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Effect of Daily Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) on Proteinuria in Pediatric Patients With Idiopathic Nephrotic Syndrome (taVNS)

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ClinicalTrials.gov Identifier: NCT04169776
Recruitment Status : Recruiting
First Posted : November 20, 2019
Last Update Posted : February 12, 2020
Sponsor:
Information provided by (Responsible Party):
Northwell Health

Brief Summary:
This study evaluates the impact of transcutaneous auricular Vagus Nerve stimulation (taVNS) therapy on the incidence of nephrotic syndrome relapses in children with idiopathic nephrotic syndrome. Participants will perform taVNS 5 minutes a day for 6 months total, monitoring for signs of nephrotic syndrome relapse with both labwork and clinical symptoms.

Condition or disease Intervention/treatment Phase
Idiopathic Nephrotic Syndrome Frequently Relapsing Nephrotic Syndrome Device: Transcutaneous Auricular Vagus Nerve (taVNS) stimulation Not Applicable

Detailed Description:

Idiopathic nephrotic syndrome is defined as the development of proteinuria, edema, hypoalbuminemia, and hyperlipidemia often presenting in the pediatric population. The underlying pathogenesis of idiopathic nephrotic syndrome is poorly understood but likely involves dysregulation of the immune system, and the majority of patients respond to steroid therapy and other immunosuppressive therapy. Unfortunately, relapses are common, with at least one relapse occurring in up to 90% of patients. Frequently-relapsing patients may be exposed large amounts of steroids and other immunosuppressants with a multitude of adverse effects, while others may not even respond to these treatments. Therefore, novel therapies are being studied.

Vagus nerve stimulation is a novel therapy with the potential to treat inflammatory conditions via inhibition of cytokine release by the cholinergic anti-inflammatory pathway. The purpose of the proposed study is to investigate the use of vagus nerve stimulation in the prevention of nephrotic syndrome relapses and treatment of proteinuria in pediatric patients with idiopathic nephrotic syndrome.

Patients will be enrolled if they have frequently-relapsing idiopathic nephrotic syndrome or proteinuria which does not respond to steroid therapy. These patients will perform daily transcutaneous auricular Vagus Nerve stimulation (taVNS) therapy 5 minutes a day for a 6 month period and will be monitored for urine/bloodwork or clinical signs of nephrotic syndrome relapse.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study is a prospective cohort pilot study not formally classified as a specific trial phase. The study will involve two Arms, with 15 participants in each Arm of the study. Arm 1 will recruit patients with steroid-sensitive frequently-relapsing idiopathic nephrotic syndrome. Arm 2 will recruit patients with steroid-resistant idiopathic nephrotic syndrome. All participants in both Arms of the study will perform daily transcutaneous auricular vagus nerve stimulation (taVNS) therapy for 5 minutes each day. The study period will be 6 months. The participants will be monitored for labwork and clinical evidence of nephrotic syndrome relapse, comparing the number of relapses and level or proteinuria in the 6 months before starting taVNS therapy to number of relapses and level of proteinuria in the 6 month study period.
Masking: None (Open Label)
Masking Description: This study design was chosen as it is the most realistic and practical design for this pilot study. There is no blinding or masking in this pilot study.
Primary Purpose: Treatment
Official Title: Effect of Daily Transcutaneous Auricular Vagus Nerve (taVNS) Stimulation on Proteinuria in Pediatric Patients With Idiopathic Nephrotic Syndrome
Actual Study Start Date : December 1, 2019
Estimated Primary Completion Date : December 30, 2020
Estimated Study Completion Date : December 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Steroid Sensitive Frequently-Relapsing Nephrotic Syndrome
Individuals in this arm of the study will have to have a diagnosis of steroid sensitive frequently relapsing idiopathic nephrotic syndrome. They will receive transcutaneous auricular VNS (taVNS) performed for 5minutes every day for 6 months. The settings of the taVNS device will be individualized for each patient. Data will be collected on the the number of nephrotic syndrome relapses, the time between relapses, the time to remission once relapsed, and the level of proteinuria before and while using taVNS therapy.
Device: Transcutaneous Auricular Vagus Nerve (taVNS) stimulation
Participants in this study will perform home transcutaneous auricular vagus nerve stimulation (taVNS) for 5 minutes a day for a 6-month period. The device that will be used is the commercially available Roscoe Medical TENS 7000 vagus nerve stimulator. The device will be attached to the Cymba Concha of the ear via an electrode ear clip. The intensity of the stimulation will be slowly increased and adjusted to individual tolerability for each treatment. TaVNS will be performed for 5 minutes daily for a period of 6 months.

