Longitudinal Early-onset Alzheimer's Disease Study Protocol

Alzheimer Disease Clinical Trial

— LEADS  

Official title:

Longitudinal Early-onset Alzheimer's Disease Study Protocol

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03507257
• Other study ID #: ATRI-003
• Secondary ID: R56AG057195
• Status: Recruiting
• Start date: April 30, 2018
• Est. completion date: May 31, 2024

Study information

• Verified date: May 2024
• Source: Indiana University
• Contact: IU LEADS Team
• Phone: 317-963-7436
• Email: iuLEADS[@]iupui.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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 cognitive impairment. Clinical, cognitive, imaging, biomarker, and genetic characteristics will be assessed across three cohorts: (1) early onset Alzheimer's Disease (EOAD) participants, (2) early onset non-Alzheimer's Disease (EOnonAD) participants, and (3) cognitively normal (CN) control participants.

Description:

The LEADS study is a non-randomized, natural history, non-treatment study. Enrolled participants must be 40 - 64 (inclusive) years of age, with MCI due to AD or probable AD dementia (cognitively impaired participants) or have no significant memory impairment (cognitively normal [CN] participants).

Approximately 600 participants with cognitive impairment (400 with early onset Alzheimer's Disease [EOAD] and 200 with early onset non-Alzheimer's Disease [EOnonAD]) and 100 CN participants will be enrolled at approximately 20 sites in the United States. Cognitively impaired participants will take part in the study for 48+ months; CN participants will take part in the study for 24+ months.

Participants will undergo longitudinal clinical and cognitive assessments, computerized cognitive tests, biomarker and genetic tests, PET (FDG, amyloid and tau) and MRI brain scans, and optional cerebrospinal fluid (CSF) collection. Participants will be invited to consider autopsy brain donation

The primary objectives of the LEADS study are to:

• collect longitudinal assessments and biomarker data in individuals with early onset cognitive impairment (EOAD / EOnonAD) 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 Disease (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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 700
• Est. completion date: May 31, 2024
• Est. primary completion date: May 31, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 40 Years to 64 Years

Eligibility

Inclusion Criteria for Cognitively Impaired (EOAD and EOnonAD) Cohorts 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. Age between 40-64 years (inclusive) at the time of consent

5. 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 at least 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

6. Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure

7. 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

8. Fluent in English or Spanish

Inclusion Criteria for 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 or Spanish

Exclusion Criteria for all (EOAD, EOnonAD 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, MAPT, GRN and C9ORF72 have been excluded

3. Known CLIA certified mutation in an ADAD gene (APP, PSEN1, PSEN2), or other autosomal dominant genes associated with other neurodegenerative disorders (MAPT, GRN, C9ORF72)

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. Research 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 for research-related purposes, 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. Participation in other clinical studies with neuropsychological measures, with the exception of participants who are co-enrolled in the NACC Uniform 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. (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/ul 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

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Cognitive Dysfunction
• Early Onset Alzheimer Disease
• Mild Cognitive Impairment

Intervention

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.
• 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.
• Fluorodeoxyglucose
All participants will receive a single bolus intravenous injection of approximately 5 mCi (+/- 10%, 0.5 mCi) of fluorodeoxyglucose. At approximately 30 minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	Houston Methodist Hospital	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	Mayo Clinic, Jacksonville	Jacksonville	Florida
United States	University of California, Los Angeles	Los Angeles	California
United States	Wien Center	Miami Beach	Florida
United States	Columbia University	New York	New York
United States	Stanford University	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Butler Hospital	Providence	Rhode Island
United States	Mayo Clinic, Rochester	Rochester	Minnesota
United States	Washington University, St. Louis	Saint Louis	Missouri
United States	University of California, San Francisco	San Francisco	California
United States	Banner Sun Health Research Institute	Sun City	Arizona
United States	Georgetown University	Washington	District of Columbia

Sponsors (4)

Lead Sponsor	Collaborator
Indiana University	Alzheimer's Association, Alzheimer's Therapeutic Research Institute, National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

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* Note: There are 57 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of change in cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog13)	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.	Month 0, Month 12, Month 24, Month 36 (EOAD/EOnonAD only) and Month 48 (EOAD/EOnonAD only)
Secondary	Rate of change in cognition as measured by the Clinical Dementia Rating - Sum of Boxes (CDR-SB)	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.	CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 and Month 48
Secondary	Change in tau deposition as measured by flortaucipir (18F-AV-1451) Positron Emission Tomography (PET) imaging		Month 0, Month 12 (EOAD only), Month 24 (EOAD only) and Month 36 (EOAD and EOnonAD amyloid positive participants only)
Secondary	Change in amyloid deposition as measured by florbetaben using Positron Emission Tomography (PET) imaging		Month 0, Month 12 (EOAD only), Month 24 (EOAD only) and Month 36 (EOAD/EOnonAD only
Secondary	Neurodegeneration as measured by fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) imaging compared to magnetic resonance imaging (MRI)		Month 12 (EOnonAD only) and Month 24 (CN only)
Secondary	Change in brain structure using magnetic resonance imaging (MRI)		CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24 and Month 36
Secondary	Change in cerebrospinal fluid (CSF) biomarkers		CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36
Secondary	Change in plasma biomarkers		CN participants: Month 0, Month 12 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 and Month 48