Effect of Transcutaneous Electrical Auricular Stimulation of the Vagus Nerve in Kidney Transplant Recipients

NCT04256837 | Terminated DMC

• 1 other identifier: 19-0705
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

Kidney transplantation entails the implantation of a live or deceased organ into a recipient. As a result of this event, there is an inflammatory response in the recipient elicited by the transplanted organ. At the present time, immunosuppressive treatments are routinely used to avoid rejection of the transplanted organ. Although effective in this goal, there is currently an unmet need to develop new strategies to control the innate inflammatory responses and to reduce the injury caused to the organs being transplanted. The investigators propose a novel approach to the management of this inflammatory response. The investigators will explore the "cholinergic anti-inflammatory pathway" as a potential target, a pathway first characterized in the basic science laboratories of the Feinstein Institute for Medical Research. In short, the vagus nerve activates the splenic nerve which activates choline acetyltransferase expressing T cells in the spleen. Stimulation of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) on macrophages by acetylcholine reduces production of multiple pro-inflammatory cytokines. Currently, vagus nerve stimulation is used to treat a number of human diseases, including epilepsy, depression and migraine headaches. Many of these treatments activate the vagus nerve non-invasively by stimulating a branch of the vagus that innervates the ear. In this study, the investigators will stimulate this branch of the vagus nerve, and look for changes in inflammatory markers in the blood of kidney transplant recipients of both live and deceased donors. Successful completion of this study will allow for future studies in organ transplant recipients.

Conditions

Vagus Nerve Stimulation

Keywords

Vagus Nerve; Stimulation; Immune System

Outcome Measures

Primary Outcomes (1)

• Levels of blood inflammatory cytokines in kidney transplant recipients after transcutaneous auricular electrical vagus nerve stimulation.

  The present study will measure systemic cytokines IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, IL-22, IL-23, TNF, IFN-gamma, HMGB1, TGF-beta, GM-CSF, CXCL8, G-CSFas well as complement 1-9 in the blood of kidney transplant recipients who have undergone transcutaneous auricular electrical vagus nerve stimulation.

  24 months

Study Arms (4)

VNS - Live donor kidney recipients.

EXPERIMENTAL

Live donor kidney recipients. VNS will be applied for 5 minutes prior to start of surgery. The device to be used for VNS will include a handheld electrical pulse generator and a pair of electrodes to be placed at the left ear for stimulation, targeting the auricular branch of the vagus nerve which innervates the skin overlying the cymba conchae of the ear canal.

Device: Transcutaneous electrical auricular vagus nerve stimulation (VNS)

sham VNS - Live donor kidney recipients.

SHAM COMPARATOR

Live donor kidney recipients. As above, but without applying any VNS

Device: Transcutaneous electrical auricular vagus nerve stimulation (VNS)

VNS - Deceased donor kidney recipients.

EXPERIMENTAL

Deceased donor kidney recipients. VNS will be applied for 5 minutes prior to start of surgery. The device to be used for VNS will include a handheld electrical pulse generator and a pair of electrodes to be placed at the left ear for stimulation, targeting the auricular branch of the vagus nerve which innervates the skin overlying the cymba conchae of the ear canal.

Device: Transcutaneous electrical auricular vagus nerve stimulation (VNS)

sham VNS - Deceased donor kidney recipients.

SHAM COMPARATOR

Deceased donor kidney recipients. As above, but without applying any VNS

Device: Transcutaneous electrical auricular vagus nerve stimulation (VNS)

Interventions

Transcutaneous electrical auricular vagus nerve stimulation (VNS) DEVICE

Electrical auricular stimulation is accomplished using a Roscoe Medical TENS 7000 that delivers a programmable electrical current density, frequency, and pulse width. The TENS 7000 will be connected to ear clip (or hand held) electrodes to transcutaneously stimulate the cymba conchae of the ear to activate the auricular branch of the vagus nerve (diagram above), also known as Arnold's nerve, which provides sensory innervation to the skin surrounding the ear canal. Through a neural reflex arc, activation of this sensory nerve sends a neural signal to the brainstem that then activates the efferent vagus nerve through the nucleus of the solitary tract (NTS). This is a well-described and clinically accepted neuromodulatory pathway, as transcutaneous electrical auricular stimulation has been studied to treat seizures, similarly to how invasive electrical vagus nerve stimulation has been approved by the FDA for the past two decades for the same indication.

VNS - Deceased donor kidney recipients.; VNS - Live donor kidney recipients.; sham VNS - Deceased donor kidney recipients.; sham VNS - Live donor kidney recipients.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Kidney transplant recipients of both live and deceased donors

You may not qualify if:

• Refusal to participate in the study

Sponsors & Collaborators

• Northwell Health: lead

Study Sites (1)

Northwell Health

Manhasset, New York, 11030, United States

Location

Related Publications (18)

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  PMID: 25835947 BACKGROUND

• Yuan H, Silberstein SD. Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part II. Headache. 2016 Feb;56(2):259-66. doi: 10.1111/head.12650. Epub 2015 Sep 18.

  PMID: 26381725 BACKGROUND

• Ben-Menachem E. Vagus nerve stimulation, side effects, and long-term safety. J Clin Neurophysiol. 2001 Sep;18(5):415-8. doi: 10.1097/00004691-200109000-00005.

