Clinical trial NCT05685108: Optimizing Ultrasound-induced Anti-inflammation in Human Subjects
Official title: Optimizing Ultrasound-induced Anti-inflammation in Human Subjects
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Healthy Subjects
Keywords: Cholinergic anti-inflammatory pathway
Vagus nerve
Cytokines
Neuromodulation
Lead sponsor: University of Virginia
Sponsor class: OTHER
First posted: 2023-01-13
Enrollment: 30
Sex: ALL
Minimum age (years): 25
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: After screening, eligible participants will be assigned to one of the two groups and randomized to order of treatments.
Primary purpose: BASIC_SCIENCE

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.

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.

Primary outcomes:
measure: Change in concentrations of immune cells and cytokines depending on ultrasound stimulation intensity
timeFrame: 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.
measure: Change in concentrations of immune cells and cytokines depending on ultrasound stimulation site
timeFrame: 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 outcomes:
measure: Distribution of immune cells
timeFrame: The secondary outcome will be assessed before and max 48-hours after receiving ultrasound stimulation.
Other outcomes:
measure: Participant comfort, experience, and new-onset sensations by questionnaire
timeFrame: The outcome will be assessed immediately after, within 24 to 48 hours, and 2 weeks after receiving ultrasound stimulation
Locations:
city: Charlottesville
country: United States
facility: University of Virginia, Division of Nephrology; Center for Immunity, Inflammation & Regenerative Medicine
state: Virginia
Study officials:
affiliation: University of Virginia
name: Mark D. Okusa, MD, FASN
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.