Open Label Study for the Use of Transcranial Ultrasound for Treatment of Age-Related Frailty (fUS-ARF)

The purpose of this Phase I open label study is to evaluate longer term tolerability and potential effectiveness of transcranial ultrasound in people with age-related frailty.

Study Overview

• Status: Enrolling by invitation
• Conditions: Frailty; Aging
• Intervention / Treatment: Device: Focused Ultrasound

Detailed Description

This study is designed to evaluate the safety and efficacy of focused ultrasound in patients with age-related frailty characterized by reduced physical and immunological functioning. The safety of this protocol will be closely monitored and data will be used to determine whether any significant safety issues exist when using focused ultrasound. Adverse events will be noted whenever they occur but will be recorded at the time of the procedure and throughout routine follow-ups, which will persist weekly throughout the duration of the active study protocol. Patients deemed potentially appropriate candidates for focused ultrasound therapy will be treated with 8 sessions of transcranial ultrasound, each of which consists of 10 to 30 minutes of active administration. Clinical and safety outcome measures will be obtained throughout and after completion of the study protocol.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Santa Monica, California, United States, 90403
      • Neurological Associates of West Los Angeles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age eligibility requirements fall in a range from 60 to 95 years of age
• Clinical appraisal by physician indicating signs of frailty (apart from a co-occuring condition), scoring 3<x<7 as denoted by the CSHA Clinical Frailty Scale (Rockwood, Song, MacKnight, et al, 2005; Golpanian, DiFede, Pujol, et al., 2016)
• MRI of the brain including volume measurement of the hypothalamus

Exclusion Criteria:

• Subjects unable to give informed consent
• Subjects who would not be able to lay down without excessive movement in a calm environment sufficiently long enough to be able to achieve sleep
• Pregnancy, women who may become pregnant or are breastfeeding
• Advanced terminal illness
• Subjects with scalp rash or open wounds on the scalp (for example from treatment of squamous cell cancer)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental; Participants will undergo ten to thirty minutes of transcranial ultrasound treatment. The sanitation device will be aimed at the hypothalamus. Targeting will include reference to scalp fiducials based on the obtained MRI; confirmation of target accuracy will either be obtained by Doppler waveform confirmation or optical tracking technology which co-registers patient neuroimaging with real space.

Device: Focused Ultrasound; The DWL Doppler ultrasound device enables visual and auditory waveform confirmation of the middle cerebral artery, and optical tracking technology (e.g., AntNeuro Visor2™ system) may be used in tandem with the Brainsonix ultrasound device to track a patient's brain in virtual space as well as their physical location, thereby ensuring accurate placement.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Frailty Scale (CFS)	The CFS is a 9-point scoring guide for physicians to use upon clinical appraisal of frailty-related symptoms. The lowest rating is 1 ("Very Fit") and the highest rating is 9 ("Terminally Ill"). The range of acceptable ratings for screened participants is from 3 ("Managing Well") to 7 ("Severely Frail").	Baseline
Clinical Frailty Scale (CFS)	The CFS is a 9-point scoring guide for physicians to use upon clinical appraisal of frailty-related symptoms. The lowest rating is 1 ("Very Fit") and the highest rating is 9 ("Terminally Ill"). The range of acceptable ratings for screened participants is from 3 ("Managing Well") to 7 ("Severely Frail"). Scoring on the CFS will be noted as significant for those who improve by at least one level.	Final Evaluation (8 weeks from baseline)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montreal Cognitive Assessment (MoCA)	The MoCA evaluates frontal-executive functions (e.g., verbal abstraction and mental calculation), language (e.g., confrontation naming, phonemic fluency), orientation (e.g., person, place, date, day of the week, and time), visuospatial construction (e.g., simple figure copy), divided visual attention, and immediate and delayed memory of unstructured information. MoCA scores range from 0-30 possible points; 26 or greater is considered to reflect normal cognitive status.	Baseline
Beck Anxiety Inventory (BAI)	The BAI is a 21-question multiple-choice self-report inventory that is used for measuring the severity of anxiety symptoms. Each of the 21 items asks whether the patient has experienced various anxiety symptoms in the last two weeks, and if so, how severely. Each question/answer is scored on a scale value of "0" (not at all) to "3" (severely). Higher total scores indicate more severe anxiety symptoms. The maximum total score possible is 63 points. The standard cutoff scores are: 0-7 = minimal anxiety; 8-15 = mild anxiety; 16-25 = moderate anxiety; 26-63 = severe anxiety. A reduction in score by at least 30% is considered clinically meaningful.	Baseline
Beck Depression Inventory (BDI-II)	The BDI-II is a 21-question multiple-choice self-report inventory. Each question involves four possible responses, ranging in intensity from "0" (this item does not apply) to "3" (this item applies severely). The test is scored as the sum of all of the response values; this number is used to determine the severity of depressive symptoms. A score of 0 to 3 is possible for each question with a maximum total score of 63 points. The standard cutoff scores are as follows: 0-13 total points = minimal depression; 14-19 total points = mild depression; 20-28 total points = moderate depression; and 29-63 total points = severe depression. A reduction in the total score by at least 30% is considered to be clinically significant.	Baseline
Short Physical Performance Battery (SPPB)	The SPPB is a series of tests used to evaluate lower extremity function and mobility in older people. The test consists of three major components, each of which are scored independently: 3 static balance tests, gait speed, and five timed sit-to-stand tests. Points are assigned based on performance, with a maximum possible score of 12 points. Higher scores are indicative of better functioning. A score of 0 on any item indicates lack of ability or functioning. The minimum clinically important difference for the total SPPB score is 1 point.	Baseline
Short Physical Performance Battery (SPPB)	The SPPB is a series of tests used to evaluate lower extremity function and mobility in older people. The test consists of three major components, each of which are scored independently: 3 static balance tests, gait speed, and five timed sit-to-stand tests. Points are assigned based on performance, with a maximum possible score of 12 points. Higher scores are indicative of better functioning. A score of 0 on any item indicates lack of ability or functioning. The minimum clinically important difference for the total SPPB score is 1 point.	Final Evaluation (8 weeks from baseline)
Multidimensional Fatigue Inventory (MFI)	The MFI is a 20-item scale designed to evaluate five dimensions of fatigue: general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue. Respondents use a scale ranging from 1 to 7 to indicate how aptly certain statements regarding fatigue represent their experiences. Several positively phrased items are reverse- scored. Higher total scores correspond with more acute levels of fatigue. Responses for the Multidimensional Fatigue Inventory will be defined as clinically significant when there is a 2-point difference.	Baseline
Multidimensional Fatigue Inventory (MFI)	The MFI is a 20-item scale designed to evaluate five dimensions of fatigue: general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue. Respondents use a scale ranging from 1 to 7 to indicate how aptly certain statements regarding fatigue represent their experiences. Several positively phrased items are reverse- scored. Higher total scores correspond with more acute levels of fatigue. Responses for the Multidimensional Fatigue Inventory will be defined as clinically significant when there is a 2-point difference.	Final Evaluation (8 weeks from baseline)
Montreal Cognitive Assessment (MoCA)	The MoCA evaluates frontal-executive functions (e.g., verbal abstraction and mental calculation), language (e.g., confrontation naming, phonemic fluency), orientation (e.g., person, place, date, day of the week, and time), visuospatial construction (e.g., simple figure copy), divided visual attention, and immediate and delayed memory of unstructured information. MoCA scores range from 0-30 possible points; 26 or greater is considered to reflect normal cognitive status.	Final Evaluation (8 weeks from baseline)
Beck Depression Inventory (BDI-II)	The BDI-II is a 21-question multiple-choice self-report inventory. Each question involves four possible responses, ranging in intensity from "0" (this item does not apply) to "3" (this item applies severely). The test is scored as the sum of all of the response values; this number is used to determine the severity of depressive symptoms. A score of 0 to 3 is possible for each question with a maximum total score of 63 points. The standard cutoff scores are as follows: 0-13 total points = minimal depression; 14-19 total points = mild depression; 20-28 total points = moderate depression; and 29-63 total points = severe depression. A reduction in the total score by at least 30% is considered to be clinically significant.	Final Evaluation (8 weeks from baseline)
Beck Anxiety Inventory (BAI)	The BAI is a 21-question multiple-choice self-report inventory that is used for measuring the severity of anxiety symptoms. Each of the 21 items asks whether the patient has experienced various anxiety symptoms in the last two weeks, and if so, how severely. Each question/answer is scored on a scale value of "0" (not at all) to "3" (severely). Higher total scores indicate more severe anxiety symptoms. The maximum total score possible is 63 points. The standard cutoff scores are: 0-7 = minimal anxiety; 8-15 = mild anxiety; 16-25 = moderate anxiety; 26-63 = severe anxiety. A reduction in score by at least 30% is considered clinically meaningful.	Final Evaluation (8 weeks from baseline)
Community Healthy Activities Model Program for Seniors (CHAMPS)	This self-report questionnaire assesses weekly frequency and duration of a variety of lifestyle physical activities that are meaningful and appropriate for older adults. It includes activities of various intensities (from light to vigorous) such as walking, running, hiking, swimming, bicycling, dancing, tennis, aerobics, yoga/tai chi, gardening, and housework. Intensity is reflected in the item stem (e.g., light and heavy gardening are separate items). The questionnaire is self-administered, although it can be interviewer administered. It is formatted to accommodate increasing visual problems with age by using a large font, adequate space on the page, and high contrast. A total caloric expenditure is calculated based on reported participant activity. Responses for the CHAMPS questionnaire will be defined as clinically significant when there is a 8 kcal/kg/week difference.	Baseline
Community Healthy Activities Model Program for Seniors (CHAMPS)	This self-report questionnaire assesses weekly frequency and duration of a variety of lifestyle physical activities that are meaningful and appropriate for older adults. It includes activities of various intensities (from light to vigorous) such as walking, running, hiking, swimming, bicycling, dancing, tennis, aerobics, yoga/tai chi, gardening, and housework. Intensity is reflected in the item stem (e.g., light and heavy gardening are separate items). The questionnaire is self-administered, although it can be interviewer administered. It is formatted to accommodate increasing visual problems with age by using a large font, adequate space on the page, and high contrast. A total caloric expenditure is calculated based on reported participant activity. Responses for the CHAMPS questionnaire will be defined as clinically significant when there is a 8 kcal/kg/week difference.	Final Evaluation (8 weeks from baseline)
Grip Strength (Dynamometer Performance)	Participants will be asked to demonstrate grip strength in standard fashion for clinical evaluation. Using the JAMAR Technologies Hydraulic Hand Dynamometer, participants will squeeze the instrument with their dominant hand and generate a reading of grip strength in the output reading (units = kg). The MCID of the grip strength test is a change of at least 5.0 kg.	Baseline
Grip Strength (Dynamometer Performance)	Participants will be asked to demonstrate grip strength in standard fashion for clinical evaluation. Using the JAMAR Technologies Hydraulic Hand Dynamometer, participants will squeeze the instrument with their dominant hand and generate a reading of grip strength in the output reading (units = kg). The MCID of the grip strength test is a change of at least 5.0 kg.	Final Evaluation (8 weeks from baseline)
Global Rating of Change (GRC)	The GRC consists of a single likert-scale ranging from "-5" (very much worse) to "0" (neutral/no change) to "5" (very much better). The GRC is obtained in an interview format to assess a patient's perceived change in status following a treatment. A score that is at least 2 or greater is considered to indicate clinically significant change.	Final Evaluation (8 weeks from baseline)

