnestic MCI with or without positive AD imaging pathology, 2) probable AD with positive imaging AD pathology, and 3) controls who have normal cognition and do not have memory complaints.


Condition or disease Intervention/treatment Phase
Alzheimer Disease Mild Cognitive Impairment Drug: Pramlintide challenge test Early Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Multi-Center Development of a Novel Diagnostic Test for Alzheimer's Disease
Actual Study Start Date : February 4, 2020
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Probable AD
Participants with probable AD with positive imaging AD pathology will receive the pramlintide challenge test.
 Drug: Pramlintide challenge test
Enrolled subjects will have a pre-trial blood draw (3 ml) and will be placed with an IV needle for future blood draws. Pramlintide will be subcutaneously injected in the abdominal area. For each arm the participants will be randomized so that half will be given a dose of 0.8 mcg/kg and the other half of the arm a dose of 1.6 mcg/kg. Blood will be drawn before and at 5, 30, 60, and 180 min after injection. Vital signs and blood glucose will also be checked at these time points. Thirty minutes after the injection, subjects will be offered a standard meal. Subjects will have a final check of vital signs and blood glucose approximately 15 min before discharge.
Other Name: Symlin
Active Comparator: Amnestic MCI
Participants with amnestic MCI with or without positive AD imaging pathology will receive the pramlintide challenge test.
 Drug: Pramlintide challenge test
Enrolled subjects will have a pre-trial blood draw (3 ml) and will be placed with an IV needle for future blood draws. Pramlintide will be subcutaneously injected in the abdominal area. For each arm the participants will be randomized so that half will be given a dose of 0.8 mcg/kg and the other half of the arm a dose of 1.6 mcg/kg. Blood will be drawn before and at 5, 30, 60, and 180 min after injection. Vital signs and blood glucose will also be checked at these time points. Thirty minutes after the injection, subjects will be offered a standard meal. Subjects will have a final check of vital signs and blood glucose approximately 15 min before discharge.
Other Name: Symlin
Active Comparator: Control- Normal Cognition
Participants with normal cognition without any memory complaints will receive the pramlintide challenge test.
 Drug: Pramlintide challenge test
Enrolled subjects will have a pre-trial blood draw (3 ml) and will be placed with an IV needle for future blood draws. Pramlintide will be subcutaneously injected in the abdominal area. For each arm the participants will be randomized so that half will be given a dose of 0.8 mcg/kg and the other half of the arm a dose of 1.6 mcg/kg. Blood will be drawn before and at 5, 30, 60, and 180 min after injection. Vital signs and blood glucose will also be checked at these time points. Thirty minutes after the injection, subjects will be offered a standard meal. Subjects will have a final check of vital signs and blood glucose approximately 15 min before discharge.
Other Name: Symlin


Outcome Measures
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Primary Outcome Measures :
  1. Plasma Aβ and t-tau changes [ Time Frame: 5, 30, 60, and 180 min after challenge test ]
    Plasma Aβ1-40 and Aβ1-42 data will be analyzed. For each peptide, the mean ± SD, median, 25%, 75%, and range

  2. Plasma inflammatory changes [ Time Frame: 5, 30, 60, and 180 min after challenge test ]
    Changes in proinflammatory-related biomarkers: particularly the IL-1β/IL-1Ra pathway, as well as GM-CSF, G-CSF, Trem2, CD36, and CD163, CD68 will be measured applying high-density multiplex ELISA assays (RayBiotech, Norcross, GA)

  3. Plasma metabolic changes in blood [ Time Frame: 5, 30, 60, and 180 min after a pramlintide challenge test ]
    Changes in 2. Metabolism biomarkers associated with amylin: leptin, GLP-1, RBP4, Insulin R, ApoE, and ApoJwill be measured applying high-density multiplex ELISA assays (RayBiotech, Norcross, GA)


Secondary Outcome Measures :
  1. Change in MMSE [ Time Frame: baseline, 12 and 24 months post challenge ]
    MMSE range is from 1-30, we expect a positive challenge test will have a decrease of MMSE

  2. Change in CDR [ Time Frame: baseline, 12 and 24 months post challenge ]
    CDR range is from 0-3, we expect a positive challenge test for increased CDR score

  3. Change in NAB [ Time Frame: baseline, 12 and 24 months post challenge ]
    We expect NAB to be decreased

  4. Change in WMS-III Logical Memory [ Time Frame: baseline, 12 and 24 months post challenge ]
    WMS-III range is from 0-25, we expect a decrease in WMS-III Logical memory

  5. Change in CLOX paradigm [ Time Frame: baseline, 12 and 24 months post challenge ]
    CLOX paradigm range is from 0-3, we expect a decrease in this paradigm

  6. Change in Trailmaking Test Part B [ Time Frame: baseline, 12 and 24 months post challenge ]
    Trailmaking Test Part B range is from 0-300 seconds, we expect an increase in this test

  7. Change in Controlled Oral Word Association Test [ Time Frame: baseline, 12 and 24 months post challenge ]
    Controlled Oral Word Association Test has no range, we expect this to be decreased


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Current research subjects at the BU ADC, VA BHS, or IU ADC
  • A consensus diagnosis of probable AD, amnestic MCI, or control
  • BMI of 20-35
  • Probable AD subjects must be confirmed for positive AD pathology in the CNS
  • Probable AD subjects must have a designated research proxy signed before they became demented.

Exclusion Criteria:

  • Diabetes mellitus
  • Gastroparesis
  • Use of insulin, pramlintide, other injectable anti-hyperglycemic agents, such as glucagon like peptide-1 (GLP-1), or oral anti-diabetic products
  • Unexplained hypoglycemia (glucose ≤ 60 mg/dL) or hyperglycemia (glucose ≥ 126 mg/dL) pre-injection
  • History of stroke
  • Seizures or use of anti-seizure medications
  • History of brain injury and loss of consciousness
  • Diagnosed cerebral amyloid angiopathy (CAA)
  • Infection within 1 month
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03560960


Contacts
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Contact: Wendy Qiu, MD PhD (617) 358-1886 wqiu67@bu.edu
Contact: Indira Swetha Itchapurapu, MPH BDS 617-358-1886 swetha@bu.edu

Locations
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United States, Indiana
Indiana University Alzheimer Disease Center Enrolling by invitation
Indianapolis, Indiana, United States, 46202
United States, Massachusetts
BU Alzheimer Disease Center Recruiting
Boston, Massachusetts, United States, 02118
Contact: Wendy Qiu, MD PhD    617-638-4336    wqiu67@bu.edu   
Memory Center VA Boston Healthcare Enrolling by invitation
Jamaica Plain, Massachusetts, United States, 02130
Sponsors and Collaborators
Boston University
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Wendy Qiu, MD PhD Boston Medical Center and BUSM
More Information
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Responsible Party: Boston University
ClinicalTrials.gov Identifier: NCT03560960    
Other Study ID Numbers: H-37432
1R01AG059424-01 ( U.S. NIH Grant/Contract )
First Posted: June 19, 2018    Key Record Dates
Last Update Posted: December 28, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Boston University:
Early AD diagnosis
Pramlintide challenge test
Amyloid
Amyloid PET imaging
 CSF Aβ
CSF pTau
Cognitive evaluation
Additional relevant MeSH terms:
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Alzheimer Disease
Cognitive Dysfunction
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
 Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Pramlintide
Hypoglycemic Agents
Physiological Effects of Drugs