Experimental: Steroid Resistant Idiopathic Nephrotic Syndrome
Individuals in this arm of the study will have to have a diagnosis of steroid resistant idiopathic nephrotic syndrome. They will receive transcutaneous auricular VNS (taVNS) performed for 5minutes every day for 6 months. The settings of the taVNS device will be individualized for each patient. Data will be collected on the the number of nephrotic syndrome relapses, the time between relapses, the time to remission once relapsed, and level of proteinuria before and while using taVNS therapy.
Device: Transcutaneous Auricular Vagus Nerve (taVNS) stimulation
Participants in this study will perform home transcutaneous auricular vagus nerve stimulation (taVNS) for 5 minutes a day for a 6-month period. The device that will be used is the commercially available Roscoe Medical TENS 7000 vagus nerve stimulator. The device will be attached to the Cymba Concha of the ear via an electrode ear clip. The intensity of the stimulation will be slowly increased and adjusted to individual tolerability for each treatment. TaVNS will be performed for 5 minutes daily for a period of 6 months.




Primary Outcome Measures :
  1. Safety and tolerability of taVNS (Arms 1 and 2) [ Time Frame: 6 months ]

    The endpoint of heart rate monitoring as a measure of safety of taVNS in this population was selected as this is the most concerning adverse effect of taVNS therapy. If there is no heart rate-related events during this study, it would further justify safe use of taVNS in the pediatric population.

    Tolerability is an important measure in this study but is mostly a subjective measure. Therefore, patients who withdraw due to intolerability or report side effects which are deemed intolerable will aid in determining the feasibility of taVNS use in this population.



Secondary Outcome Measures :
  1. Impact of taVNS on cytokine levels (Arms 1 and 2) [ Time Frame: 6 months ]
    TaVNS has been shown in literature to have an anti-inflammatory effect when stimulating the vagus nerve. Several studies have found that cytokine levels are increased in nephrotic syndrome relapses as compared to levels when in remission. This endpoint provides a measure of the efficacy and compliance of taVNS use while also providing a marker for the effect of taVNS on the patient. Finally, if taVNS is shown to reduce the number of relapses while also suppressing cytokine levels, it may suggest a cytokine-associated etiology of idiopathic nephrotic syndrome.

  2. Impact of taVNS on number of nephrotic syndrome relapses, time to nephrotic syndrome relapses, and time to remission (Arm 1) [ Time Frame: 6 months ]
    This outcome was chosen as an important measure of the efficacy of taVNS on patients with idiopathic nephrotic syndrome. A reduction in the number of relapses suggests that taVNS is a potential therapy for idiopathic nephrotic syndrome.

  3. Impact of taVNS on level of proteinuria (Arm 2) [ Time Frame: 6 months ]
    The marker of disease progression and worsening outcomes is the level of proteinuria in patients with steroid-resistant idiopathic nephrotic syndrome. Measurement of the urine protein to creatinine level on a first morning sample is the most feasible and accurate measure of proteinuria in this patient population.



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria (Arm 1):

  1. Subjects age 2-21 years of age
  2. eGFR > 60 ml/min/1.73 m2
  3. Diagnosis of idiopathic minimal change disease (clinical diagnosis or per biopsy)
  4. Prior history of remission of nephrotic syndrome within 4 weeks of initiation of steroid therapy (steroid sensitive nephrotic syndrome)
  5. 2 or more episodes of nephrotic syndrome relapses in a 6-month period or four or more episodes of nephrotic syndrome relapses in a 12-month period (relapse defined as 2+ proteinuria on first morning urine sample for three consecutive days or development of edema)
  6. In remission (no proteinuria - normal urine protein to creatinine ratio < 0.2) at the time of enrollment

Inclusion Criteria (Arm 2):

  1. Subjects age 2-21 years of age
  2. eGFR > 60 ml/min/1.73 m2
  3. Diagnosis idiopathic nephrotic syndrome (clinical diagnosis or per biopsy)
  4. Diagnosis of steroid-resistant nephrotic syndrome (symptoms or proteinuria not improved after 4 to 8 weeks of steroid therapy)
  5. Persistent proteinuria (first-morning urine protein to creatinine ratio > 0.2)
  6. At least 7 days since last dose of steroids

Exclusion Criteria (Arm 1):

  1. Subjects with nephrotic syndrome etiology other than idiopathic minimal change disease either biopsy-proven or by genetic testing
  2. Nephrotic syndrome due to secondary causes such as SLE, vasculitis, hepatitis, post-infectious etiology, medication-induced, etc.
  3. Subjects that did not achieve remission of nephrotic syndrome within 4 weeks of initiation of steroid therapy (steroid-resistant nephrotic syndrome)
  4. Subjects with urine protein to creatinine ratio of > 0.2 (not in remission)
  5. Subjects currently receiving any standing immunosuppressive therapy (mycophenolate mofetil, tacrolimus, rituximab - note: 1) previous exposure to these therapies does not exclude participation; 2) subjects with previous exposure to rituximab are eligible if B cells are replete)
  6. Subjects with a history of cardiac issues, including bradycardia, arrhythmias or structural abnormalities of the heart
  7. Subjects with implantable electronic devices such as pacemakers, defibrillators, hearing aids, cochlear implants or deep brain stimulators
  8. Subjects with any other known inflammatory condition (IBD, SLE, etc.)

Exclusion Criteria (Arm 2):

  1. Nephrotic syndrome due to secondary causes such as SLE, vasculitis, hepatitis, post-infectious etiology, medication-induced, etc.
  2. Subjects with a history of cardiac issues, including bradycardia, arrhythmias or structural abnormalities of the heart
  3. Subjects with implantable electronic devices such as pacemakers, defibrillators, hearing aids, cochlear implants or deep brain stimulators
  4. Subjects with any other known inflammatory condition (IBD, SLE, etc.)

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): NCT04169776


Contacts
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Contact: Kisha Laurent, MA 718-470-3499 klaurent1@northwell.edu
Contact: Kumail Merchant, MD 718-470-3491 kmerchant@northwell.edu

Locations
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United States, New York
Northwell Recruiting
New Hyde Park, New York, United States, 11040
Contact: Kisha Laurent, MA    718-470-3499    klaurent1@northwell.edu   
Principal Investigator: Christine Sethna, MD         
Sponsors and Collaborators
Northwell Health
Investigators
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Principal Investigator: Christine Sethna, MD Northwell Health
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Responsible Party: Northwell Health
ClinicalTrials.gov Identifier: NCT04169776    
Other Study ID Numbers: 19-0861
First Posted: November 20, 2019    Key Record Dates
Last Update Posted: February 12, 2020
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: This study will be conducted in accordance with the following publication and data sharing policies and regulations.National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the published results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication.This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals. Data from this study may be requested from other researchers 10 years after the completion of the primary endpoint.

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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.: No
Additional relevant MeSH terms:
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Proteinuria
Nephrotic Syndrome
Nephrosis
Nephrosis, Lipoid
Syndrome
Disease
Pathologic Processes
Urination Disorders
Urologic Diseases
Urological Manifestations
Kidney Diseases