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Vagus Nerve Stimulation for Systemic Lupus Erythematous (SLE-VNS)

Primary Purpose

Systemic Lupus Erythematosus, Autonomic Dysfunction, Autonomic Neuropathy

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Non-invasive transcutaneous vagus nerve stimulation (tVNS)
Sham vagus nerve stimulation
Sponsored by
Rigshospitalet, Denmark
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Systemic Lupus Erythematosus focused on measuring Vagus Nerve Stimulation, Fatigue, Pain, Health-Related Quality Of Life, Autonomic Nervous System Disorders, Inflammation, Autoimmunity, Kidney Diseases, Vascular Diseases, Heart Diseases

Eligibility Criteria

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

Inclusion criteria

  • Reading and understanding Danish.
  • SLE diagnosis based on SLE disease classification criteria for at least 1 year.

  • Stable disease and medication the past 28 days as defined by:

    • No change in disease modifying antirheumatic drugs or biological therapy,
    • Receiving maximally 10 mg prednisone daily.
  • Having signs of fatigue, as assessed by scoring ≤ 40 in the FACIT-Fatigue questionnaire.

  • Having signs of autonomic dysfunction, as assessed by scoring one or more of:

    1. VAGUS score ≥1
    2. SUDOSCAN score < 50µS for hands or < 70µS for feet
    3. COMPASS-31 score > 12
  • Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests and other trial procedures.
  • Sign the dated informed consent documents

Exclusion criteria

  • Significant cardiovascular disease, including congenital cardiac disease, congestive heart failure, known severe coronary artery disease, or recent myocardial infarction (within 5 years), as assessed by a physician at the screening.
  • Blood pressure < 100/60 or > 160/105
  • Clinically significant bradycardia or tachycardia
  • History of abnormal baseline ECG, prolonged QT interval or arrhythmia
  • Previous surgery on the vagus nerve or abnormal cervical anatomy
  • Implanted or portable electro-mechanical medical devices, e.g. pacemaker, defibrillator, cochlear implant and infusion pump
  • Metallic device such as a stent, bone plate or bone screw implanted at or near the neck
  • Receiving active laser treatment for proliferative retinopathy
  • Active cancer or cancer in remission
  • History of brain tumor, aneurysm, bleed, head trauma, clinically significant syncope or seizures
  • Any clinical abnormalities that, in the opinion of the investigator, may increase the risk associated with trial participation or may interfere with the interpretation of the trial results.
  • Participation in other clinical trials less than three months prior to inclusion, unless such a participation is judged to have no influence on the recordings

  • Female pregnancy (positive urine-HCG), ongoing lactation or intended pregnancy during the study period.

    • A pregnancy test is conducted at first and last visit to ensure that fertile female patients are not pregnant during the study period.
    • Further, the investigator ensures that fertile female patients use a safe contraception method during the study and for at least 15 hours after termination of the study period. Safe contraception: The combined oral contraceptive pill; intra uterine device; gestagen injection; subdermal implantation; hormone vaginal ring; and transdermal plaster.
  • Male patients who intend to father a child during the course of the study

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Sham Comparator

    Arm Label

    Active treatment

    Sham treatment

    Arm Description

    Non-invasive transcutaneous vagus nerve stimulation applied by the gammaCore device (electroCore)

    Inactive sham vagus nerve stimulation applied by the gammaCore sham device (electroCore)

    Outcomes

    Primary Outcome Measures

    Fatigue (changes during period 1 and 2)
    The FACIT-Fatigue Scale is a short, 13-item, tool that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a four-point scale for each item. The theoretical maximum value is 52 (maximal fatigue) and minimum 0 (no fatigue).

