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Using the Cholinergic Anti-Inflammatory Pathway to Treat Systemic Lupus Musculoskeletal Pain

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ClinicalTrials.gov Identifier: NCT02822989
Recruitment Status : Enrolling by invitation
First Posted : July 6, 2016
Last Update Posted : March 14, 2019
Sponsor:
Collaborator:
John and Marcia Goldman Foundation
Information provided by (Responsible Party):
Cynthia Aranow, MD, Northwell Health

Brief Summary:
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune, inflammatory disease and musculoskeletal pain is one of the most common symptoms. This study will investigate whether transcutaneous stimulation of the vagus nerve will decrease lupus musculoskeletal pain. This study will additionally investigate the biologic effects of vagus nerve stimulation on inflammation. It will be the first clinical study using one of the body's own pathways of modulating the immune system and inflammatory response, the cholinergic anti-inflammatory pathway, in SLE.

Condition or disease Intervention/treatment Phase
Lupus Erythematosus, Systemic Musculoskeletal Pain Device: Vagus nerve stimulation Device: Sham vagus nerve stimulation Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Using the Cholinergic Anit-Inflammatory Pathway to Treat Systemic Lupus Musculoskeletal Pain
Actual Study Start Date : November 1, 2017
Actual Primary Completion Date : April 30, 2018
Estimated Study Completion Date : September 1, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lupus

Arm Intervention/treatment
Active Comparator: Vagus Nerve Stimulation
Subjects randomized to this arm will receive transcutaneous vagus nerve stimulation for 5 minutes on 4 consecutive days.
Device: Vagus nerve stimulation
Patients will receive transcutaneous stimulation of the auricular branch of the left vagus nerve for 5 minutes daily for 4 consecutive days. The device is a handheld electrical pulse generator and a pair of electrodes to be placed at the ear for stimulation. The specific target at the ear will be the auricular branch of the vagus nerve which innervates the skin of the ear canal. Electrodes will be placed near/at the entrance to the canal of the ear to provide stimulation to the auricular branch.

Sham Comparator: Sham Vagus Nerve Stimulation
Subjects randomized to this arm will receive sham stimulation for 5 minutes for 4 consecutive days.
Device: Sham vagus nerve stimulation
Patients will receive sham transcutaneous stimulation of the auricular branch of the left vagus nerve for 5 minutes daily for 4 consecutive days. Sham stimulation will be performed in the identical manner as true transcutaneous stimulation except that the patient will not receive electrical stimulation of the vagus nerve.




Primary Outcome Measures :
  1. Musculoskeletal pain. [ Time Frame: 5 days ]
    Patients rate their musculoskeletal pain by making a mark on a 10cm anchored Visual Analog Scale where 0=no musculoskeletal pain and 10 =worst possible musculoskeletal pain.


Secondary Outcome Measures :
  1. SLE Disease activity [ Time Frame: 5 days ]
    SLE disease activity will be assessed using the SLEDAI, a validated disease activity instrument for SLE.

  2. Fatigue [ Time Frame: 5 days ]
    Fatigue will be measured using the FACET F questionnaire which will be completed by each subject.

  3. Fatigue [ Time Frame: 12 days ]
    Fatigue will be measured using the FACET F questionnaire which will be completed by each subject.

  4. Tender and swollen joint counts [ Time Frame: 5 days ]
    The number of tender and swollen joints of the subject will be assessed by the investigator who will examine 68 potential tender joints and 66 potential swollen joints.

  5. Tender and swollen joint counts [ Time Frame: 12 days ]
    The number of tender and swollen joints of the subject will be assessed by the investigator who will examine 68 potential tender joints and 66 potential swollen joints.

  6. SLE cutaneous activity [ Time Frame: 5 days ]
    Cutaneous activity will be assessed using the CLASI, a validated index for SLE skin disease.

  7. SLE cutaneous activity [ Time Frame: 12 days ]
    Cutaneous activity will be assessed using the CLASI, a validated index for SLE skin disease.

  8. Musculoskeletal Pain [ Time Frame: 12 days ]
    Patients rate their musculoskeletal pain by making a mark on a 10cm anchored Visual Analog Scale where 0=no musculoskeletal pain and 10 =worst possible musculoskeletal pain.

  9. Percentage of subjects with treatment emergent adverse events. [ Time Frame: 12 days ]
    The percentage of participants with treatment emergent adverse events will be assessed using the NCI-CTAEversion4.


Other Outcome Measures:
  1. TNF, HMGB1, IL-6, Il1B, IFNα and IL10 levels [ Time Frame: 5 days ]
    Levels of inflammatory cytokines (ie TNF, HMGB1, IL-6, Il1B, IFNα and IL10) will be measured in patients sera.

  2. TNF, HMGB1, IL-6, Il1B, IFNα and IL10 levels [ Time Frame: 12 days ]
    Levels of inflammatory cytokines (ie TNF, HMGB1, IL-6, Il1B, IFNα and IL10) will be measured in patients sera.

  3. Lipopolysaccharide stimulated levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 in whole blood. [ Time Frame: 5 days ]
    Whole blood will be taken from patients and stimulated by lipopolysaccharide. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.

  4. Lipopolysaccharide stimulated levels of TNF, IL-6, Il1B, IFNα and IL10 in whole blood. [ Time Frame: 12 days ]
    Whole blood will be taken from patients and stimulated by lipopolysaccharide. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.

  5. Gardiquimod stimulated levels of TNF, IL-6, Il1B, IFNα and IL10 in whole blood. [ Time Frame: 5 days ]
    Whole blood will be taken from patients and stimulated by gardiquimod.. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.

  6. Gardiquimod stimulated levels of TNF, IL-6, Il1B, IFNα and IL10 in whole blood. [ Time Frame: 12 days ]
    Whole blood will be taken from patients and stimulated by gardiquimod.. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.

  7. CpG stimulated levels of TNF, IL-6, Il1B, IFNα and IL10 in whole blood. [ Time Frame: 5 days ]
    Whole blood will be taken from patients and stimulated by CpG. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18 years,
  2. SLE (defined by the ACR or SLICC criteria),
  3. Musculoskeletal pain ≥ 4 on a non-anchored VAS 10 cm scale
  4. BILAG C on Musculoskeletal Domain of the BILAG 2004
  5. If on corticosteroids, the dose must be stable and ≤ 10mg/day (prednisone or equivalent) for at least 28 days before baseline,
  6. If on background immunosuppressive treatment the dose must be stable for at least 28 days before baseline
  7. Able and willing to give written informed consent and comply with the requirements of the study protocol.

Exclusion Criteria:

  1. Treatment with rituximab within one year of baseline (subjects with previous treatment with rituximab can enter study only with documentation of B cell repletion),
  2. Treatment with cyclophosphamide within 2 months of baseline,
  3. Expectation to increase steroids and/or immunosuppressive treatment,
  4. Anti-phospholipid syndrome,
  5. Fibromyalgia (fibromyalgia will be defined as a score > 13 on the Fibromyalgia Symptom Scale (FSS).
  6. Treatment with an anti-cholinergic medication, including over the counter medications,
  7. Implantable electronic devices such as pacemakers, defibrillators, hearing aids, cochlear implants or deep brain stimulators.
  8. Current tobacco or nicotine user,
  9. Joint replacement within 60 days prior to study enrollment or planned within the course of the study,
  10. Any planned surgical procedure requiring general anesthesia within the course of the study,
  11. Intra-articular cortisone injections within 28 days of the start of study,
  12. Chronic inflammatory disorders apart from SLE affecting the joints,
  13. Investigational drug and/or treatment during the 28 days or seven half-lives of the investigational drug prior to the start of study drug dosing (Day 0), whichever is the greater length of time,
  14. Active infection including hepatitis B or hepatitis C at baseline,
  15. Any condition which, in the opinion of the investigator, would jeopardize the subject's safety following exposure to a study intervention,
  16. Pregnancy or lactation,
  17. Comorbid disease that may require administration of corticosteroid use,
  18. Inability to comply with study and follow-up procedures.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02822989


Locations
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United States, New York
Feinstein Institute
Manhasset, New York, United States, 11030
Sponsors and Collaborators
Northwell Health
John and Marcia Goldman Foundation
Investigators
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Principal Investigator: Cynthia Aranow, M.D. Northwell Health

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Responsible Party: Cynthia Aranow, MD, Investigator, Northwell Health
ClinicalTrials.gov Identifier: NCT02822989     History of Changes
Other Study ID Numbers: 16-0171
First Posted: July 6, 2016    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cynthia Aranow, MD, Northwell Health:
Lupus Erythematosus, Systemic
Musculoskeletal Pain
Inflammation

Additional relevant MeSH terms:
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Lupus Erythematosus, Systemic
Musculoskeletal Pain
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Muscular Diseases
Musculoskeletal Diseases
Pain
Neurologic Manifestations
Signs and Symptoms
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs