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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 : September 9, 2020
Sponsor:
Collaborator:
John and Marcia Goldman Foundation
Information provided by (Responsible Party):
Cynthia Aranow, MD, Northwell Health

Tracking Information
First Submitted Date  ICMJE May 26, 2016
First Posted Date  ICMJE July 6, 2016
Last Update Posted Date September 9, 2020
Actual Study Start Date  ICMJE November 1, 2017
Actual Primary Completion Date April 30, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 5, 2016)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2016)
  • SLE Disease activity [ Time Frame: 5 days ]
    SLE disease activity will be assessed using the SLEDAI, a validated disease activity instrument for SLE.
  • Fatigue [ Time Frame: 5 days ]
    Fatigue will be measured using the FACET F questionnaire which will be completed by each subject.
  • Fatigue [ Time Frame: 12 days ]
    Fatigue will be measured using the FACET F questionnaire which will be completed by each subject.
  • 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.
  • 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.
  • SLE cutaneous activity [ Time Frame: 5 days ]
    Cutaneous activity will be assessed using the CLASI, a validated index for SLE skin disease.
  • SLE cutaneous activity [ Time Frame: 12 days ]
    Cutaneous activity will be assessed using the CLASI, a validated index for SLE skin disease.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 10, 2018)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: July 5, 2016)
  • 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.
  • 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.
  • 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.
  • Lipopolysaccharide stimulated levels of TNF, HMGB1, 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.
  • Gardiquimod 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 gardiquimod.. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.
  • Gardiquimod stimulated levels of TNF, HMGB1, 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.
  • CpG 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 CpG. Levels of TNF, HMGB1, IL-6, Il1B, IFNα and IL10 that are produced by the cells in the whole blood will be measured.
 
Descriptive Information
Brief Title  ICMJE Using the Cholinergic Anti-Inflammatory Pathway to Treat Systemic Lupus Musculoskeletal Pain
Official Title  ICMJE Using the Cholinergic Anit-Inflammatory Pathway to Treat Systemic Lupus Musculoskeletal Pain
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE
  • Lupus Erythematosus, Systemic
  • Musculoskeletal Pain
Intervention  ICMJE
  • 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.
  • 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.
Study Arms  ICMJE
  • Active Comparator: Vagus Nerve Stimulation
    Subjects randomized to this arm will receive transcutaneous vagus nerve stimulation for 5 minutes on 4 consecutive days.
    Intervention: Device: Vagus nerve stimulation
  • Sham Comparator: Sham Vagus Nerve Stimulation
    Subjects randomized to this arm will receive sham stimulation for 5 minutes for 4 consecutive days.
    Intervention: Device: Sham vagus nerve stimulation
Publications * Hannon CW, McCourt C, Lima HC, Chen S, Bennett C. Interventions for cutaneous disease in systemic lupus erythematosus. Cochrane Database Syst Rev. 2021 Mar 9;3:CD007478. doi: 10.1002/14651858.CD007478.pub2.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: July 5, 2016)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 1, 2020
Actual Primary Completion Date April 30, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02822989
Other Study ID Numbers  ICMJE 16-0171
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Cynthia Aranow, MD, Northwell Health
Study Sponsor  ICMJE Northwell Health
Collaborators  ICMJE John and Marcia Goldman Foundation
Investigators  ICMJE
Principal Investigator: Cynthia Aranow, M.D. Northwell Health
PRS Account Northwell Health
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP