Systemic Lupus Erythematosus
Conditions
Keywords
vagus nerve stimulation, systemic lupus erythematosus
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).
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.
Interventions
DEVICETENS for vagus stimulation
TENS electrodes are applied on an area of the external ear innervated by the auricular branch of the vagus nerve.
DEVICETENS for sham stimulation
TENS electrodes are applied on an area of the external ear devoid of vagus innervation.
Sponsors
Oklahoma Medical Research Foundation
University of Oklahoma
Aikaterini Thanou
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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: 1. All British Isles Lupus Assessment Group (BILAG) A scores improving to B/C/D and all BILAG level B scores improving to C/D 2. 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) 3. 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
| Measure | Time frame | Description |
|---|---|---|
| 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: 1. ≥4-point reduction from baseline in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score 2. 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) 3. 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 |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
Countries
United States
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 details
Screening and randomization occurred at the same visit. One individual failed screening due to severe depression.
Participants by arm
| Arm | Count |
|---|---|
| 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.
TENS for vagus stimulation: TENS electrodes are applied on an area of the external ear innervated by the auricular branch of the vagus nerve. | 5 |
| TENS for Sham Stimulation 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. | 2 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | TENS for Vagus Stimulation | TENS for Sham Stimulation | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 2 Participants | 6 Participants |
| Age, Continuous | 50 years | 51.5 years | 50.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 5 participants | 2 participants | 7 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants |
| Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) | 4.6 units on a scale | 4 units on a scale | 4.4 units on a scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 2 |
| other Total, other adverse events | 4 / 5 | 1 / 2 |
| serious Total, serious adverse events | 0 / 5 | 0 / 2 |
Outcome results
Primary
Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA)
Achieving a BICLA response requires to meet all of the following parameters: 1. All British Isles Lupus Assessment Group (BILAG) A scores improving to B/C/D and all BILAG level B scores improving to C/D 2. 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) 3. 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
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TENS for Vagus Stimulation | Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA) | BICLA responders | 1 Participants |
| TENS for Vagus Stimulation | Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA) | BICLA non responders | 4 Participants |
| TENS for Sham Stimulation | Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA) | BICLA responders | 0 Participants |
| TENS for Sham Stimulation | Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA) | BICLA non responders | 2 Participants |
p-value: 0.05Chi-squared
Secondary
Percentage of Participants on Active vs Sham tVNS With Improvement in Heart Rate Variability (HRV)
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
Population: Analysis not done.
Secondary
Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the Systemic Lupus Erythematosus Responder Index (SRI-4)
SRI requires meeting all of the following parameters: 1. ≥4-point reduction from baseline in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score 2. 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) 3. 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
Population: all patients randomized to active treatment or placebo that had a total SLEDAI score of at least 4 at baseline.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TENS for Vagus Stimulation | Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the Systemic Lupus Erythematosus Responder Index (SRI-4) | SRI Responders | 0 Participants |
| TENS for Vagus Stimulation | Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the Systemic Lupus Erythematosus Responder Index (SRI-4) | SRI Non-responders | 4 Participants |
| TENS for Sham Stimulation | Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the Systemic Lupus Erythematosus Responder Index (SRI-4) | SRI Responders | 0 Participants |
| TENS for Sham Stimulation | Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the Systemic Lupus Erythematosus Responder Index (SRI-4) | SRI Non-responders | 2 Participants |
Other Pre-specified
Percentage of Participants on Active vs Sham tVNS That Experience an SLE Flare by SELENA SLEDAI Flare Index
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
Population: Analysis has not been done.
Other Pre-specified
Percentage of Participants on Active vs Sham tVNS With Improvement in Quality of Life Measured by the Lupus QoL
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
Population: Analysis not done.