The Revitalize Study in Older Adults at Risk for Alzheimer's Disease

• ClinicalTrials.gov Identifier: NCT04018092
• Recruitment Status: Recruiting
• First Posted: July 12, 2019
• Last Update Posted: June 30, 2022
• Sponsor: University of Florida
• Collaborators: University of Arizona; National Institute on Aging (NIA)
• Information provided by (Responsible Party): University of Florida

Study Description

Brief Summary:

The goal of this multi-site double blinded randomized sham-controlled Phase II clinical trial is to test a novel, relatively low cost, low risk, and potentially high impact therapeutic intervention in older adults who are at increased risk for Alzheimer's disease. The intervention involves transcranial and intranasal delivery of near infrared (NIR) light via light emitting diodes, aka photobiomodulation. The overall hypothesis, based on animal and pilot studies, is that exposure to NIR stimulation will have beneficial effects on brain health via influence on mitochondrial function as measured by changes in 31P MRS-based markers of ATP, neural network changes in functional connectivity (rs-fMRI), and improved cognitive performance. To test this hypothesis, 168 older adults with subjective cognitive complaints, and a first-degree family history of Alzheimer's disease will be randomized to sham or real treatment groups. Neuromiaging and ocgnitive outcome measures will be obtained, before and after a 12-week intervention involving transcranial and intranasal NIR-PBM. The intervention protocol will involve "lab" and "home" sessions, and a 3 month post-intervention follow-up. This trial will determine: 1) whether NIR stimulation, relative to sham, improves performance on memory and executive tasks sensitive to hippocampal and frontal brain function in older adults with increased risk for Alzheimer's disease; 2) whether NIR stimulation, relative to sham, enhances brain function and connectivity measured by changes in MRS phosphorous ATP and resting state functional connectivity; and 3) how differences in demographic, neuroimaging, and Alzheimer-related risk factors influence the brain response to NIR stimulation versus sham in older adults with increased risk for Alzheimer's disease. Results will provide key insights into whether this novel NIR intervention can enhance cognition in older adults with increased risk for Alzheimer's disease and will provide the necessary data for a future Phase III randomized clinical trial.

Condition or disease	Intervention/treatment	Phase
Cognitive Aging; Alzheimer Disease, Protection Against	Device: Active NIR-PBM; Device: Sham NIR-PBM	Phase 2

Detailed Description:

This multi-site randomized sham controlled trial proposes to test a novel, non-invasive, low risk and low cost brain stimulation approach for enhancing cognition and brain health in cognitively normal older adults who are at increased risk for Alzheimer's disease. The intervention involves transcranial and intranasal delivery of near-infrared light (NIR; 808-904 nm) via light emitting diodes placed on the scalp or intranasally using a dosing that resulted in positive effects in our pilot studies. We plan to test the hypothesis that targeted NIR stimulation will have positive effects on brain health via influence on mitochondrial function as measured by changes in Magnetic Resonance Spectroscopy (MRS)-based markers of ATP, neural network changes as indexed by changes in functional connectivity based on resting state-fMRI, and improved cognitive performance. We plan to randomize 168 older adults, ages 65-89 years, to Active or Sham intervention conditions. To be included, participants must have subjective cognitive complaints, based on an index of Subjective Cognitive Impairment (SCI), and a family history of Alzheimer's disease in a first degree relative. Performance on standardized neuropsychological measures must be unimpaired psychometricallyl. The intervention itself will last for 12 weeks and include lab sessions (16 total) and daily at home sessions. In the lab, both transcranial and intranasal delivery of NIR light will be delivered using Medx and Vielight stimulation technologies, whereas the daily at home sessions will involve intranasal stimulation only. The sham and active conditions are identical in all respects except that sham devices will not deliver NIR stimulation. The primary outcome is an episodic memory measure involving spatial navigation that is linked to hippocampal function, sensitive to MCI and Alzheimer's disease, and an analogue to the Morris Water maze. Secondary outcomes include executive function task and neuroimaging indicators of ATP function (31-P MRS) and connectivity changes based on rs-fMRI. Exploratory outcomes include 'traditional' neuropsychological measures that are used clinically, along with measures and indices (e.g., APOE-4 status)that might potentially mediate or moderate study outcome. Assessments will occur at baseline (Month 1), after 12 weeks of intervention (Month 4), and 3 month post intervention (Month 7). Imaging outcomes will be assessed only at baseline and at Month 4. Our primary aim is focused on cognition and will test whether NIR intervention, relative to sham, will produce pre-post improvement on tasks of recent memory (primary outcome) and executive function in older adults who are at increased risk for Alzheimer's disease. Our secondary aim is focused on neuroimaging and will test whether NIR intervention, relative to sham, will enhance brain markers of MRS-ATP (secondary outcome) and increase functional connectivity as indexed by resting state fMRI. The 3rd aim is exploratory and will evaluated how baseline demographic, genetic, neuroimaging and other factors influence individual differences in cognitive outcome for NIR intervention.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 168 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants who meet eligibility criteria will be randomized to the Active or Sham condition. The study biostatistician will randomize participants using a 1:1 allocation scheme with stratification based on age, education, and sex. When a new participant arrives, she/he will be randomized to Active or Sham groups depending on covariate characteristics (age, education, sex) and the cumulative distribution of assignments regarding these variables at that point.
• Masking: Triple (Participant, Investigator, Outcomes Assessor)

Masking Description

Use of a sham-controlled approach provides stringent experimental control, enabling the investigators to control for placebo/expectations, behavioral activation (engaging in study procedures) and practice effects related to repeated administration of the same cognitive tasks.

The MedX and Vielight devices used for delivery of active and sham NIR stimulation are identical in all respects regarding design, warmth and operation, except that no stimulation is delivered by the sham devices. Because NIR light is invisible, participants will not be able to discern if receiving active or sham stimulation. The participants, interventionists, and outcome assessors will be blinded to the participants' intervention status: Active vs Sham. At completion of the study, all participants will receive a Placebo Control Questionnaire that asks questions pertaining to what group the participant had been assigned. This data will be examined to determine the effectiveness of blinding.

• Primary Purpose: Treatment
• Official Title: Revitalizing Cognition in Older Adults at Risk for Alzheimer's Disease With Near-Infrared Photobiomodulation
• Actual Study Start Date: August 12, 2020
• Estimated Primary Completion Date: April 2024
• Estimated Study Completion Date: April 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Active NIR-PBM; For transcranial stimulation, the study team will use two MedX units (1116 Rehab Console, MedX Health), whereas intranasal stimulation is delivered using the 810 Intranasal device (Vielight Inc). During each lab session, six transcranial LED clusters will be placed on the scalp in two distinct configurations guided by 10-20 EEG system. Total transcranial stimulation time is 40 minutes, 20 min per cluster. Concurrently, two 810 intranasal devices will be placed in each nostril for 25 min of total dose per nostril. For at home sessions, participants will use the standalone 810 Intranasal device only. Total amount of sessions: 16 sessions of stimulation will occur in the laboratory. Each session will last approximately 90 minutes and will include two 20-minute segments of NIR stimulation. AND; 44 sessions of intranasal stimulation in the home. Each session will last 25 minutes and will occur on weekdays when there is no in-lab session.	Device: Active NIR-PBM; See Experimental arm for description.
Sham Comparator: Sham NIR-PBM; Participants randomized to the Sham control group will undergo identical procedures as the Active group. The only difference is that the "sham" NIR devices are modified not to deliver stimulation. Because NIR is invisible, participants are unable to detect whether NIR is being delivered.	Device: Sham NIR-PBM; See Sham Comparator arm for description.

Outcome Measures

Primary Outcome Measures :

1. Change in Active group ARENA scores compared to Sham group ARENA scores [ Time Frame: Baseline; Week 12 ]
   The primary outcome measure is a spatial navigation task (ARENA), a human analogue to the Morris WaterMaze. Participants navigate a virtual room on a computer. The task consists of 3 phases: practice, learning, and memory probe. During the learning trials, the target is invisible until the participant hovers over it. The target is located in the same location and the participant must use spatial cues to locate it. In the memory probe trial, the target is removed unbeknownst to the participant. On each learning trial, path length, time to acquire the target, and target acquisition (yes-no) are recorded. On the probe trial, path length and percent of time spent in each quadrant are recorded. The primary outcome is a composite z score, consisting of mean z scores for the following: path length(.25 weight)+time to acquire target (.25 weight)+time spent in proximal target on trial 9(.50 weight). Higher Z scores indicate better performance. Expected range of composite Z is -4 to 4.

