Transcranial Photobiomodulation for Alzheimer's Disease (TRAP-AD)

• ClinicalTrials.gov Identifier: NCT04784416
• Recruitment Status: Recruiting
• First Posted: March 5, 2021
• Last Update Posted: February 28, 2024
• Sponsor: NYU Langone Health
• Collaborators: National Institutes of Health (NIH); Alzheimer's Association; LiteCure LLC
• Information provided by (Responsible Party): NYU Langone Health

Study Description

Brief Summary:

This multi-site study will be the first to evaluate the dose-dependent effects of t-PBM in amnestic Mild Cognitive Impairment (aMCI) and early Alzheimer's Disease (AD) (CDR of 0.5-1, FAST 1-4; age 65-85) in a randomized clinical trial of 8 weeks of t-PBM vs. sham. At baseline, all subjects will complete initial neuropsychological testing. To elucidate mechanisms of action of t-PBM, prior to treatment, subjects will undergo neuroimaging related to critical features of AD: tau 18F MK-6240 load (PET), measures of brain bioenergetics (31P-MRS), and functional connectivity (rs-fMRI). After undergoing target engagement testing (t-PBM session performed during fMRI to detect BOLD changes with active t-PBM), subjects will then be randomized to t-PBM/sham and complete 24 t-PBM/sham treatments, ~11 min per day, 3 days per week, for 8 weeks. t-PBM will be administered via continuous, 808 nm wavelength laser delivery to the forehead bilaterally (at standard EEG electrode positions F4, F3).

Condition or disease	Intervention/treatment	Phase
Mild Cognitive Impairment; Alzheimer Disease	Device: Active tPBM-2.0; Device: Sham tPBM-2.0; Drug: 18F-MK-6240	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 125 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Transcranial Photobiomodulation for Alzheimer's Disease (TRAP-AD)
• Actual Study Start Date: April 27, 2021
• Estimated Primary Completion Date: June 30, 2025
• Estimated Study Completion Date: November 30, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Transcranial Photobiomodulation (t-PBM)	Device: Active tPBM-2.0; The NIR continuous wave (average irradiance = 300 mW/cm2) will be used. The duration or irradiation will be for ~11 minutes (666 seconds).; Drug: 18F-MK-6240; PET tracer to be injected prior to PET imaging session, which will occur during baseline assessments
Sham Comparator: Sham	Device: Sham tPBM-2.0; The sham mode (0 mW/cm2) will be used. The duration or sham "irradiation" will be for ~11 minutes (666 seconds).; Drug: 18F-MK-6240; PET tracer to be injected prior to PET imaging session, which will occur during baseline assessments

Outcome Measures

Primary Outcome Measures :

1. Change in Repeatable Battery for the Assessment of Neuropsychological Status Update (RBANS) Total Scale Index Score. [ Time Frame: Baseline, Week 8 ]
   RBANS is s a brief, individually administered battery to measure cognitive decline or improvement. Total Scale Index Score Range = 40-160. A higher score indicates better performance.

Secondary Outcome Measures :

1. Change in Repeatable Battery for the Assessment of Neuropsychological Status Update (RBANS) Total Scale Index Score. [ Time Frame: Baseline, Month 3 ]
   RBANS is s a brief, individually administered battery to measure cognitive decline or improvement. Total Scale Index Score Range = 40-160. A higher score indicates better performance.
2. Addenbrooke's Cognitive Examination (ACE-III) Score [ Time Frame: Baseline ]
   ACE-III is a screening test that is composed of tests of attention, orientation, memory, language, visual perceptual and visuospatial skills. The total range of raw score is 0-100. A higher score indicates more intact cognitive functioning.
3. Addenbrooke's Cognitive Examination (ACE-III) Score [ Time Frame: Week 8 ]
   ACE-III is a screening test that is composed of tests of attention, orientation, memory, language, visual perceptual and visuospatial skills. The total range of raw score is 0-100. A higher score indicates more intact cognitive functioning.
4. Addenbrooke's Cognitive Examination (ACE-III) Score [ Time Frame: Month 3 ]
   ACE-III is a screening test that is composed of tests of attention, orientation, memory, language, visual perceptual and visuospatial skills. The total range of raw score is 0-100. A higher score indicates more intact cognitive functioning.
5. Letter Comparison Test Score [ Time Frame: Baseline ]
   The total range of score is 0-21. A higher raw score indicates better performance.
6. Letter Comparison Test Score [ Time Frame: Week 8 ]
   The total range of score is 0-21. A higher raw score indicates better performance.
7. Letter Comparison Test Score [ Time Frame: Month 3 ]
   The total range of score is 0-21. A higher raw score indicates better performance.
8. Pattern Comparison Test Score [ Time Frame: Baseline ]
   The total range of score is 0-30. A higher raw score indicates better performance.
9. Pattern Comparison Test Score [ Time Frame: Week 8 ]
   The total range of score is 0-30. A higher raw score indicates better performance.
10. Pattern Comparison Test Score [ Time Frame: Month 3 ]
    The total range of score is 0-30. A higher raw score indicates better performance.
11. Stroop Color and Word Test (SCWT) [ Time Frame: Baseline ]
    SCWT is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect. This study will use T-scores, range = 20 - 80. A higher T-score indicates better performance.
12. Stroop Color and Word Test (SCWT) [ Time Frame: Week 8 ]
    SCWT is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect. This study will use T-scores, range = 20 - 80. A higher T-score indicates better performance.
13. Stroop Color and Word Test (SCWT) [ Time Frame: Month 3 ]
    SCWT is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect. This study will use T-scores, range = 20 - 80. A higher T-score indicates better performance.
14. Difference in Score Between Trail Making Test-A (TMT-A) and Trail Making Test-B (TMT-B) [ Time Frame: Baseline ]

    Trails Making Test (Trails) is a neuropsychological test of visual attention and task switching. Both parts of the Trail Making Test consist of 25 circles distributed over a sheet of paper. In Part A, the circles are numbered 1-25, and the patient should draw lines to connect the numbers in ascending order. In Part B, the circles include both numbers (1-13) and letters (A-L); as in Part A, the patient draws lines to connect the circles in an ascending pattern (alternating numbers and letters). The time it takes to connect the "trail" is recorded.

    Reported as B - A. Range = 0 - 100+ (measured in seconds). A higher B - A score indicates poorer performance.

15. Difference in Score Between Trail Making Test-A (TMT-A) and Trail Making Test-B (TMT-B) [ Time Frame: Week 8 ]

    Trails Making Test (Trails) is a neuropsychological test of visual attention and task switching. Both parts of the Trail Making Test consist of 25 circles distributed over a sheet of paper. In Part A, the circles are numbered 1-25, and the patient should draw lines to connect the numbers in ascending order. In Part B, the circles include both numbers (1-13) and letters (A-L); as in Part A, the patient draws lines to connect the circles in an ascending pattern (alternating numbers and letters). The time it takes to connect the "trail" is recorded.

    Reported as B - A. Range = 0 - 100+ (measured in seconds). A higher B - A score indicates poorer performance.

16. Difference in Score Between Trail Making Test-A (TMT-A) and Trail Making Test-B (TMT-B) [ Time Frame: Month 3 ]

    TMT is a neuropsychological test of visual attention and task switching. Both parts of the Trail Making Test consist of 25 circles distributed over a sheet of paper. In Part A, the circles are numbered 1-25, and the patient should draw lines to connect the numbers in ascending order. In Part B, the circles include both numbers (1-13) and letters (A-L); as in Part A, the patient draws lines to connect the circles in an ascending pattern (alternating numbers and letters). The time it takes to connect the "trail" is recorded.

    Reported as B - A. Range = 0 - 100+ (measured in seconds). A higher B - A score indicates poorer performance.

