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Optimizing Ultrasound-induced Anti-inflammation in Human Subjects

Primary Purpose

Healthy Subjects

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Ultrasound stimulation intensity
Ultrasound stimulation site
Sponsored by
University of Virginia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Healthy Subjects focused on measuring Cholinergic anti-inflammatory pathway, Vagus nerve, Cytokines, Neuromodulation

Eligibility Criteria

25 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria: Male or female, aged 25-50 years Provision of signed and dated informed consent form Able to comprehend the study goals and procedures, stated willingness to comply with all study procedures, and availability for the duration of the study Considered English proficient so that the subject can follow verbal commands during the ultrasound procedure In good general health, as evidenced by medical history Laboratory results indicating normal blood count and adequate organ function Agreement to adhere to Lifestyle Considerations throughout study duration. Exclusion Criteria: Chronic medical conditions, including cancer (in remission or active cancer), cerebrovascular disease, chronic kidney disease, heart conditions (such as heart failure, coronary artery disease, cardiomyopathies), lung disease, liver disease, hypertension, diabetes mellitus type 1 and 2, human immunodeficiency virus infection, primary immunodeficiencies, solid organ or hematopoietic cell transplantation, tuberculosis, and cystic fibrosis, autoimmune disorders (e.g., rheumatoid arthritis, inflammatory bowel disease), sickle cell anemia or other anemia syndromes Mean systolic and diastolic blood pressure values during screening of ≥160 and ≥100 mm Hg, respectively, hypertension on non-selective beta-blockers and/or alpha-methyl dopa, or hypertension requiring more than two anti-hypertension medications Obesity (body mass index ≥30 kg/m2) Use of anti-inflammatory or immunomodulatory medication, such as non- steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or other immunosuppressants, within one week of receiving ultrasound delivery Use of anticoagulant drugs (e.g., coumadin, direct oral anticoagulants) or antiplatelet drugs (e.g., aspirin, clopidogrel) within one week of receiving ultrasound delivery Pregnancy, breastfeeding, or planning to become pregnant during the study Active bacterial or viral infection; febrile illness within 2 weeks of receiving ultrasound delivery Known allergic reactions to ultrasound gel Treatment with another investigational drug or other intervention within 1 month of receiving ultrasound delivery Any vaccination received within 1 month of receiving ultrasound delivery Current smoker or nicotine use within 2 weeks of receiving ultrasound delivery Use of recreational drugs within 2 weeks of receiving ultrasound delivery History of arrythmia (e.g., clinically significant bradycardia, atrial flutter, atrial fibrillation, ventricular arrythmias) History of deep vein thrombosis or pulmonary embolism History of bleeding disorder History of seizure History of unilateral or bilateral vagotomy Participants with an implantable medical device, such as pacemaker, hearing aid implant, or any implanted electronic device Surgery or traumatic injury (e.g., visceral injury, cerebral injury) in the past 3 months Prior surgery on thyroid or parathyroid glands, esophagus, stomach, or spleen Participant is considered by the Investigator, after reviewing medical and psychiatric history, physical examination, and laboratory evaluations, to be unsuitable for any other reason that may either place the patient at increased risk during participation or interfere with the interpretation of the study. outcomes.

Sites / Locations

  • University of Virginia, Division of Nephrology; Center for Immunity, Inflammation & Regenerative MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Group 1

Group 2

Arm Description

In Subgroup 1, individuals will receive pulsed ultrasound with a mechanical index of 0.6 and 1.4 delivered to the splenic hilum. In Subgroup 2, individuals will receive pulsed ultrasound with a mechanical index of 1.0 and 1.8 delivered to the splenic hilum. The two doses will be administered in separate visits with min. 14 days between each stimulation. In both Subgroups, the two doses will be administered in separate visits with min. 14 days between each stimulation.

Individuals will receive pulsed ultrasound with a mechanical index of 1.4 delivered to the splenic hilum and the cervical vagus nerve. The two doses will be administered in separate visits with min. 14 days between each stimulation.

Outcomes

Primary Outcome Measures

Change in concentrations of immune cells and cytokines depending on ultrasound stimulation intensity
The primary outcome is to determine ultrasound intensities that have a biological effect on immune cells measured as a statistically significant change in the level of cytokines produced by immune cells. White blood cells will be isolated from peripheral blood and treated ex vivo with inflammatory stimuli to evaluate their capacity for cytokine production. The cytokines to be measured are (all will be measured in pg/ml): sCD40L; EGF; Eotaxin; FGF-2; FLT-3L; Fractalkine; G-CSF; GM-CSF; GRO; IFNα2; IFNy; IL-1α; IL-1β; IL-1Ra; IL-2; IL-3; IL-4; IL-5; IL-6; IL-7; IL-8; IL-9; IL-10; IL-12p40; IL-12p70; IL-13; IL-15; IL-17A; IL-17E; IL-17F; IL-18; IL-22; IL-27; IP-10; MCP-1; MCP-3; M-CSF; MDC; MIG; MIP-1α; MIP-1β; PDGF-AA; PDGF-AB/BB; TGFα; TNFα; TNFβ; VEGF-A.
Change in concentrations of immune cells and cytokines depending on ultrasound stimulation site
The primary outcome is to determine the effects of spleen-targeted versus cervical vagus-targeted ultrasound stimulation on the inflammatory capacity of immune cells. This will be measured by stimulating white blood cells from peripheral blood ex vivo with inflammatory stimuli to evaluate their capacity for cytokine production. The cytokines to be measured are (all will be measured in pg/ml): sCD40L; EGF; Eotaxin; FGF-2; FLT-3L; Fractalkine; G-CSF; GM-CSF; GRO; IFNα2; IFNy; IL-1α; IL-1β; IL-1Ra; IL-2; IL-3; IL-4; IL-5; IL-6; IL-7; IL-8; IL-9; IL-10; IL-12p40; IL-12p70; IL-13; IL-15; IL-17A; IL-17E; IL-17F; IL-18; IL-22; IL-27; IP-10; MCP-1; MCP-3; M-CSF; MDC; MIG; MIP-1α; MIP-1β; PDGF-AA; PDGF-AB/BB; TGFα; TNFα; TNFβ; VEGF-A.

Secondary Outcome Measures

Distribution of immune cells
The secondary outcome is to determine the effects of ultrasound stimulation on the distribution of immune cells measured as a statistically significant change in the distribution of white blood cells using flow cytometry associated with the inflammatory response following delivery of ultrasound.

Full Information

First Posted
December 15, 2022
Last Updated
May 15, 2023
Sponsor
University of Virginia
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1. Study Identification

Unique Protocol Identification Number
NCT05685108
Brief Title
Optimizing Ultrasound-induced Anti-inflammation in Human Subjects
Official Title
Optimizing Ultrasound-induced Anti-inflammation in Human Subjects
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 1, 2022 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Virginia

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a feasibility study to determine whether pulsed ultrasound stimulation targeting the splenic nerve or the cervical vagus nerve can elicit an anti-inflammatory immune response in healthy volunteers.
Detailed Description
Recent advances have shown that neural pathways are able to regulate immunity and inflammation. The cholinergic anti-inflammatory pathway is a well-characterized neural circuit that consists of the vagus nerve to spleen circuit, which has been stimulated with implantable devices to improve autoimmune conditions such as rheumatoid arthritis. Recently, the use of pulsed ultrasonic waves to modulate the neuroimmune pathway has gained interest due to its potential in treating inflammatory disorders non-invasively. This study is designed to test the hypothesis that pulsed ultrasound stimulation can be used effectively in human subjects to control pathogenic inflammatory responses. The overall goal of this project is to determine which, if any, ultrasound stimulation protocols are able to restrict the inflammatory response of immune cells collected from healthy subjects post-ultrasound stimulation. Four different levels of ultrasound intensity ("doses") will be tested in this study to determine the dose(s) capable of producing an anti-inflammatory effect. The doses will be defined in terms of mechanical index and each subject will receive two different doses of ultrasound. In addition, the study will investigate the efficacy of cervical vagus (neck)-targeted ultrasound, given that it may have an effect similar to spleen-targeted ultrasound through upstream vagus nerve modulation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Healthy Subjects
Keywords
Cholinergic anti-inflammatory pathway, Vagus nerve, Cytokines, Neuromodulation