Eligibility Criteria

• Ages Eligible for Study: 65 Years to 89 Years (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Age 65-89 years, at least 8th grade education, community dwelling
• Subjective report of cognitive complaints with scores >16 on the Cognitive Change Index (CCI-20)
• No evidence of dementia or mild cognitive impairment based on cognitive screening (i.e., Montreal Cognitive Assessment (MoCA) score within normal limits for age, education and sex using the NACC Uniform Data Set (UDS) norms.
• No psychometric evidence of cognitive impairment based on performance on the Neuropsychological Battery from the NACC Unified Data Set, version 3. Scores on these measures cannot be lower than 1.0 SD (16th %ile) below normative values based on age, education, and gender.
• Reading at > 8th grade level based on the reading subtest of the Wide Range Achievement Test- IV.
• Global Clinic Dementia Rating (CDR) score must be 0
• Family history of dementia/probable Alzheimer's disease in first degree relative (parents, children, siblings)
• Willingness to be randomized to Sham or Active Intervention
• Can devote 12 weeks to the intervention with additional time for pre and post testing
• Normal functional behavior in terms of daily activities, based on the Functional Activities Scale
• Able to perform cognitive and emotion measures on a computer
• In line with recommendations of SCD task force an informant must be available for two reasons: a) to provide information about the participant's complaints using the informant version of the CCI-20, and b) to corroborate normal IADL's on the Functional Activity Questionnaire.

Exclusion Criteria:

• Sensory loss (vision, hearing) or motor deficits that would preclude participation in the experimental tasks or neuropsychological assessment
• English as a second language
• Inability to undergo brain imaging due to claustrophobia or implants such as pacemakers, heart valves, brain aneurysm clips, orthodontics, non-removable body jewelry, or shrapnel containing ferromagnetic metal
• Previous major strokes or other known significant brain abnormalities or diseases affecting the brain and/or cognition (e.g.,Parkinson disease, multiple sclerosis, seizure disorder, brain surgery, moderate TBI, REM Behavior Sleep Disorder, untreated sleep apnea, etc.)
• Unstable and uncontrolled medical conditions (metastatic cancer, HIV, moderate-severe kidney disease, uncontrolled diabetes, uncontrolled hypertension, severe cardiac disease, etc.). No current cancer diagnosis.
• Current or past history of major psychiatric disturbance including schizophrenia, or active psychosis, bipolar disorder, current major depressive episode, current alcohol or substance abuse or history thereof within the past six months.
• Use of antipsychotics, sedatives, or other medications with significant anticholinergic properties (due to potential influence on memory)
• Use of prescribed 'memory enhancing' medications such as Aricept or Namenda
• Use of photo-sensitive medications such as steroids or retin-A within 15 days of the study intervention.
• Previous participation in a cognitive training study within the last 6 months or current involvement in another study involving cognitive, physical or other intervention at the time of participation

Contacts and Locations

Contacts

Contact: Dawn Bowers, Ph.D.; 352-273-6152; dawnbowers@phhp.ufl.edu

Contact: Adam J Woods, Ph.D.; 352-294-5842; ajwoods@phhp.ufl.edu

Locations

United States, Arizona

University of Arizona; Not yet recruiting

Tucson, Arizona, United States, 85721

United States, Florida

University of Florida McKnight Brain Institute; Recruiting

Gainesville, Florida, United States, 32610

Principal Investigator: Adam J. Woods, PhD

Sponsors and Collaborators

University of Florida

University of Arizona

National Institute on Aging (NIA)

Investigators

• Principal Investigator: Dawn Bowers, Ph.D; University of Florida
• Principal Investigator: Adam J Woods, Ph.D.; University of Florida
• Principal Investigator: Gene Alexander, Ph.D.; University of Arizona

More Information

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT04018092
• Other Study ID Numbers: IRB201901780 -N; R01AG064587 ( U.S. NIH Grant/Contract ); F31AG071264 ( U.S. NIH Grant/Contract )
• First Posted: July 12, 2019
• Last Update Posted: June 30, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders