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Closed Loop Vagal Nerve Stimulation for Patients With Posttraumatic Stress Disorder

Primary Purpose

PostTraumatic Stress Disorder

Status

Completed

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

GammaCore/electroCore non-invasive VNS device

Sham gammaCore/electroCore

O-15 water

About this trial

This is an interventional other trial for PostTraumatic Stress Disorder focused on measuring stress disorders, post-traumatic, posttraumatic stress disorder, PTSD, vagal nerve

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Phase 1:

Do not meet criteria for post traumatic stress disorder (PTSD) or other major mental disorder as determined by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5 SCID) interview for PTSD
Have a history of psychological trauma as defined by DSM-5.

Phase 2:

- Meet criteria for PTSD as determined by the Structured Clinical Interview for DSM-5 (SCID) interview for PTSD.

Exclusion Criteria:

Positive pregnancy test
Meningitis
Traumatic brain injury
Neurological disorder or organic mental disorder
History of loss of consciousness greater than one minute
Alcohol abuse or substance abuse or dependence based on the SCID within the past 12 months
Positive toxicology screen
Current or lifetime history of schizophrenia, schizoaffective disorder, or bulimia, based on the SCID
A history of serious medical or neurological illness, such as cardiovascular, gastrointestinal, hepatic, renal, neurologic or other systemic illness
Evidence of a major medical or neurological illness on physical examination or as a result of laboratory studies (complete blood count (CBC), blood urea nitrogen (BUN), creatinine, blood sugar, electrolytes, liver and thyroid function tests, urinalysis, and EKG)
Active implantable device (i.e. pacemaker)
Carotid atherosclerosis
Cervical vagotomy

Sites / Locations

Emory University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Vagal Nerve Stimulation

Sham Stimulation

Arm Description

Participants randomized to this arm will receive stimulation of the vagus nerve in conjunction with stress exposure.

Participants randomized to this arm will receive sham stimulation of the vagus nerve in conjunction with stress exposure.

Outcomes

Primary Outcome Measures

Level of Interleukin-6 (IL6)

IL6 level will be collected via blood draw. Change is defined as the difference in IL6 level from baseline to post emotional stress testing.

Secondary Outcome Measures

Level of Tryptophan

Tryptophan level will be collected via blood draw. Change is defined as the difference in tryptophan level from baseline to post emotional stress testing.

Level of Kynurenine

Kynurenine level will be collected via blood draw. Change is defined as the difference in kynurenine level from baseline to post emotional stress testing.

Level of Kynurenic Acid

Kynurenic acid level will be collected via blood draw. Change is defined as the difference in kynurenic acid level from baseline to post emotional stress testing.

Level of 3-3 Hydroxykynurenine

3-3 hydroxykynurenine level will be collected via blood draw. Change is defined as the difference in 3-3 hydroxykynurenine level from baseline to post emotional stress testing.

Level of Anthranilic Acid

Anthranilic Acid level will be collected via blood draw. Change is defined as the difference in anthranilic acid level from baseline to post emotional stress testing.

Level of Tumor Necrosis Factor (TNF)-Alpha

TNF-alpha level will be collected via blood draw. Change is defined as the difference in TNF-alpha level from baseline to post emotional stress testing.

Level of Interferon-Gamma

Interferon-Gamma level will be collected via blood draw. Change is defined as the difference in Interferon-Gamma level from baseline to post emotional stress testing.

Level of Interleukin-1 Beta

Interleukin-1 Beta level will be collected via blood draw. Change is defined as the difference in Interleukin-1 Beta level from baseline to post emotional stress testing.

Level of Interleukin-2 (IL2)

IL2 level will be collected via blood draw. Change is defined as the difference in IL2 level from baseline to post emotional stress testing.

Level of Interleukin-4 (IL4)

IL4 level will be collected via blood draw. Change is defined as the difference in IL4 level from baseline to post emotional stress testing.

Level of Interleukin-8 (IL8)

IL8 level will be collected via blood draw. Change is defined as the difference in IL8 level from baseline to post emotional stress testing.

Level of Interleukin-10 (IL10)

IL10 level will be collected via blood draw. Change is defined as the difference in IL10 level from baseline to post emotional stress testing.