    Secondary Outcome Measures

    Questionnaire on autonomic symptoms: Composite Autonomic Symptoms Score 31 (COMPASS-31)
    The COMPASS-31 is a validated questionnaire of 31 questions providing a quantitative measure of autonomic nervous system dysfunction symptoms. The score ranges from 0 (no symptoms) to 100 (most severe autonomic symptoms).
    Questionnaire on SLE disease activity: Patient Global Assessment (PtGA)
    The participants rate their subjectively perceived disease activity on a scale from 0 to 10, in which 0 = no disease activity and 10 = worst imaginable disease activity.
    Questionnaire on SLE disease activity: Systemic Lupus Activity Questionnaire (SLAQ)
    In the SLAQ the participants rate their perceived disease activity by rating the severity of 24 disease activity related symptoms by either "no problem", "mild", "moderate" or "severe" In the SLAQ the participants rate their perceived disease activity by rating the severity of 24 disease activity related symptoms by either "no problem", "mild", "moderate" or "severe" and a Patient Global Disease Activity measure as mentioned in (3).
    Questionnaire on quality of life: Short form-12 (SF-12)
    From the validated 12-item SF-12 a physical and mental component score of patient-reported health related quality of life is calculated. Component scores range from 0-100 (lowest to highest level of self-reported health) and are calculated by giving specific weights to each of the 12 individual items/questions, calculating a weighted sum, and finally adding the sum to a component specific constant.
    Questionnaire on pain: Visual analog rating scale (VAS)
    Participants will assess the level of musculoskeletal pain within the previous 7 days by scoring the level on the VAS (0 to 10, where 0 = no pain and 10 = worst imaginable pain).
    SLE disease activity: SLE Disease Activity Index 2000 (SLEDAI-2K)
    The validated SLEDAI-2K entails 24 weighted descriptors of disease activity across 9 organ systems. The SLEDAI-2K-score ranges from 0 (no activity) to a theoretical maximum score of 105 and reports on manifestations occurring up to 10 days before the examination.
    SLE disease activity: SLEDAI Responder Index 50% (SRI-50)
    The SRI-50 is a validated derivation of SLEDAI-2K that considers clinically significant improvements (≥ 50%) between visits.
    SLE disease activity: SLE Disease Activity Score (SLE-DAS)
    The SLE-DAS is a validated index containing 17 clinical and laboratory descriptors and is a global measure of SLE disease activity suggested to have improved sensitivity to change and specificity as compared with the SLEDAI-2K.
    SLE disease activity: Physician Global Assessment (PGA)
    The PGA measures disease activity in SLE is determined by the physician's judgement of overall disease activity. It is scored by answering "How do you rate your patient's current disease activity?" with 1=mild, 2=moderate or 3=most active disease imaginable.
    SLE disease activity: Painful and swollen joints
    The number of painful and swollen joints are assessed according to the Disease Activity Score-28 (Swollen joints: 0 = no, and 28 = 28 swollen. Painful joints: 0 = n, and 28 = 28 painful joints).
    Autonomic function: Resting heart rate variability (HRV)
    With the VagusTM device, 5 minutes of resting HRV is measured. Classical time (SDNN, RMSSD) and frequency (LF, HF, total and LF/HF) domain heart rate variability parameters will be assessed.
    Autonomic function: Resting Cardiac Vagal Tone (CVT)
    Cardiac vagal tone reflecting parasympathetic activity is measured through three chest electrocardiography electrodes. A cardiac monitor, the eMotion Faros device is attached to the electrodes and the electrocardiogram is sampled at 8 kHz for 5 minutes, from which the cardiac vagal tone is derived.
    Autonomic function: Cardiovascular autonomic reflex tests - heart rate response
    The heart rate response to three cardiovascular autonomic reflex tests are assessed with the VagusTM-device for estimation of the degree of autonomic dysfunction: The ratio of the maximum and minimum heart rate in relation to a) standing, b) deep breathing and, c) a Valsalva maneuver. By comparing results of the cardiovascular reflex tests with age-dependent cut-off levels, the degree of autonomic dysfunction is divided into categories: no, early (one) and manifest (two or three abnormal tests).
    Autonomic function: Cardiovascular autonomic reflex tests - blood pressure response
    The blood pressure response to one cardiovascular autonomic reflex test is assessed. After a supine 5-min rest, the orthostatic blood pressure is measured. The participant stands for 5 minutes while the blood pressure is measured each minute. Blood pressure drops (systolic 20 mmHg or diastolic 10 mmHg) indicate impaired, especially, sympathetic function.
    Autonomic function: Continuous heart rate and HRV monitoring
    A small patch sensor (ePatch) will be used to monitor the heart rate variability during a period of 7 days. Classical time (RR-interval, SDNN, SDNNi, SDANN, RMSSD) and frequency (VLF, LF, HF and LF/HF) domain heart rate variability parameters will be assessed.
    Autonomic function: Sweat secretion
    The Sudoscan® provides a quick, non-invasive and reproducible assessment of sympathetically controlled sudomotor function, and is based on a reaction between electrodes and chloride ions after a low-voltage sweat gland stimulation as the patient is situated with their hands and feet on two different measure pads for 3 minutes.
    Pain tolerability: Cold pressor test
    The left hand is immersed in circulated ice-chilled water (2.0°C). The subject will be instructed to tolerate to hold the hand in the water for up to 120 seconds or when intolerable pain is reached. At different timepoints throughout the stimulation, the participants are asked to rate the sensation on a numerical rating scale from 0 to 10, where 0 = no pain and 10 = worst pain.
    Pain tolerability: Conditioned pain modulation (CMP)
    The CPM-capacity response can be quantified by applying a "test-pain" (muscle pressure on right quadriceps) before and after the conditioning stimulus. The difference in pressure stimulus intensity before, during, and after induction of cold pressor pain provides a quantitative index of CPM capacity in the individual participant. The techniques used for pressure stimulation and cold pressor test described above will be combined to measure CPM.
    Cardiac function
    Cardiac function is assessed with echocardiography, which is a non-invasive ultrasound examination elapsing from 15 -30 minutes, performed with the patient in supine position. A transducer is run across the thorax for visualization of cardiac diastolic and systolic function, anatomical structures, arterial stiffness as well as muscle and chamber sizes to describe systolic and diastolic cardiac function.
    Vascular function: Microvascular function
    Nailfold video capillaroscopy is a non-invasive diagnostic technique that evaluates the morphology of the capillaries in the nailfold through direct visualization. It can reveal both the architecture of capillary rows and fine details of each vessel.
    SLE routine status
    SLE clinical status is assessed by performing routine blood-based analyses of hematological, serological and urinary markers for different organ-specific and SLE-specific characteristics.
    SLE inflammatory status - Multiplex plasma cytokine analysis
    SLE inflammatory status is assessed by analyzing the blood plasma for especially activation markers: TNF, IL-1b, sIL-2Ra, IL-6, IL-8, IL-17, IFN-g, IFN-alfa and Inhibition markers: sTNFr, IL-1RA, IL-10, TGF-b.
    SLE inflammatory status - Interferon-regulated gene expression
    SLE inflammatory status is assessed by analyzing interferon-regulated gene expression in whole blood (nCounter platform, NanoString Technologies, Seattle, WA).
    SLE inflammatory status - Immune cell population distribution in whole blood
    SLE inflammatory status is assessed by analyzing the immune cell population distribution in whole blood (fluorescence-activated cell sorting).
    SLE inflammatory status - Functional immune cell stimulation
    SLE inflammatory status is assessed by analyzing immune cell stimulation in whole blood (TruCulture).
    Kidney function
    Kidney function is assessed by analyzing urine (3*24 hours) for kidney specific markers such as urine albumin- and protein/creatinine-ratio.
    Metabolic control
    Metabolic control is assessed at the hospital by analyzing blood plasma for lipid and glucose profiles
    Medication usage
    Changes in medication status within the time frame of the study and 3 months after study completion is recorded by accessing the participants medication file.

    Full Information

    First Posted
    February 25, 2022
    Last Updated
    May 2, 2022
    Sponsor
    Rigshospitalet, Denmark
    Collaborators
    Aalborg University Hospital
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05315739
    Brief Title
    Vagus Nerve Stimulation for Systemic Lupus Erythematous
    Acronym
    SLE-VNS
    Official Title
    Vagus Nerve Stimulation as a Novel Treatment for Systemic Lupus Erythematous: A Double Blinded Randomized Controlled Trail
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    May 2022
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    May 2022 (Anticipated)
    Primary Completion Date
    September 2023 (Anticipated)
    Study Completion Date
    September 2023 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Rigshospitalet, Denmark
    Collaborators
    Aalborg University Hospital

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    Yes
    Product Manufactured in and Exported from the U.S.
    Yes
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    This trial uses a double blinded, randomized 1:1 (active:sham) placebo controlled, parallel group design, investigating the effects of transcutaneous vagus nerve stimulation (tVNS) in patients with systemic lupus erythematosus (SLE). The main objective is to evaluate whether adjuvant treatment with tVNS in SLE patients with signs of autonomic dysfunction and fatigue improves patient perceived levels of fatigue. Secondary outcomes include tVNS induced changes to: patient reported outcomes, autonomic nervous system function, SLE disease activity, immunologic profile, tolerability of pain and organ (cardiac, vascular and kidney) functions. Participants are randomized to received either active non-invasive transcutaneous vagus nerve stimulation (tVNS) or inactive sham stimulation. The study period is divided in two periods. The first period investigates the effects of short-term, high-intensity tVNS treatment. The second phase investigates the effects of long-term, middle-intensity tVNS treatment.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Systemic Lupus Erythematosus, Autonomic Dysfunction, Autonomic Neuropathy, Fatigue
    Keywords
    Vagus Nerve Stimulation, Fatigue, Pain, Health-Related Quality Of Life, Autonomic Nervous System Disorders, Inflammation, Autoimmunity, Kidney Diseases, Vascular Diseases, Heart Diseases

