Clinical trial NCT04169776: Effect of Daily Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) on Proteinuria in Pediatric Patients With Idiopathic Nephrotic Syndrome
Official title: Effect of Daily Transcutaneous Auricular Vagus Nerve (taVNS) Stimulation on Proteinuria in Pediatric Patients With Idiopathic Nephrotic Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Idiopathic Nephrotic Syndrome
Frequently Relapsing Nephrotic Syndrome
Lead sponsor: Northwell Health
Sponsor class: OTHER
First posted: 2019-11-20
Enrollment: 7
Sex: ALL
Minimum age (years): 2
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: DEVICE_FEASIBILITY

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.

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.

Eligibility 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.)

Primary outcomes:
measure: Safety and tolerability of taVNS (Arms 1 and 2)
timeFrame: 6 months
Secondary outcomes:
measure: Impact of taVNS on cytokine levels (Arms 1 and 2)
timeFrame: 6 months
measure: Impact of taVNS on number of nephrotic syndrome relapses, time to nephrotic syndrome relapses, and time to remission (Arm 1)
timeFrame: 6 months
measure: Impact of taVNS on level of proteinuria (Arm 2)
timeFrame: 6 months
Other outcomes:
Locations:
city: New Hyde Park
country: United States
facility: Northwell
state: New York
Study officials:
affiliation: Northwell Health
name: Christine Sethna, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Merchant K, Zanos S, Datta-Chaudhuri T, Deutschman CS, Sethna CB. Transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of pediatric nephrotic syndrome: a pilot study. Bioelectron Med. 2022 Jan 26;8(1):1. doi: 10.1186/s42234-021-00084-6.