Level of Interleukin-12p70 (IL12p70)

IL12p70 level will be collected via blood draw. Change is defined as the difference in IL12p70 level from baseline to post emotional stress testing.

Level of Interleukin-12p (IL12p)

IL12p level will be collected via blood draw. Change is defined as the difference in IL12p level from baseline to post emotional stress testing.

Level of Interleukin-13 (IL13)

IL13 level will be collected via blood draw. Change is defined as the difference in IL13 level from baseline to post emotional stress testing.

Level of Macrophage Migration Inhibitory Factor

Macrophage migration inhibitory factor will be collected via blood draw. Change is defined as the difference in factor level from baseline to post emotional stress testing.

Level of High-Mobility Group Protein B1

High-mobility group protein B1 level will be collected via blood draw. Change is defined as the difference in high-mobility group protein B1 level from baseline to post emotional stress testing.

Level of Adrenocorticotropic Hormone

Adrenocorticotropic hormone level will be collected via blood draw. Change is defined as the difference in adrenocorticotropic hormone level from baseline to post emotional stress testing.

Level of Cortisol

Cortisol level will be collected via blood draw. Change is defined as the difference in cortisol level from baseline to post emotional stress testing.

Level of Epinephrine

Epinephrine level will be collected via blood draw. Change is defined as the difference in epinephrine level from baseline to post emotional stress testing.

Level of Dopamine

Dopamine level will be collected via blood draw. Change is defined as the difference in dopamine level from baseline to post emotional stress testing.

Level of Norepinephrine

Norepinephrine level will be collected via blood draw. Change is defined as the difference in norepinephrine level from baseline to post emotional stress testing.

Full Information

NCT ID

NCT02992899

First Posted

December 12, 2016

Last Updated

May 20, 2021

Sponsor

Emory University

Collaborators

Georgia Institute of Technology

1. Study Identification

Unique Protocol Identification Number

NCT02992899

Brief Title

Closed Loop Vagal Nerve Stimulation for Patients With Posttraumatic Stress Disorder

Official Title

Closed Loop Vagal Nerve Stimulation in Patients With Posttraumatic Stress Disorder

Study Type

Interventional

2. Study Status

Record Verification Date

May 2021

Overall Recruitment Status

Completed

Study Start Date

April 19, 2017 (Actual)

Primary Completion Date

September 21, 2019 (Actual)

Study Completion Date

September 21, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Emory University

Collaborators

Georgia Institute of Technology

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The tasks of the project are to map the potency and kinetics of the neurologic, autonomic peripheral, inflammatory, and behavioral responses to vagal nerve stimulation (VNS) vs. sham treatment, at baseline and in response to stressful traumatic scripts related to personal traumatic events, as well as a series of other stressors.

Detailed Description

The purpose of this project is to develop the fundamental physiological understanding of feedback controlled vagal nerve stimulation (VNS) using positron emission tomography (PET) brain imaging and blood biomarker measurement with stress in healthy individuals and individuals with PTSD. Healthy human subjects with a history of psychological trauma but without the diagnosis of a psychiatric disorder (Phase 1), and human subjects with a history of PTSD (Phase 2), undergo PET imaging of the brain in conjunction with VNS or a sham treatment during exposure to neutral scripts and scripts of personal traumatic events. Blood is drawn simultaneously for measurement of a variety of stress responsive biomarkers, including inflammatory markers and neurohormones. A second PET scan with biomarkers assesses the delayed effects of VNS. On two other days subjects undergo exposure to random stressors with VNS or sham in conjunction with measurement of stress biomarkers.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

PostTraumatic Stress Disorder

Keywords

stress disorders, post-traumatic, posttraumatic stress disorder, PTSD, vagal nerve

7. Study Design

Primary Purpose

Other

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Participant

Allocation

Randomized

Enrollment

56 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Vagal Nerve Stimulation

Arm Type

Experimental

Arm Description

Participants randomized to this arm will receive stimulation of the vagus nerve in conjunction with stress exposure.

Arm Title

Sham Stimulation

Arm Type

Sham Comparator

Arm Description

Participants randomized to this arm will receive sham stimulation of the vagus nerve in conjunction with stress exposure.

Intervention Type

Device

Intervention Name(s)

GammaCore/electroCore non-invasive VNS device

Intervention Description

Vasal nerve stimulation (VNS) is self-administered using the electroCore non-invasive VNS device. The intensity of the stimulus (the current amplitude) is adjusted by the user, to the maximum tolerable level to ensure VNS without causing excessive pain (typically 10-30 V), the burst frequency to 5 kilohertz (kHz), and the envelope frequency to 25 Hz. These are the standard frequency settings that electroCore has demonstrated to be most effective in capturing the vagus nerve based on evoked potential studies. The duration of delivery is 2 minutes, one minute into which the high-resolution positron emission tomography (HR-PET) scan is conducted; following an additional 8 minutes, a second VNS delivery is administered, after which another scan is obtained.

Intervention Type

Device

Intervention Name(s)

Sham gammaCore/electroCore

Intervention Description

Sham vasal nerve stimulation (VNS) is self-administered using the electroCore non-invasive VNS device. The device is programmed such that no actual stimulation is given to the vagus nerve. The duration of delivery is 2 minutes, one minute into which the HR-PET scan is conducted; following an additional 8 minutes, a second sham VNS delivery is administered, after which another scan is obtained.

Intervention Type

Drug

Intervention Name(s)

O-15 water

Intervention Description

Oxygen-15 labelled water is a radioactive variation of regular water, in which the oxygen atom has been replaced by oxygen-15 (15O), a positron-emitting isotope. 15O-water is used as a radioactive tracer for measuring and quantifying blood flow using positron emission tomography (PET) . H2[15O] will be prepared on-site in the Emory PET Center cyclotron. During the hours of the test, an intravenous infusion of normal saline will be started to permit the bolus injection of H2[15O]. Subjects will receive a 20 mCi intravenous bolus of H2[15O] for each of the 14 scans during exposure to neutral and traumatic scripts.

Primary Outcome Measure Information:

Title

Level of Interleukin-6 (IL6)

Description

IL6 level will be collected via blood draw. Change is defined as the difference in IL6 level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Secondary Outcome Measure Information:

Title

Level of Tryptophan

Description

Tryptophan level will be collected via blood draw. Change is defined as the difference in tryptophan level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Kynurenine

Description

Kynurenine level will be collected via blood draw. Change is defined as the difference in kynurenine level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Kynurenic Acid

Description

Kynurenic acid level will be collected via blood draw. Change is defined as the difference in kynurenic acid level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of 3-3 Hydroxykynurenine

Description

3-3 hydroxykynurenine level will be collected via blood draw. Change is defined as the difference in 3-3 hydroxykynurenine level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Anthranilic Acid

Description

Anthranilic Acid level will be collected via blood draw. Change is defined as the difference in anthranilic acid level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Tumor Necrosis Factor (TNF)-Alpha

Description

TNF-alpha level will be collected via blood draw. Change is defined as the difference in TNF-alpha level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Interferon-Gamma

Description

Interferon-Gamma level will be collected via blood draw. Change is defined as the difference in Interferon-Gamma level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Interleukin-1 Beta

Description

Interleukin-1 Beta level will be collected via blood draw. Change is defined as the difference in Interleukin-1 Beta level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Interleukin-2 (IL2)

Description

IL2 level will be collected via blood draw. Change is defined as the difference in IL2 level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Interleukin-4 (IL4)

Description

IL4 level will be collected via blood draw. Change is defined as the difference in IL4 level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Interleukin-8 (IL8)

Description

IL8 level will be collected via blood draw. Change is defined as the difference in IL8 level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Interleukin-10 (IL10)

Description

IL10 level will be collected via blood draw. Change is defined as the difference in IL10 level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Interleukin-12p70 (IL12p70)

Description

IL12p70 level will be collected via blood draw. Change is defined as the difference in IL12p70 level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Interleukin-12p (IL12p)

Description

IL12p level will be collected via blood draw. Change is defined as the difference in IL12p level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Interleukin-13 (IL13)

Description

IL13 level will be collected via blood draw. Change is defined as the difference in IL13 level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Macrophage Migration Inhibitory Factor

Description

Macrophage migration inhibitory factor will be collected via blood draw. Change is defined as the difference in factor level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of High-Mobility Group Protein B1

Description

High-mobility group protein B1 level will be collected via blood draw. Change is defined as the difference in high-mobility group protein B1 level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Adrenocorticotropic Hormone

Description

Adrenocorticotropic hormone level will be collected via blood draw. Change is defined as the difference in adrenocorticotropic hormone level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Cortisol

Description

Cortisol level will be collected via blood draw. Change is defined as the difference in cortisol level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Epinephrine

Description

Epinephrine level will be collected via blood draw. Change is defined as the difference in epinephrine level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Dopamine

Description

Dopamine level will be collected via blood draw. Change is defined as the difference in dopamine level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

Title

Level of Norepinephrine

Description

Norepinephrine level will be collected via blood draw. Change is defined as the difference in norepinephrine level from baseline to post emotional stress testing.

Time Frame

Baseline, Post Stress Testing (Up to 4 Hours)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Phase 1: Do not meet criteria for post traumatic stress disorder (PTSD) or other major mental disorder as determined by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5 SCID) interview for PTSD Have a history of psychological trauma as defined by DSM-5. Phase 2: - Meet criteria for PTSD as determined by the Structured Clinical Interview for DSM-5 (SCID) interview for PTSD. Exclusion Criteria: Positive pregnancy test Meningitis Traumatic brain injury Neurological disorder or organic mental disorder History of loss of consciousness greater than one minute Alcohol abuse or substance abuse or dependence based on the SCID within the past 12 months Positive toxicology screen Current or lifetime history of schizophrenia, schizoaffective disorder, or bulimia, based on the SCID A history of serious medical or neurological illness, such as cardiovascular, gastrointestinal, hepatic, renal, neurologic or other systemic illness Evidence of a major medical or neurological illness on physical examination or as a result of laboratory studies (complete blood count (CBC), blood urea nitrogen (BUN), creatinine, blood sugar, electrolytes, liver and thyroid function tests, urinalysis, and EKG) Active implantable device (i.e. pacemaker) Carotid atherosclerosis Cervical vagotomy

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

James D Bremner, MD

Organizational Affiliation

Emory University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Emory University

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

34292205

Citation

Wittbrodt MT, Gurel NZ, Nye JA, Shandhi MMH, Gazi AH, Shah AJ, Pearce BD, Murrah N, Ko YA, Shallenberger LH, Vaccarino V, Inan OT, Bremner JD. Noninvasive Cervical Vagal Nerve Stimulation Alters Brain Activity During Traumatic Stress in Individuals With Posttraumatic Stress Disorder. Psychosom Med. 2021 Nov-Dec 01;83(9):969-977. doi: 10.1097/PSY.0000000000000987.

Results Reference

derived

PubMed Identifier

33344717

Citation

Gurel NZ, Wittbrodt MT, Jung H, Shandhi MMH, Driggers EG, Ladd SL, Huang M, Ko YA, Shallenberger L, Beckwith J, Nye JA, Pearce BD, Vaccarino V, Shah AJ, Inan OT, Bremner JD. Transcutaneous cervical vagal nerve stimulation reduces sympathetic responses to stress in posttraumatic stress disorder: A double-blind, randomized, sham controlled trial. Neurobiol Stress. 2020 Oct 20;13:100264. doi: 10.1016/j.ynstr.2020.100264. eCollection 2020 Nov.

Results Reference

derived

PubMed Identifier

32960179

Citation

Gazi AH, Gurel NZ, Richardson KLS, Wittbrodt MT, Shah AJ, Vaccarino V, Bremner JD, Inan OT. Digital Cardiovascular Biomarker Responses to Transcutaneous Cervical Vagus Nerve Stimulation: State-Space Modeling, Prediction, and Simulation. JMIR Mhealth Uhealth. 2020 Sep 22;8(9):e20488. doi: 10.2196/20488.

Results Reference

derived

Learn more about this trial

Closed Loop Vagal Nerve Stimulation for Patients With Posttraumatic Stress Disorder

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