Collaborators and Investigators

• Sponsor: Neurological Associates of West Los Angeles
• Investigators: Principal Investigator: Sheldon Jordan, MD, Neurological Associates - the Interventional Group

Publications and helpful links

General Publications

• Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet. 2013 Mar 2;381(9868):752-62. doi: 10.1016/S0140-6736(12)62167-9. Epub 2013 Feb 8. Erratum In: Lancet. 2013 Oct 19;382(9901):1328.
• Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I, Mitnitski A. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005 Aug 30;173(5):489-95. doi: 10.1503/cmaj.050051.
• Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217. doi: 10.1016/j.cell.2013.05.039.
• Song X, Mitnitski A, Rockwood K. Prevalence and 10-year outcomes of frailty in older adults in relation to deficit accumulation. J Am Geriatr Soc. 2010 Apr;58(4):681-7. doi: 10.1111/j.1532-5415.2010.02764.x. Epub 2010 Mar 22.
• Tompkins BA, DiFede DL, Khan A, Landin AM, Schulman IH, Pujol MV, Heldman AW, Miki R, Goldschmidt-Clermont PJ, Goldstein BJ, Mushtaq M, Levis-Dusseau S, Byrnes JJ, Lowery M, Natsumeda M, Delgado C, Saltzman R, Vidro-Casiano M, Da Fonseca M, Golpanian S, Premer C, Medina A, Valasaki K, Florea V, Anderson E, El-Khorazaty J, Mendizabal A, Green G, Oliva AA, Hare JM. Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Gerontol A Biol Sci Med Sci. 2017 Oct 12;72(11):1513-1522. doi: 10.1093/gerona/glx137.
• Zhang Y, Kim MS, Jia B, Yan J, Zuniga-Hertz JP, Han C, Cai D. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature. 2017 Aug 3;548(7665):52-57. doi: 10.1038/nature23282. Epub 2017 Jul 26. Erratum In: Nature. 2018 Aug;560(7719):E33.
• Juma S, Taabazuing MM, Montero-Odasso M. Clinical Frailty Scale in an Acute Medicine Unit: a Simple Tool That Predicts Length of Stay. Can Geriatr J. 2016 Jun 29;19(2):34-9. doi: 10.5770/cgj.19.196. eCollection 2016 Jun.
• Islam A, Muir-Hunter SW, Speechley M, Montero-Odasso M. Facilitating Frailty Identification: Comparison of Two Methods among Community-Dwelling Order Adults. J Frailty Aging. 2014;3(4):216-21. doi: 10.14283/jfa.2014.27.

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2023
• Primary Completion (Anticipated): September 30, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: February 22, 2021
• First Submitted That Met QC Criteria: February 22, 2021
• First Posted (Actual): February 25, 2021

Study Record Updates

• Last Update Posted (Actual): September 28, 2022
• Last Update Submitted That Met QC Criteria: September 26, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Frailty
• Other Study ID Numbers: fUS-Frailty

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes