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Longitudinal Early-onset Alzheimer's Disease Study Protocol (LEADS)

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ClinicalTrials.gov Identifier: NCT03507257
Recruitment Status : Recruiting
First Posted : April 25, 2018
Last Update Posted : June 5, 2018
Sponsor:
Collaborators:
Alzheimer's Therapeutic Research Institute
National Institute on Aging (NIA)
Alzheimer's Association
Information provided by (Responsible Party):
Liana Apostolova, Indiana University School of Medicine

Brief Summary:
The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a non-randomized, natural history, non-treatment study designed to look at disease progression in individuals with early onset Alzheimer's disease (EOAD). Clinical/cognitive, imaging, biomarker, and genetic characteristics will be assessed across two cohorts: (1) individuals with EOAD and (2) cognitively normal (CN) control participants.

Condition or disease Intervention/treatment
Early Onset Alzheimer Disease Alzheimer Disease Mild Cognitive Impairment Drug: Flortaucipir Drug: Florbetaben

Detailed Description:

The LEADS study is a non-randomized, natural history, non-treatment study. Enrolled participants must be 40 - 26 (inclusive) years of age, with MCI due to AD or probable AD (EOAD) or have no significant memory impairment (CN).

Approximately 400 EOAD participants and 100 CN participants will be enrolled at approximately 15 sites in the United States. EOAD participants will take part in the study for 24 months; CN participants will take part in the study for 12 months.

Participants will undergo longitudinal clinical and cognitive assessments, computerized cognitive batteries, biomarker and genetic tests, PET (amyloid and tau) and MRI brain scans, and cerebral spinal fluid (CSF) collection.

The primary objectives of the LEADS study are to:

  • collect longitudinal assessments and biomarker data in individuals with early onset Alzheimer's disease (EOAD) and cognitively normal (CN) controls;
  • to compare baseline and longitudinal cognitive and functional characteristics, between EOAD and CN, and EOAD and Late Onset Alzheimer's Diseases (LOAD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI); and
  • to study the associations of longitudinal clinical and cognitive assessments with multimodal imaging and biofluid markers that capture different elements of the AD pathophysiological cascade

Study Type : Observational
Estimated Enrollment : 500 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Longitudinal Early-onset Alzheimer's Disease Study Protocol
Actual Study Start Date : April 30, 2018
Estimated Primary Completion Date : August 31, 2022
Estimated Study Completion Date : August 31, 2023

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Early Onset Alzheimer's Disease (EOAD)
  • Diagnosis of NIA-AA criteria of MCI due to AD or probable AD dementia
  • Amyloid positive status (florbetaben PET scan with evidence of elevated amyloid as determined by a central read)
  • CDR score ≤ 1.0
  • CDR score ≤ 1.0
  • flortaucipir (18F-AV-1451) PET scanning
Drug: Flortaucipir
All participants will receive a single bolus intravenous injection of approximately 10 mCi (+/- 10%, 20μg mass dose) of flortaucipir (18F-AV-1451). At approximately 75-minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.
Other Name: 18F-AV-1451 (also known as [F-18]T807 or LY3191748)

Drug: Florbetaben
All participants will receive a single bolus intravenous injection of approximately 8 mCi +/- .8mCi of florbetaben (AV-45). At approximately 90-minutes (+/- 10 minutes) post dose, scanning will begin. An approximately 20-minute image acquisition scan will be performed.
Other Name: AV-45, Neuraceq

Cognitively Normal (CN) Controls
  • Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions and activities of daily living
  • Mini-Mental State Exam score between 26-30
  • CDR score = 0
  • flortaucipir (18F-AV-1451) PET scanning
Drug: Flortaucipir
All participants will receive a single bolus intravenous injection of approximately 10 mCi (+/- 10%, 20μg mass dose) of flortaucipir (18F-AV-1451). At approximately 75-minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.
Other Name: 18F-AV-1451 (also known as [F-18]T807 or LY3191748)

Drug: Florbetaben
All participants will receive a single bolus intravenous injection of approximately 8 mCi +/- .8mCi of florbetaben (AV-45). At approximately 90-minutes (+/- 10 minutes) post dose, scanning will begin. An approximately 20-minute image acquisition scan will be performed.
Other Name: AV-45, Neuraceq




Primary Outcome Measures :
  1. Rate of change in cognition as measured by by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog13) [ Time Frame: Month 0, Month 12 and Month 24 (EOAD only) ]
    The ADAS-Cog is an in-person examiner-administered, structured scale that evaluates memory (word recall, word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope) and constructional praxis (copying geometric designs). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions are also obtained.


Secondary Outcome Measures :
  1. Rate of change in cognition as measured by the Clinical Dementia Rating - Sum of Boxes (CDR-SB) [ Time Frame: Month 0, Month 12 and Month 24 (EOAD only) ]
    The CDR is a semi-structured interview of the informant and participant that assesses for impairment in 8 areas of functioning - memory, orientation, judgment and problem solving, community affairs, home and hobbies, personal care, behavior, personality, and language.

  2. Rate of change in cognition as measured by the Clinician Judgment of Symptoms form from the NACC UDS. [ Time Frame: Month 0, Month 12 and Month 24 (EOAD only) ]
    Clinician Judgment of Symptoms form from the NACC UDS is a 23 question form that evaluates cognitive, behavioral and motor syndrome changes over time.

  3. Rate of change in cognition as measured by the Neurological Examination Findings form from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS). [ Time Frame: Month 0, Month 12 and Month 24 (EOAD only) ]
  4. Change in tau deposition as measured by flortaucipir (18F-AV-1451) Positron Emission Tomography (PET) imaging [ Time Frame: Month 0, Month 12 and Month 24 (EOAD only) ]
  5. Change in amyloid deposition as measured by florbetaben using Positron Emission Tomography (PET) imaging [ Time Frame: Month 0, Month 12, Month 24 (EOAD only) ]
  6. Change in brain structure using magnetic resonance imaging (MRI) [ Time Frame: Month 0, Month 12 and Month 24 (EOAD only) ]
  7. Change in cerebral spinal fluid (CSF) biomarkers [ Time Frame: Month 0, Month 12 and Month 24 (EOAD only) ]

Biospecimen Retention:   Samples With DNA
blood, cerebrospinal fluid


Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Early Onset Alzheimer Disease (EOAD) Participants and Cognitively Normal (C) Control Participants
Criteria

Inclusion Criteria (EOAD Cohort Only):

  1. Meets NIA-AA criteria for MCI due to AD or probable AD dementia
  2. Have a global CDR score ≤ 1.0
  3. Have capacity to provide informed consent (IC) or has a legal authorized representative or guardian who provides IC
  4. Amyloid positive status (PET scan with evidence of elevated amyloid)
  5. Age between 40-64 years (inclusive) at the time of consent
  6. Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI
  7. Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure
  8. Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan
  9. Fluent in English

Inclusion Criteria (Cognitively Normal (CN) Cohort Only):

  1. Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living
  2. Have a global CDR score = 0
  3. Have capacity to provide informed consent
  4. Have a Mini-Mental State Exam score between 26-30 (inclusive). Exceptions may be made for participant with less than 8 years of education at the discretion of the Site PI
  5. Age between 40-64 years (inclusive) at the time of consent
  6. Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI
  7. Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure
  8. Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan
  9. Fluent in English

Exclusion Criteria (EOAD and CN Cohorts):

  1. Meets core clinical criteria for non-AD dementia
  2. Two or more first degree relatives with a history of early-onset dementia suggestive of autosomal dominant transmission, unless known pathogenic mutations in APP, PSEN1, PSEN2 have been excluded
  3. Known mutation in an ADAD gene (APP, PSEN1, PSEN2) or other autosomal dominant genes associated with other neurodegenerative disorders
  4. Contraindications to 3T MRI (e.g., claustrophobia, pacemaker, select aneurismal clip, artificial heart valve, select ear implants, select stents incompatible with 3T MRI, metal fragments or foreign objects in the eyes, skin or body, etc.)
  5. Lifetime medical history of a brain disorder other than the disorder causing dementia except for headache (exceptions are allowed at the discretion of the Site PI - e.g., seizure disorder thought to be due to EOAD).
  6. MRI scan with evidence of infection or focal lesions, cortical strokes, multiple lacunes (single lacune is allowable unless it meets criteria for strategic lacune affecting cognition)
  7. Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol (at the discretion of the Site PI)
  8. Medical radiation exposure will be assessed by the study physician. If the candidate participant has had more than one nuclear medicine study in the prior 12 months, study inclusion will require approval from the PET Core
  9. Investigational agents are prohibited 30 days prior to entry
  10. Previous enrollment in a therapeutic trial targeting amyloid or tau
  11. Must agree not to participate in other clinical studies with neuropsychological measures, with the exception of participants who are co-enrolled in the NACC Uniformed Data Set (UDS) protocol (Note: This criterion is intended to reduce repeat measures effects during neuropsychological testing. Exceptions are allowed at the discretion of the Site PI)
  12. Lifetime history of schizophrenia spectrum disorders (DSM-5 criteria)
  13. Current history (in previous 12 months) of DSM-5 diagnosis of mania, bipolar disorder with or without psychotic features
  14. Current history (in previous 6 months) of moderate or severe substance abuse (nicotine or caffeine is allowed)
  15. Suicidal behaviors in the past 12 months or active suicidal ideations
  16. Residing in a 24-hour care skilled nursing facility (at the time of screening)
  17. History of torsades de pointes or taking medications known to prolong the QT interval
  18. Corrected QT (QTc) interval < 458 msec in males or < 474 msec in females
  19. (For optional lumbar puncture procedure only):

    a. Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be not clinically significant by the Site PI i. Platelet count <100,000/µl ii. INR>1.2 iii. Abnormal PT or PTT at screening b. Contraindications to the procedure, including but not limited to severe degenerative joint disease, deformity of the spine, history of a bleeding disorder c. Suspected elevated intracranial pressure, Arnold Chiari malformation or mass lesion d. Use of the anticoagulant medications such as but not limited to warfarin, rivaroxaban, dabigatran

  20. Deemed ineligible by the Site PI for any other reason

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): NCT03507257


Contacts
Contact: Nikki Mehdiyoun, MA, CCRP 317-963-4593 nmehdiyo@iupui.edu

Locations
United States, Indiana
Indiana University Recruiting
Bloomington, Indiana, United States, 47405
Contact: Meredith Phillips       merphill@iu.edu   
Principal Investigator: Liana Apostolova, MD         
Sponsors and Collaborators
Liana Apostolova
Alzheimer's Therapeutic Research Institute
National Institute on Aging (NIA)
Alzheimer's Association
Investigators
Principal Investigator: Liana Apostolova, MD Indiana University
  Study Documents (Full-Text)

Documents provided by Liana Apostolova, Indiana University School of Medicine:
Study Protocol  [PDF] February 28, 2018


Publications:

Responsible Party: Liana Apostolova, Professor in Neurology, Radiology, Medical and Molecular Genetics, Indiana University School of Medicine
ClinicalTrials.gov Identifier: NCT03507257     History of Changes
Other Study ID Numbers: ATRI-003
R56AG057195 ( U.S. NIH Grant/Contract )
First Posted: April 25, 2018    Key Record Dates
Last Update Posted: June 5, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Study data will be shared broadly through the Laboratory of NeuroImaging (LONI), with aggregate data sharing through the Global Alzheimer's Association Interactive Network (GAAIN). MRI and PET data will also be available for download from the LEADS Image and Data Archive (IDA) website. Genetics, genomics, and related data will be shared with other researchers pursuant to the NIA Genetics Sharing Policy. National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site, with other NIA-approved sites, will make genetic, genomic and related data and associated phenotypic data available to qualified investigators for secondary analysis in accordance with standards established by NIA.
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
URL: http://www.loni.usc.edu

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Liana Apostolova, Indiana University School of Medicine:
Cognitively Normal
Amyloid
Plaques
Neuroimaging
Biomarkers
Cognition Disorder
Dementia
Tau
Early Onset Alzheimer's Disease
Alzheimer's Disease
Mild Cognitive Impairment

Additional relevant MeSH terms:
Alzheimer Disease
Cognitive Dysfunction
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders