TRUST: Transcutaneous Vagus Nerve Stimulation for the Treatment of Lupus

• Sponsor: Aikaterini Thanou (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02917265
• Collaborator: Oklahoma Medical Research Foundation (Other), University of Oklahoma (Other)
• Enrollment: 7
• Location: 1
• Arms: 2
• Actual Duration (Months): 36
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a 3-month double blinded randomized controlled study of transcutaneous electrical vagus nerve stimulation (tVNS) compared to a sham stimulation for the treatment of patients with active systemic lupus erythematosus (SLE).

Condition or Disease	Intervention/Treatment	Phase
Systemic Lupus Erythematosus	Device: TENS for vagus stimulation; Device: TENS for sham stimulation	Phase 2

Detailed Description

Patients with SLE and active, non-organ-threatening disease are eligible to participate in this prospective randomized double blind trial of active or sham transcutaneous electrical vagus nerve stimulation (tVNS). Active tNVS is performed by the use of a transcutaneous electrical nerve stimulation (TENS) device with electrodes attached to an area of the external ear innervated by the auricular branch of the vagus nerve. The same protocol is followed in the sham tVNS arm, but the pads are placed on an area of the external ear that is devoid of vagus innervation.TENS is applied for 60 to 120 minutes daily as tolerated and participants keep a detailed log of their daily TENS sessions. Patients return to clinic at weeks 4, 8 and 12 for study related assessments.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Transcutaneous Vagus Nerve Stimulation for the Treatment of Systemic Lupus Erythematosus
• Actual Study Start Date: Nov 1, 2015
• Actual Primary Completion Date: May 1, 2017
• Actual Study Completion Date: Nov 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TENS for vagus stimulation A transcutaneous electrical nerve stimulation (TENS) unit is applied to an area of the external ear that is innervated by the auricular branch of the vagus nerve.	Device: TENS for vagus stimulation; TENS electrodes are applied on an area of the external ear innervated by the auricular branch of the vagus nerve.
Sham Comparator: TENS for sham stimulation A TENS unit is applied to an area of the external ear that is devoid of vagus innervation.	Device: TENS for sham stimulation; TENS electrodes are applied on an area of the external ear devoid of vagus innervation.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA) [12 weeks]

   Achieving a BICLA response requires to meet all of the following parameters: All British Isles Lupus Assessment Group (BILAG) A scores improving to B/C/D and all BILAG level B scores improving to C/D No single new BILAG A & not >1 new BILAG B scores, no worsening of the baseline Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) total score AND no worsening in the Physician Global Assessment (PGA) (<10% worsening from baseline) No initiation of non-protocol treatments or premature study discontinuation The range of values for the above instruments are listed below, with higher scores indicating more active disease: BILAG: 0 to 96 SLEDAI: 0 to 105 PGA: 0-3

Secondary Outcome Measures

1. Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the Systemic Lupus Erythematosus Responder Index (SRI-4) [12 weeks]

   SRI requires meeting all of the following parameters: ≥4-point reduction from baseline in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score No single new British Isles Lupus Assessment Group (BILAG) A score & not >1 new BILAG B scores AND no worsening in the Physician Global Assessment (PGA) (<10% worsening from baseline) No initiation of non-protocol treatments or premature study discontinuation The range of values for the above instruments are listed below, with higher scores indicating more active disease: BILAG: 0 to 96 SLEDAI: 0 to 108 PGA: 0-3

2. Percentage of Participants on Active vs Sham tVNS With Improvement in Heart Rate Variability (HRV) [12 weeks]

   HRV is measured by time domain (RMSSD and pNN50) and frequency domain [high frequency (HF), low to high frequency (LF/HF) ratio] parameters.

Other Outcome Measures

1. Percentage of Participants on Active vs Sham tVNS That Experience an SLE Flare by SELENA SLEDAI Flare Index [12 weeks]

   The SELENA SLEDAI flare index captures flares in the preceding 30 days by a combination of clinical descriptors and medications rules.

2. Percentage of Participants on Active vs Sham tVNS With Improvement in Quality of Life Measured by the Lupus QoL [12 weeks]

   The Lupus QoL is a patient reported outcome developed for measurement of quality of life of patients with SLE in clinical research

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients with SLE age 18-70 meeting the American College of Rheumatology Classification Criteria. Patients need to meet a minimum of 4 out of 11 criteria simultaneously or serially on two separate occasions.

2. Positive antinuclear antibody or anti-dsDNA within one year of screening

3. Non-serological SLEDAI ≥4 or ≥1 BILAG B or A and presence of inflammatory arthritis (defined by at least 3 swollen and 3 tender joints) at screening

4. Patients may receive on one or more of the following immune suppressive therapies: hydroxychloroquine, quinacrine, methotrexate, azathioprine, mycophenolate mofetil, tacrolimus, sirolimus, belimumab, abatacept. Immune suppressive medications should have been administered at stable doses for ≥30 days prior to baseline. Patients may also be on prednisone up to 10mg daily or equivalent steroid treatment at the baseline visit.

Exclusion Criteria:

1. Acute lupus nephritis defined as class II,III, IV or V nephritis diagnosed within 6 months or prot/creat > 1.5 gm/gm due to active lupus or in process of receiving induction therapy for nephritis

2. Active CNS lupus affecting mental status

3. Any other organ threatening or life threatening manifestation of SLE as well as those, who, in the opinion of the investigator, have severe multi-organ or refractory lupus

4. Rituximab treatment within 6 months prior to screening and/or without return of B cells to baseline levels

5. Treatment with cyclophosphamide within a month prior to screening

6. Treatment with any investigational drug within 3 months or 5 half-lives whichever is longer

7. Recurrent vaso-vagal syncopal episodes

8. Unilateral or bilateral vagotomy

9. Presence of any evidence of vagus nerve pathology or injury

10. Heart failure (NYHA class III or IV)

11. Known atherosclerotic disease, including severe carotid artery disease, uncontrolled hypertension, uncontrolled diabetes, and history of myocardial infarction (MI), cardiomyopathy or stroke within the past year. Clinically stable patients with coronary artery disease, but no recent MI (within the past year) and no current symptoms of angina are not however excluded.

12. Valvular and other structural heart disease that is evident by transthoracic echocardiogram and is associated with heart failure (NYHA class III or IV)

13. Prolonged QT interval or abnormal baseline ECG - sick sinus syndrome, Mobitz type 2 second or third degree heart block, atrial fibrillation, atrial flutter, recent history of ventricular tachycardia or ventricular fibrillation or clinically significant premature ventricular contraction

14. Individuals currently implanted with an electrical and/or neurostimulator device, such as cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain stimulator, spinal stimulator, bone growth stimulator, or cochlear implant

15. Known respiratory disease that has decreased any pulmonary function test more than 25% below expected values or has resulted in hospitalization within the past year

16. All diagnosed syndromes affecting the central nervous system (CNS) or autonomic nervous system

17. Major psychiatric disorders including evidence of major depressive disorder (DSM-5 diagnostic criteria) that is not currently controlled by medications

18. Hemoglobin below 9.0 gm/dL (by the most recent CBC)

19. Pregnancy or breast feeding

20. Inability or unwillingness to understand and/or sign informed consent

21. Any other medical condition, whether or not related to lupus, which, in the opinion of the investigator, would render the patient inappropriate or too unstable to complete the study protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma	United States	73104

Sponsors and Collaborators

• Aikaterini Thanou
• Oklahoma Medical Research Foundation
• University of Oklahoma

Investigators

• Principal Investigator: Aikaterini Thanou, MD, Oklahoma Medical Research Foundation

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 29, 2016

More Information

Publications

None provided.

• Responsible Party: Aikaterini Thanou, Research Affiliate, Oklahoma Medical Research Foundation
• ClinicalTrials.gov Identifier: NCT02917265
• Other Study ID Numbers: H15-141
• First Posted: Sep 28, 2016
• Last Update Posted: Mar 3, 2020
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by Aikaterini Thanou, Research Affiliate, Oklahoma Medical Research Foundation: vagus nerve stimulation; systemic lupus erythematosus
• Additional relevant MeSH terms: Lupus Erythematosus, Systemic

Study Results

Participant Flow

Recruitment Details	Participants were recruited at the Rheumatology Research Clinic of the Oklahoma Medical Research Foundation between 9.2015 and 5.2017.
Pre-assignment Detail	Screening and randomization occurred at the same visit. One individual failed screening due to severe depression.