  PMID: 11709646 BACKGROUND

• Yuan H, Silberstein SD. Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part III. Headache. 2016 Mar;56(3):479-90. doi: 10.1111/head.12649. Epub 2015 Sep 14.

  PMID: 26364805 BACKGROUND

• Ben-Menachem E, Revesz D, Simon BJ, Silberstein S. Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Eur J Neurol. 2015 Sep;22(9):1260-8. doi: 10.1111/ene.12629. Epub 2015 Jan 23.

  PMID: 25614179 BACKGROUND

• Kreuzer PM, Landgrebe M, Husser O, Resch M, Schecklmann M, Geisreiter F, Poeppl TB, Prasser SJ, Hajak G, Langguth B. Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. Front Psychiatry. 2012 Aug 7;3:70. doi: 10.3389/fpsyt.2012.00070. eCollection 2012.

  PMID: 22891061 BACKGROUND

• Shim HJ, Kwak MY, An YH, Kim DH, Kim YJ, Kim HJ. Feasibility and Safety of Transcutaneous Vagus Nerve Stimulation Paired with Notched Music Therapy for the Treatment of Chronic Tinnitus. J Audiol Otol. 2015 Dec;19(3):159-67. doi: 10.7874/jao.2015.19.3.159. Epub 2015 Dec 18.

  PMID: 26771015 BACKGROUND

• Huston JM, Tracey KJ. The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J Intern Med. 2011 Jan;269(1):45-53. doi: 10.1111/j.1365-2796.2010.02321.x.

  PMID: 21158977 BACKGROUND

• Huston JM, Rosas-Ballina M, Xue X, Dowling O, Ochani K, Ochani M, Yeboah MM, Chatterjee PK, Tracey KJ, Metz CN. Cholinergic neural signals to the spleen down-regulate leukocyte trafficking via CD11b. J Immunol. 2009 Jul 1;183(1):552-9. doi: 10.4049/jimmunol.0802684.

  PMID: 19542466 BACKGROUND

• Huston JM, Wang H, Ochani M, Ochani K, Rosas-Ballina M, Gallowitsch-Puerta M, Ashok M, Yang L, Tracey KJ, Yang H. Splenectomy protects against sepsis lethality and reduces serum HMGB1 levels. J Immunol. 2008 Sep 1;181(5):3535-9. doi: 10.4049/jimmunol.181.5.3535.

  PMID: 18714026 BACKGROUND

• Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, Chavan S, Tracey KJ. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):11008-13. doi: 10.1073/pnas.0803237105. Epub 2008 Jul 31.

  PMID: 18669662 BACKGROUND

• Huston JM, Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M, Ashok M, Goldstein RS, Chavan S, Pavlov VA, Metz CN, Yang H, Czura CJ, Wang H, Tracey KJ. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit Care Med. 2007 Dec;35(12):2762-8. doi: 10.1097/01.CCM.0000288102.15975.BA.

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• Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K, Pavlov VA, Gallowitsch-Puerta M, Ashok M, Czura CJ, Foxwell B, Tracey KJ, Ulloa L. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med. 2006 Jul 10;203(7):1623-8. doi: 10.1084/jem.20052362. Epub 2006 Jun 19.

  PMID: 16785311 BACKGROUND

• Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA, Reardon C, Tusche MW, Pavlov VA, Andersson U, Chavan S, Mak TW, Tracey KJ. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011 Oct 7;334(6052):98-101. doi: 10.1126/science.1209985. Epub 2011 Sep 15.

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• Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, Al-Abed Y, Wang H, Metz C, Miller EJ, Tracey KJ, Ulloa L. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004 Nov;10(11):1216-21. doi: 10.1038/nm1124. Epub 2004 Oct 24.

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• Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003 Jan 23;421(6921):384-8. doi: 10.1038/nature01339. Epub 2002 Dec 22.

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  PMID: 10839541 BACKGROUND

Study Officials

• Ernesto P Molmenti, MD PhD MBA

  Northwell Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: A randomization schema will be generated by the BU-FIMR by study strata (recipients of a kidney from a living donor and recipients of a kidney from a deceased donor) using the method of permuted blocks. For those receiving their kidneys from living donors, subjects will be randomly assigned in a 1:1 ratio to either 'aVNS' or 'sVNS. For those receiving their kidneys from deceased donors, subjects will also be randomly assigned in a 1:1 ratio to either 'aVNS' or 'sVNS'. Details of the randomization procedure, including required record keeping will be further developed upon approval of the protocol.
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The objective of this pilot, feasibility study is to examine the effects of transcutaneous electrical auricular vagus nerve stimulation (VNS) in adult patients undergoing a single kidney transplant using donors who are either living or deceased. Kidney transplantation patients will be stratified into two groups, namely, those receiving their kidney from a living donor and those receiving their kidney from a deceased donor. Within each strata, patients will be randomized to receive either active VNS or sham VNS. VNS will be applied for 5 minutes prior to start of surgery. The device to be used for VNS will include a handheld electrical pulse generator and a pair of electrodes to be placed at the left ear for stimulation, targeting the auricular branch of the vagus nerve which innervates the skin overlying the cymba conchae of the ear canal.

Study Record Dates

• First Submitted: January 21, 2020
• First Posted: February 5, 2020
• Study Start: January 13, 2020
• Primary Completion: January 7, 2021
• Study Completion: January 7, 2021
• Last Updated: December 14, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)