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
After screening, eligible participants will be assigned to one of the two groups and randomized to order of treatments.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group 1
Arm Type
Active Comparator
Arm Description
In Subgroup 1, individuals will receive pulsed ultrasound with a mechanical index of 0.6 and 1.4 delivered to the splenic hilum. In Subgroup 2, individuals will receive pulsed ultrasound with a mechanical index of 1.0 and 1.8 delivered to the splenic hilum. The two doses will be administered in separate visits with min. 14 days between each stimulation. In both Subgroups, the two doses will be administered in separate visits with min. 14 days between each stimulation.
Arm Title
Group 2
Arm Type
Active Comparator
Arm Description
Individuals will receive pulsed ultrasound with a mechanical index of 1.4 delivered to the splenic hilum and the cervical vagus nerve. The two doses will be administered in separate visits with min. 14 days between each stimulation.
Intervention Type
Device
Intervention Name(s)
Ultrasound stimulation intensity
Intervention Description
A clinical ultrasound transducer will be placed against the abdomen or neck of an individual in order to administer insonification to the splenic nerve.
Intervention Type
Device
Intervention Name(s)
Ultrasound stimulation site
Intervention Description
A clinical ultrasound transducer will be placed against the abdomen or neck of an individual in order to administer insonification to the splenic nerve and the cervical vagus nerve.
Primary Outcome Measure Information:
Title
Change in concentrations of immune cells and cytokines depending on ultrasound stimulation intensity
Description
The primary outcome is to determine ultrasound intensities that have a biological effect on immune cells measured as a statistically significant change in the level of cytokines produced by immune cells. White blood cells will be isolated from peripheral blood and treated ex vivo with inflammatory stimuli to evaluate their capacity for cytokine production. The cytokines to be measured are (all will be measured in pg/ml): sCD40L; EGF; Eotaxin; FGF-2; FLT-3L; Fractalkine; G-CSF; GM-CSF; GRO; IFNα2; IFNy; IL-1α; IL-1β; IL-1Ra; IL-2; IL-3; IL-4; IL-5; IL-6; IL-7; IL-8; IL-9; IL-10; IL-12p40; IL-12p70; IL-13; IL-15; IL-17A; IL-17E; IL-17F; IL-18; IL-22; IL-27; IP-10; MCP-1; MCP-3; M-CSF; MDC; MIG; MIP-1α; MIP-1β; PDGF-AA; PDGF-AB/BB; TGFα; TNFα; TNFβ; VEGF-A.
Time Frame
Immune cells will be stimulated and assessed prior to and within 24 to 48 hours post-ultrasound treatment. Results of Luminex analysis of the pre- and post-ultrasound stimulation supernatants will be compared to quantify the impacts of the treatment.
Title
Change in concentrations of immune cells and cytokines depending on ultrasound stimulation site
Description
The primary outcome is to determine the effects of spleen-targeted versus cervical vagus-targeted ultrasound stimulation on the inflammatory capacity of immune cells. This will be measured by stimulating white blood cells from peripheral blood ex vivo with inflammatory stimuli to evaluate their capacity for cytokine production. The cytokines to be measured are (all will be measured in pg/ml): sCD40L; EGF; Eotaxin; FGF-2; FLT-3L; Fractalkine; G-CSF; GM-CSF; GRO; IFNα2; IFNy; IL-1α; IL-1β; IL-1Ra; IL-2; IL-3; IL-4; IL-5; IL-6; IL-7; IL-8; IL-9; IL-10; IL-12p40; IL-12p70; IL-13; IL-15; IL-17A; IL-17E; IL-17F; IL-18; IL-22; IL-27; IP-10; MCP-1; MCP-3; M-CSF; MDC; MIG; MIP-1α; MIP-1β; PDGF-AA; PDGF-AB/BB; TGFα; TNFα; TNFβ; VEGF-A.
Time Frame
Immune cells will be stimulated and assessed prior to and within 24 to 48 hours post-ultrasound treatment. Results of Luminex analysis of the pre- and post-ultrasound stimulation supernatants will be compared to quantify the impacts of the treatment.
Secondary Outcome Measure Information:
Title
Distribution of immune cells
Description
The secondary outcome is to determine the effects of ultrasound stimulation on the distribution of immune cells measured as a statistically significant change in the distribution of white blood cells using flow cytometry associated with the inflammatory response following delivery of ultrasound.
Time Frame
The secondary outcome will be assessed before and max 48-hours after receiving ultrasound stimulation.
Other Pre-specified Outcome Measures:
Title
Participant comfort, experience, and new-onset sensations by questionnaire
Description
Participants will complete a questionnaire based on a dichotomous scale ("yes" or "no") to evaluate their experience of discomfort and new-onset sensations following ultrasound stimulation.
Time Frame
The outcome will be assessed immediately after, within 24 to 48 hours, and 2 weeks after receiving ultrasound stimulation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Male or female, aged 25-50 years Provision of signed and dated informed consent form Able to comprehend the study goals and procedures, stated willingness to comply with all study procedures, and availability for the duration of the study Considered English proficient so that the subject can follow verbal commands during the ultrasound procedure In good general health, as evidenced by medical history Laboratory results indicating normal blood count and adequate organ function Agreement to adhere to Lifestyle Considerations throughout study duration. Exclusion Criteria: Chronic medical conditions, including cancer (in remission or active cancer), cerebrovascular disease, chronic kidney disease, heart conditions (such as heart failure, coronary artery disease, cardiomyopathies), lung disease, liver disease, hypertension, diabetes mellitus type 1 and 2, human immunodeficiency virus infection, primary immunodeficiencies, solid organ or hematopoietic cell transplantation, tuberculosis, and cystic fibrosis, autoimmune disorders (e.g., rheumatoid arthritis, inflammatory bowel disease), sickle cell anemia or other anemia syndromes Mean systolic and diastolic blood pressure values during screening of ≥160 and ≥100 mm Hg, respectively, hypertension on non-selective beta-blockers and/or alpha-methyl dopa, or hypertension requiring more than two anti-hypertension medications Obesity (body mass index ≥30 kg/m2) Use of anti-inflammatory or immunomodulatory medication, such as non- steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or other immunosuppressants, within one week of receiving ultrasound delivery Use of anticoagulant drugs (e.g., coumadin, direct oral anticoagulants) or antiplatelet drugs (e.g., aspirin, clopidogrel) within one week of receiving ultrasound delivery Pregnancy, breastfeeding, or planning to become pregnant during the study Active bacterial or viral infection; febrile illness within 2 weeks of receiving ultrasound delivery Known allergic reactions to ultrasound gel Treatment with another investigational drug or other intervention within 1 month of receiving ultrasound delivery Any vaccination received within 1 month of receiving ultrasound delivery Current smoker or nicotine use within 2 weeks of receiving ultrasound delivery Use of recreational drugs within 2 weeks of receiving ultrasound delivery History of arrythmia (e.g., clinically significant bradycardia, atrial flutter, atrial fibrillation, ventricular arrythmias) History of deep vein thrombosis or pulmonary embolism History of bleeding disorder History of seizure History of unilateral or bilateral vagotomy Participants with an implantable medical device, such as pacemaker, hearing aid implant, or any implanted electronic device Surgery or traumatic injury (e.g., visceral injury, cerebral injury) in the past 3 months Prior surgery on thyroid or parathyroid glands, esophagus, stomach, or spleen Participant is considered by the Investigator, after reviewing medical and psychiatric history, physical examination, and laboratory evaluations, to be unsuitable for any other reason that may either place the patient at increased risk during participation or interfere with the interpretation of the study. outcomes.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mark D. Okusa, MD, FASN
Phone
+14349242187
Email
mdo7y@virginia.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Igor A. Shumilin, PhD
Phone
+14349249691
Email
IAS2N@hscmail.mcc.virginia.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark D. Okusa, MD, FASN
Organizational Affiliation
University of Virginia
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Virginia, Division of Nephrology; Center for Immunity, Inflammation & Regenerative Medicine
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22903
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mark D. Okusa, MD, FASN
Phone
434-924-2187
Email
mdo7y@virginia.edu
First Name & Middle Initial & Last Name & Degree
Igor A. Shumilin, PhD
Phone
+14349249691
Email
IAS2N@hscmail.mcc.virginia.edu