Arm/Group Title	TENS for Vagus Stimulation	TENS for Sham Stimulation
Arm/Group Description	A transcutaneous electrical nerve stimulation (TENS) unit is applied to tragus, the area of the external ear innervated by the auricular branch of the vagus nerve. TENS for vagus stimulation: TENS electrodes are applied the tragus of the external ear.	A TENS unit is applied to the earlobe, an area of the external ear that is devoid of vagus innervation. TENS for sham stimulation: TENS electrodes are applied on the earlobe.
Period Title: Overall Study
STARTED	5	2
COMPLETED	3	2
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	TENS for Vagus Stimulation	TENS for Sham Stimulation	Total
Arm/Group Description	A transcutaneous electrical nerve stimulation (TENS) unit is applied to an area of the external ear that is innervated by the auricular branch of the vagus nerve. TENS for vagus stimulation: TENS electrodes are applied on an area of the external ear innervated by the auricular branch of the vagus nerve.	A TENS unit is applied to an area of the external ear that is devoid of vagus innervation. TENS for sham stimulation: TENS electrodes are applied on an area of the external ear devoid of vagus innervation.	Total of all reporting groups
Overall Participants	5	2	7
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	4 80%	2 100%	6 85.7%
>=65 years	1 20%	0 0%	1 14.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	50	51.5	50.4
Sex: Female, Male (Count of Participants)
Female	3 60%	2 100%	5 71.4%
Male	2 40%	0 0%	2 28.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	5 100%	2 100%	7 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 20%	0 0%	1 14.3%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 40%	1 50%	3 42.9%
White	2 40%	1 50%	3 42.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	5 100%	2 100%	7 100%
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	4.6	4	4.4

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA)
Description	Achieving a BICLA response requires to meet all of the following parameters: All British Isles Lupus Assessment Group (BILAG) A scores improving to B/C/D and all BILAG level B scores improving to C/D No single new BILAG A & not >1 new BILAG B scores, no worsening of the baseline Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) total score AND no worsening in the Physician Global Assessment (PGA) (<10% worsening from baseline) No initiation of non-protocol treatments or premature study discontinuation The range of values for the above instruments are listed below, with higher scores indicating more active disease: BILAG: 0 to 96 SLEDAI: 0 to 105 PGA: 0-3
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TENS for Vagus Stimulation	TENS for Sham Stimulation
Arm/Group Description	A transcutaneous electrical nerve stimulation (TENS) unit is applied to tragus, the area of the external ear innervated by the auricular branch of the vagus nerve. TENS for vagus stimulation: TENS electrodes are applied the tragus of the external ear.	A TENS unit is applied to the earlobe, an area of the external ear that is devoid of vagus innervation. TENS for sham stimulation: TENS electrodes are applied on the earlobe.
Measure Participants	5	2
BICLA responders	1 20%	0 0%
BICLA non responders	4 80%	2 100%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TENS for Vagus Stimulation, TENS for Sham Stimulation
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the Systemic Lupus Erythematosus Responder Index (SRI-4)
Description	SRI requires meeting all of the following parameters: ≥4-point reduction from baseline in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score No single new British Isles Lupus Assessment Group (BILAG) A score & not >1 new BILAG B scores AND no worsening in the Physician Global Assessment (PGA) (<10% worsening from baseline) No initiation of non-protocol treatments or premature study discontinuation The range of values for the above instruments are listed below, with higher scores indicating more active disease: BILAG: 0 to 96 SLEDAI: 0 to 108 PGA: 0-3
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

all patients randomized to active treatment or placebo that had a total SLEDAI score of at least 4 at baseline.

Arm/Group Title	TENS for Vagus Stimulation	TENS for Sham Stimulation
Arm/Group Description	A transcutaneous electrical nerve stimulation (TENS) unit is applied to tragus, the area of the external ear innervated by the auricular branch of the vagus nerve. TENS for vagus stimulation: TENS electrodes are applied the tragus of the external ear.	A TENS unit is applied to the earlobe, an area of the external ear that is devoid of vagus innervation. TENS for sham stimulation: TENS electrodes are applied on the earlobe.
Measure Participants	4	2
SRI Responders	0 0%	0 0%
SRI Non-responders	4 80%	2 100%

3. Secondary Outcome

Title	Percentage of Participants on Active vs Sham tVNS With Improvement in Heart Rate Variability (HRV)
Description	HRV is measured by time domain (RMSSD and pNN50) and frequency domain [high frequency (HF), low to high frequency (LF/HF) ratio] parameters.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Analysis not done.

Arm/Group Title	TENS for Vagus Stimulation	TENS for Sham Stimulation
Arm/Group Description	A transcutaneous electrical nerve stimulation (TENS) unit is applied to tragus, the area of the external ear innervated by the auricular branch of the vagus nerve. TENS for vagus stimulation: TENS electrodes are applied the tragus of the external ear.	A TENS unit is applied to the earlobe, an area of the external ear that is devoid of vagus innervation. TENS for sham stimulation: TENS electrodes are applied on the earlobe.
Measure Participants	0	0

4. Other Pre-specified Outcome

Title	Percentage of Participants on Active vs Sham tVNS That Experience an SLE Flare by SELENA SLEDAI Flare Index
Description	The SELENA SLEDAI flare index captures flares in the preceding 30 days by a combination of clinical descriptors and medications rules.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Analysis has not been done.

Arm/Group Title	TENS for Vagus Stimulation	TENS for Sham Stimulation
Arm/Group Description	A transcutaneous electrical nerve stimulation (TENS) unit is applied to tragus, the area of the external ear innervated by the auricular branch of the vagus nerve. TENS for vagus stimulation: TENS electrodes are applied the tragus of the external ear.	A TENS unit is applied to the earlobe, an area of the external ear that is devoid of vagus innervation. TENS for sham stimulation: TENS electrodes are applied on the earlobe.
Measure Participants	0	0

5. Other Pre-specified Outcome

Title	Percentage of Participants on Active vs Sham tVNS With Improvement in Quality of Life Measured by the Lupus QoL
Description	The Lupus QoL is a patient reported outcome developed for measurement of quality of life of patients with SLE in clinical research
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Analysis not done.

Arm/Group Title	TENS for Vagus Stimulation	TENS for Sham Stimulation
Arm/Group Description	A transcutaneous electrical nerve stimulation (TENS) unit is applied to an area of the external ear that is innervated by the auricular branch of the vagus nerve. TENS for vagus stimulation: TENS electrodes are applied on an area of the external ear innervated by the auricular branch of the vagus nerve.	A TENS unit is applied to an area of the external ear that is devoid of vagus innervation. TENS for sham stimulation: TENS electrodes are applied on an area of the external ear devoid of vagus innervation.
Measure Participants	0	0

Adverse Events

Time Frame	12 weeks (baseline to Month 3)
Arm/Group Title	TENS for Vagus Stimulation		TENS for Sham Stimulation
Arm/Group Description	A transcutaneous electrical nerve stimulation (TENS) unit is applied to tragus, the area of the external ear innervated by the auricular branch of the vagus nerve. TENS for vagus stimulation: TENS electrodes are applied the tragus of the external ear.		A TENS unit is applied to the earlobe, an area of the external ear that is devoid of vagus innervation. TENS for sham stimulation: TENS electrodes are applied on the earlobe.
All Cause Mortality
	TENS for Vagus Stimulation		TENS for Sham Stimulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/2 (0%)
Serious Adverse Events
	TENS for Vagus Stimulation		TENS for Sham Stimulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	TENS for Vagus Stimulation		TENS for Sham Stimulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		1/2 (50%)
Gastrointestinal disorders
nausea	1/5 (20%)	1	0/2 (0%)	0
Nervous system disorders
headache	1/5 (20%)	1	1/2 (50%)	1
paresthesias	0/5 (0%)	0	1/2 (50%)	1
carpal tunnel syndrome	1/5 (20%)	1	0/2 (0%)	0
Renal and urinary disorders
Urinary tract infections	1/5 (20%)	1	0/2 (0%)	0
Respiratory, thoracic and mediastinal disorders
cough	1/5 (20%)	1	0/2 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.