17. TMT-B T-Score [ Time Frame: Baseline ]
    In TMT-B, the circles include both numbers (1-13) and letters (A-L); the patient draws lines to connect the circles in an ascending pattern (alternating numbers and letters). The time is takes to connect the "trail" is recorded. Range = 0 - 100. A higher T-score indicates better performance
18. TMT-B T-Score [ Time Frame: Week 8 ]
    In TMT-B, the circles include both numbers (1-13) and letters (A-L); the patient draws lines to connect the circles in an ascending pattern (alternating numbers and letters). The time is takes to connect the "trail" is recorded. Range = 0 - 100. A higher T-score indicates better performance
19. TMT-B T-Score [ Time Frame: Month 3 ]
    In TMT-B, the circles include both numbers (1-13) and letters (A-L); the patient draws lines to connect the circles in an ascending pattern (alternating numbers and letters). The time is takes to connect the "trail" is recorded. Range = 0 - 100. A higher T-score indicates better performance
20. Face-Name Associative Memory Exam (FNAME-12) Score [ Time Frame: Baseline ]
    FNAME-12 is an associative memory test where participants see a series of facial photos and names and are asked to remember the face-name pairs.
21. Face-Name Associative Memory Exam (FNAME-12) Score [ Time Frame: Week 8 ]
    FNAME-12 is an associative memory test where participants see a series of facial photos and names and are asked to remember the face-name pairs.
22. Face-Name Associative Memory Exam (FNAME-12) Score [ Time Frame: Month 3 ]
    FNAME-12 is an associative memory test where participants see a series of facial photos and names and are asked to remember the face-name pairs.
23. Letter Number Sequencing Score [ Time Frame: Baseline ]
    this study will use T-scores, range = 20 - 80. A higher T-score indicates better performance.
24. Letter Number Sequencing Score [ Time Frame: Week 8 ]
    this study will use T-scores, range = 20 - 80. A higher T-score indicates better performance.
25. Letter Number Sequencing Score [ Time Frame: Month 3 ]
    this study will use T-scores, range = 20 - 80. A higher T-score indicates better performance.
26. Change in Systemic Assessment for Treatment Emergent Events - Specific Inquiry (SAFTEE-SI) Score [ Time Frame: Baseline, up to Week 8 ]
    SAFTEE-SI is a list of 55 symptoms. Participants indicate how bothersome each symptom has been for them by circling the appropriate number (0-none, 1-mild, 2-moderate, 3-severe). The total range of score is 0 - 165. The higher the score, the more severely bothersome the symptoms are.

Eligibility Criteria

• Ages Eligible for Study: 65 Years to 85 Years (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Able to give written informed consent and follow study procedures.
2. Age > or = 65 years and < or = 85 years.
3. Meets the Petersen MCI criteria for Amnestic MCI (single and multiple domain) with a Clinical Dementia Rating (CDR) between 0.5-1.0, and a Functional Assessment Staging (FAST) of 1-4.
4. Be willing to identify an informed relative, family member, spouse, or friend for study staff to interview to confirm subject reports as per UDS 3.0 guidelines; however the lack of a study informant is not exclusionary.
5. Have at least a high school diploma/12 years of education.
6. Participants with current mild MDD may be allowed to participate, given that mild MDD does not affect cognition and does not pose increased risk to the participant, as determined by site PI on a case-by-case basis.

Exclusion Criteria:

1. Unwilling/unable to comply with study procedures.
2. Other diagnosis of dementia (i.e. not Alzheimer's type), history of brain tumor, MRI evidence of brain damage or brain disease including significant trauma, hydrocephalus, seizures, intellectual disability, or other serious neurological disorder (e.g. Parkinson's disease or other movement disorders).
3. History of significant cerebrovascular pathology (e.g., significant stroke). Subjects with a history of cardiovascular disease (e.g., myocardial infarction) will be allowed to participate at site PI's discretion, on a case-by-case basis, given that the cardiovascular disease is stable and does not reflect the presence of significant cerebrovascular pathology.
4. Clinically unstable systemic medical disorders.
5. Current DSM-5 diagnosis of alcohol or drug use disorder or other major psychiatric illness (e.g., schizophrenia, bipolar, PTSD, depression). Participants with current mild MDD may be allowed to participate, given that mild MDD does not affect cognition and does not pose increased risk to the participant, as determined by site PI on a case-by-case basis. Participants with current moderate/severe MDD will be excluded.
6. Clinical or laboratory evidence of hypothyroidism.
7. Clinically significant abnormal findings of laboratory parameters or at physical examination.
8. Medications affecting cognition (e.g., narcotic analgesics; chronic use of medications with anticholinergic activity, anti-Parkinsonian medications, antipsychotic meds, etc.). Stable use (i.e., = 6 months) of memantine or acetylcholinesterase inhibitors will be allowed.
9. Family history of early onset (<60 y/o) dementia.
10. Past intolerance or hypersensitivity to t-PBM.
11. Significant skin conditions on the subject's scalp in the area of the procedure sites.
12. Any use of light-activated drugs (photodynamic therapy) within 14 days prior to study enrollment.
13. Any type of implants in the head, whose functioning might be affected by t-PBM.
14. The completion of study imaging procedures is highly encouraged, but not mandatory for participants with extenuating circumstances (e.g., having prosthetic devices or metallic foreign bodies that constitute hazards for MRI, unable to get PET due to previous level of radiation exposure, having claustrophobia, having a large body size and shape).

Contacts and Locations

Contacts

Contact: Dan Iosifescu, MD; 646-754-5156; dan.iosifescu@nyulangone.org

Contact: Anna Peterson, MA; 646-754-2260; anna.peterson@nyulangone.org

Locations

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Paolo Cassano, MD, PhD 617-726-6421 PCASSANO@mgh.harvard.edu

Contact: MGH Team 617-724-8780 pbm@mgh.harvard.edu

Principal Investigator: Paolo Cassano, MD, PhD

Sub-Investigator: Aura Hurtado, MD

Sub-Investigator: Eva Ratai, PhD

United States, New York

NYU Langone Health; Recruiting

New York, New York, United States, 10016

Contact: Dan Iosifescu, MD 646-754-5156 dan.iosifescu@nyulangone.org

Contact: Anna Peterson, MA 646-754-2260 anna.peterson@nyulangone.org

Principal Investigator: Dan Iosifescu, MD

Principal Investigator: Ricardo Osorio, MD

Sub-Investigator: Martin Sadowski, MD, PhD, DSci

Sub-Investigator: Ryan Brown, PhD

Sub-Investigator: Thaddeus Tarpey, PhD

Nathan Kline Institute; Recruiting

Orangeburg, New York, United States, 10962

Contact: Dan Iosifescu, MD 646-754-5156 dan.iosifescu@nyulangone.org

Contact: Zamfira Parincu 845-398-6571 zamfira.parincu@nki.rfmh.org

Principal Investigator: Dan Iosifescu, MD

Principal Investigator: Ricardo Osorio, MD

Sub-Investigator: Antonio Convit, MD

Sub-Investigator: Kathy Yates, PhD

Sub-Investigator: Nunzio Pomara, MD

Sub-Investigator: Matthew Hoptman, PhD

Sub-Investigator: Umit Tural, MD

Sub-Investigator: Katherine Collins, MSW, PhD

Sponsors and Collaborators

NYU Langone Health

National Institutes of Health (NIH)

Alzheimer's Association

LiteCure LLC

Investigators

• Principal Investigator: Dan Iosifescu, MD; NYU Langone Health and Nathan Kline Institute
• Principal Investigator: Ricardo Osorio, MD; NYU Langone Health and Nathan Kline Institute
• Principal Investigator: Paolo Cassano, MD, PhD; Massachusetts General Hospital

More Information

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT04784416
• Other Study ID Numbers: 20-00865
• First Posted: March 5, 2021
• Last Update Posted: February 28, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be provided upon reasonable request.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• Access Criteria: The investigator who proposed to use the data will have access upon reasonable request.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by NYU Langone Health:

Transcranial Photobiomodulation

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