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Currently, there are no plans to make individual participant data available.
Citations:
PubMed Identifier
28970585
Citation
Okusa MD, Rosin DL, Tracey KJ. Targeting neural reflex circuits in immunity to treat kidney disease. Nat Rev Nephrol. 2017 Nov;13(11):669-680. doi: 10.1038/nrneph.2017.132. Epub 2017 Oct 3.
Results Reference
background
PubMed Identifier
32508112
Citation
Cai J, Nash WT, Okusa MD. Ultrasound for the treatment of acute kidney injury and other inflammatory conditions: a promising path toward noninvasive neuroimmune regulation. Am J Physiol Renal Physiol. 2020 Jul 1;319(1):F125-F138. doi: 10.1152/ajprenal.00145.2020. Epub 2020 Jun 8.
Results Reference
background
PubMed Identifier
25644106
Citation
Gigliotti JC, Huang L, Bajwa A, Ye H, Mace EH, Hossack JA, Kalantari K, Inoue T, Rosin DL, Okusa MD. Ultrasound Modulates the Splenic Neuroimmune Axis in Attenuating AKI. J Am Soc Nephrol. 2015 Oct;26(10):2470-81. doi: 10.1681/ASN.2014080769. Epub 2015 Feb 2.
Results Reference
background
PubMed Identifier
30862827
Citation
Cotero V, Fan Y, Tsaava T, Kressel AM, Hancu I, Fitzgerald P, Wallace K, Kaanumalle S, Graf J, Rigby W, Kao TJ, Roberts J, Bhushan C, Joel S, Coleman TR, Zanos S, Tracey KJ, Ashe J, Chavan SS, Puleo C. Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation. Nat Commun. 2019 Mar 12;10(1):952. doi: 10.1038/s41467-019-08750-9. Erratum In: Nat Commun. 2020 Mar 9;11(1):1336.
Results Reference
background

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Optimizing Ultrasound-induced Anti-inflammation in Human Subjects

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