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    84 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Active treatment
    Arm Type
    Active Comparator
    Arm Description
    Non-invasive transcutaneous vagus nerve stimulation applied by the gammaCore device (electroCore)
    Arm Title
    Sham treatment
    Arm Type
    Sham Comparator
    Arm Description
    Inactive sham vagus nerve stimulation applied by the gammaCore sham device (electroCore)
    Intervention Type
    Device
    Intervention Name(s)
    Non-invasive transcutaneous vagus nerve stimulation (tVNS)
    Other Intervention Name(s)
    GammaCore Sapphire device
    Intervention Description
    tVNS delivers an electrical current to the cervical branch of the vagus nerve. Four minutes of bilateral stimulation 4 times per day for 7 days (period 1) and 2 times per day for 8 weeks (period 2) are performed. The two periods are separated by a 2 weeks wash-out period.
    Intervention Type
    Device
    Intervention Name(s)
    Sham vagus nerve stimulation
    Other Intervention Name(s)
    GammaCore Sapphire sham device
    Intervention Description
    The sham device produces a slight vibrating sound, but does not produce an electical current and hence, does not activate the vagus nerve. Four minutes of bilateral stimulation 4 times per day for 7 days (period 1) and 2 times per day for 8 weeks (period 2). The two periods are separated by a 2 weeks wash-out period.
    Primary Outcome Measure Information:
    Title
    Fatigue (changes during period 1 and 2)
    Description
    The FACIT-Fatigue Scale is a short, 13-item, tool that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a four-point scale for each item. The theoretical maximum value is 52 (maximal fatigue) and minimum 0 (no fatigue).
    Time Frame
    During period 1: At baseline, daily (day 2-6) until- and at follow-up (day 7). During period 2: At baseline, at day 7-visit, weekly (week 3-7) until- and at follow-up (week 8).
    Secondary Outcome Measure Information:
    Title
    Questionnaire on autonomic symptoms: Composite Autonomic Symptoms Score 31 (COMPASS-31)
    Description
    The COMPASS-31 is a validated questionnaire of 31 questions providing a quantitative measure of autonomic nervous system dysfunction symptoms. The score ranges from 0 (no symptoms) to 100 (most severe autonomic symptoms).
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Questionnaire on SLE disease activity: Patient Global Assessment (PtGA)
    Description
    The participants rate their subjectively perceived disease activity on a scale from 0 to 10, in which 0 = no disease activity and 10 = worst imaginable disease activity.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit, weekly (week 3-7) until- and at follow-up (week 8).
    Title
    Questionnaire on SLE disease activity: Systemic Lupus Activity Questionnaire (SLAQ)
    Description
    In the SLAQ the participants rate their perceived disease activity by rating the severity of 24 disease activity related symptoms by either "no problem", "mild", "moderate" or "severe" In the SLAQ the participants rate their perceived disease activity by rating the severity of 24 disease activity related symptoms by either "no problem", "mild", "moderate" or "severe" and a Patient Global Disease Activity measure as mentioned in (3).
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit, and at follow-up (week 8).
    Title
    Questionnaire on quality of life: Short form-12 (SF-12)
    Description
    From the validated 12-item SF-12 a physical and mental component score of patient-reported health related quality of life is calculated. Component scores range from 0-100 (lowest to highest level of self-reported health) and are calculated by giving specific weights to each of the 12 individual items/questions, calculating a weighted sum, and finally adding the sum to a component specific constant.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit, and at follow-up (week 8).
    Title
    Questionnaire on pain: Visual analog rating scale (VAS)
    Description
    Participants will assess the level of musculoskeletal pain within the previous 7 days by scoring the level on the VAS (0 to 10, where 0 = no pain and 10 = worst imaginable pain).
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit, weekly (week 3-7) until- and at follow-up (week 8).
    Title
    SLE disease activity: SLE Disease Activity Index 2000 (SLEDAI-2K)
    Description
    The validated SLEDAI-2K entails 24 weighted descriptors of disease activity across 9 organ systems. The SLEDAI-2K-score ranges from 0 (no activity) to a theoretical maximum score of 105 and reports on manifestations occurring up to 10 days before the examination.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    SLE disease activity: SLEDAI Responder Index 50% (SRI-50)
    Description
    The SRI-50 is a validated derivation of SLEDAI-2K that considers clinically significant improvements (≥ 50%) between visits.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    SLE disease activity: SLE Disease Activity Score (SLE-DAS)
    Description
    The SLE-DAS is a validated index containing 17 clinical and laboratory descriptors and is a global measure of SLE disease activity suggested to have improved sensitivity to change and specificity as compared with the SLEDAI-2K.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    SLE disease activity: Physician Global Assessment (PGA)
    Description
    The PGA measures disease activity in SLE is determined by the physician's judgement of overall disease activity. It is scored by answering "How do you rate your patient's current disease activity?" with 1=mild, 2=moderate or 3=most active disease imaginable.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    SLE disease activity: Painful and swollen joints
    Description
    The number of painful and swollen joints are assessed according to the Disease Activity Score-28 (Swollen joints: 0 = no, and 28 = 28 swollen. Painful joints: 0 = n, and 28 = 28 painful joints).
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Autonomic function: Resting heart rate variability (HRV)
    Description
    With the VagusTM device, 5 minutes of resting HRV is measured. Classical time (SDNN, RMSSD) and frequency (LF, HF, total and LF/HF) domain heart rate variability parameters will be assessed.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Autonomic function: Resting Cardiac Vagal Tone (CVT)
    Description
    Cardiac vagal tone reflecting parasympathetic activity is measured through three chest electrocardiography electrodes. A cardiac monitor, the eMotion Faros device is attached to the electrodes and the electrocardiogram is sampled at 8 kHz for 5 minutes, from which the cardiac vagal tone is derived.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Autonomic function: Cardiovascular autonomic reflex tests - heart rate response
    Description
    The heart rate response to three cardiovascular autonomic reflex tests are assessed with the VagusTM-device for estimation of the degree of autonomic dysfunction: The ratio of the maximum and minimum heart rate in relation to a) standing, b) deep breathing and, c) a Valsalva maneuver. By comparing results of the cardiovascular reflex tests with age-dependent cut-off levels, the degree of autonomic dysfunction is divided into categories: no, early (one) and manifest (two or three abnormal tests).
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Autonomic function: Cardiovascular autonomic reflex tests - blood pressure response
    Description
    The blood pressure response to one cardiovascular autonomic reflex test is assessed. After a supine 5-min rest, the orthostatic blood pressure is measured. The participant stands for 5 minutes while the blood pressure is measured each minute. Blood pressure drops (systolic 20 mmHg or diastolic 10 mmHg) indicate impaired, especially, sympathetic function.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Autonomic function: Continuous heart rate and HRV monitoring
    Description
    A small patch sensor (ePatch) will be used to monitor the heart rate variability during a period of 7 days. Classical time (RR-interval, SDNN, SDNNi, SDANN, RMSSD) and frequency (VLF, LF, HF and LF/HF) domain heart rate variability parameters will be assessed.
    Time Frame
    During period 1: From baseline to follow-up (day 7). During period 2: From baseline to day 7-visit.
    Title
    Autonomic function: Sweat secretion
    Description
    The Sudoscan® provides a quick, non-invasive and reproducible assessment of sympathetically controlled sudomotor function, and is based on a reaction between electrodes and chloride ions after a low-voltage sweat gland stimulation as the patient is situated with their hands and feet on two different measure pads for 3 minutes.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Pain tolerability: Cold pressor test
    Description
    The left hand is immersed in circulated ice-chilled water (2.0°C). The subject will be instructed to tolerate to hold the hand in the water for up to 120 seconds or when intolerable pain is reached. At different timepoints throughout the stimulation, the participants are asked to rate the sensation on a numerical rating scale from 0 to 10, where 0 = no pain and 10 = worst pain.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Pain tolerability: Conditioned pain modulation (CMP)
    Description
    The CPM-capacity response can be quantified by applying a "test-pain" (muscle pressure on right quadriceps) before and after the conditioning stimulus. The difference in pressure stimulus intensity before, during, and after induction of cold pressor pain provides a quantitative index of CPM capacity in the individual participant. The techniques used for pressure stimulation and cold pressor test described above will be combined to measure CPM.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Cardiac function
    Description
    Cardiac function is assessed with echocardiography, which is a non-invasive ultrasound examination elapsing from 15 -30 minutes, performed with the patient in supine position. A transducer is run across the thorax for visualization of cardiac diastolic and systolic function, anatomical structures, arterial stiffness as well as muscle and chamber sizes to describe systolic and diastolic cardiac function.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Vascular function: Microvascular function
    Description
    Nailfold video capillaroscopy is a non-invasive diagnostic technique that evaluates the morphology of the capillaries in the nailfold through direct visualization. It can reveal both the architecture of capillary rows and fine details of each vessel.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    SLE routine status
    Description
    SLE clinical status is assessed by performing routine blood-based analyses of hematological, serological and urinary markers for different organ-specific and SLE-specific characteristics.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    SLE inflammatory status - Multiplex plasma cytokine analysis
    Description
    SLE inflammatory status is assessed by analyzing the blood plasma for especially activation markers: TNF, IL-1b, sIL-2Ra, IL-6, IL-8, IL-17, IFN-g, IFN-alfa and Inhibition markers: sTNFr, IL-1RA, IL-10, TGF-b.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    SLE inflammatory status - Interferon-regulated gene expression
    Description
    SLE inflammatory status is assessed by analyzing interferon-regulated gene expression in whole blood (nCounter platform, NanoString Technologies, Seattle, WA).
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    SLE inflammatory status - Immune cell population distribution in whole blood
    Description
    SLE inflammatory status is assessed by analyzing the immune cell population distribution in whole blood (fluorescence-activated cell sorting).
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    SLE inflammatory status - Functional immune cell stimulation
    Description
    SLE inflammatory status is assessed by analyzing immune cell stimulation in whole blood (TruCulture).
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Kidney function
    Description
    Kidney function is assessed by analyzing urine (3*24 hours) for kidney specific markers such as urine albumin- and protein/creatinine-ratio.
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Metabolic control
    Description
    Metabolic control is assessed at the hospital by analyzing blood plasma for lipid and glucose profiles
    Time Frame
    During period 1: At baseline and follow-up (day 7). During period 2: At baseline, at day 7-visit and at follow-up (week 8).
    Title
    Medication usage
    Description
    Changes in medication status within the time frame of the study and 3 months after study completion is recorded by accessing the participants medication file.
    Time Frame
    Medication status is reported at all visits (period 1: baseline and follow-up (day 7); period 2: baseline, day 7 and follow-up (week 8)) and three months after completing the study

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion criteria Reading and understanding Danish. SLE diagnosis based on SLE disease classification criteria for at least 1 year. Stable disease and medication the past 28 days as defined by: No change in disease modifying antirheumatic drugs or biological therapy, Receiving maximally 10 mg prednisone daily. Having signs of fatigue, as assessed by scoring ≤ 40 in the FACIT-Fatigue questionnaire. Having signs of autonomic dysfunction, as assessed by scoring one or more of: VAGUS score ≥1 SUDOSCAN score < 50µS for hands or < 70µS for feet COMPASS-31 score > 12 Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests and other trial procedures. Sign the dated informed consent documents Exclusion criteria Significant cardiovascular disease, including congenital cardiac disease, congestive heart failure, known severe coronary artery disease, or recent myocardial infarction (within 5 years), as assessed by a physician at the screening. Blood pressure < 100/60 or > 160/105 Clinically significant bradycardia or tachycardia History of abnormal baseline ECG, prolonged QT interval or arrhythmia Previous surgery on the vagus nerve or abnormal cervical anatomy Implanted or portable electro-mechanical medical devices, e.g. pacemaker, defibrillator, cochlear implant and infusion pump Metallic device such as a stent, bone plate or bone screw implanted at or near the neck Receiving active laser treatment for proliferative retinopathy Active cancer or cancer in remission History of brain tumor, aneurysm, bleed, head trauma, clinically significant syncope or seizures Any clinical abnormalities that, in the opinion of the investigator, may increase the risk associated with trial participation or may interfere with the interpretation of the trial results. Participation in other clinical trials less than three months prior to inclusion, unless such a participation is judged to have no influence on the recordings Female pregnancy (positive urine-HCG), ongoing lactation or intended pregnancy during the study period. A pregnancy test is conducted at first and last visit to ensure that fertile female patients are not pregnant during the study period. Further, the investigator ensures that fertile female patients use a safe contraception method during the study and for at least 15 hours after termination of the study period. Safe contraception: The combined oral contraceptive pill; intra uterine device; gestagen injection; subdermal implantation; hormone vaginal ring; and transdermal plaster. Male patients who intend to father a child during the course of the study
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Søren Jacobsen, DMSc
    Phone
    +45 3545 0545
    Email
    soeren.jacobsen.01@regionh.dk
    First Name & Middle Initial & Last Name or Official Title & Degree
    Amanda H Zinglersen, MD
    Phone
    +45 3545 1292
    Email
    amanda.hempel.zinglersen.01@regionh.dk
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Søren Jacobsen, DMSc
    Organizational Affiliation
    Rigshospitalet, Denmark
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    Data can be provided upon request.
    IPD Sharing Time Frame
    From study end.
    IPD Sharing Access Criteria
    Researchers who provide a methodological sound proposal
    Citations:
    PubMed Identifier
    36127117
    Citation
    Zinglersen AH, Drange IL, Myhr KA, Fuchs A, Pfeiffer-Jensen M, Brock C, Jacobsen S. Vagus nerve stimulation as a novel treatment for systemic lupus erythematous: study protocol for a randomised, parallel-group, sham-controlled investigator-initiated clinical trial, the SLE-VNS study. BMJ Open. 2022 Sep 20;12(9):e064552. doi: 10.1136/bmjopen-2022-064552.
    Results Reference
    derived

    Learn more about this trial

    Vagus Nerve Stimulation for Systemic Lupus Erythematous

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