taVNS for Nephrotic Syndrome in Children

(kidNEY-VNS Trial)

Recruiting at 1 trial location

Overseen By Suzanne Vento, RN

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: Northwell Health

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Secondary nephrotic syndrome, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 16

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for nephrotic syndrome in children, a kidney condition where the body leaks too much protein into the urine, using a non-invasive technique called transcutaneous auricular vagus nerve stimulation (taVNS). The goal is to determine if this method can manage the condition without the side effects of long-term steroid use. Researchers will divide participants into two groups: one receiving the active treatment and the other receiving a sham (inactive) treatment for comparison. The trial seeks children aged 3-17 who have experienced frequently relapsing nephrotic syndrome but are currently in remission. As an unphased trial, this study offers participants a unique opportunity to contribute to innovative research that could lead to new treatment options.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have been exposed to steroids within 14 days of enrollment or are receiving any standing immunosuppression.

What prior data suggests that taVNS is safe for children with nephrotic syndrome?

Research has shown that transcutaneous auricular vagus nerve stimulation (taVNS) is generally safe for children. In previous studies, taVNS treated nephrotic syndrome, a kidney condition, without causing major side effects. One study found that taVNS not only aided recovery from the condition but also reduced protein in urine, a common issue with this illness, without negative effects. Another study showed it lowered levels of TNF-α, an inflammation marker, again with no reported side effects. These findings suggest that taVNS could be a safe and promising treatment for children with nephrotic syndrome. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about transcutaneous auricular vagus nerve stimulation (taVNS) for nephrotic syndrome in children because it offers a non-invasive way to potentially modulate the nervous system and reduce inflammation. Unlike current treatments, which often involve steroids and immunosuppressants with significant side effects, taVNS uses gentle electrical pulses to stimulate the vagus nerve through the skin of the ear. This method is unique as it targets the body's natural pathways to promote healing and could reduce reliance on medications that may have long-term adverse effects.

What evidence suggests that taVNS is effective for nephrotic syndrome in children?

Research has shown that transcutaneous auricular vagus nerve stimulation (taVNS), a treatment that participants in this trial may receive, might help children with frequently relapsing nephrotic syndrome (FRNS). Studies have found that taVNS can lead to periods of symptom improvement and, in some cases, reduce protein levels in urine. Additionally, taVNS has been associated with lower levels of TNF-α, a substance that can cause inflammation, without harmful side effects. These findings suggest that taVNS could be a promising option for managing relapses in nephrotic syndrome. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

This trial is for children aged 3-17 with frequently relapsing nephrotic syndrome, specifically those diagnosed with Minimal Change Disease or Focal Segmental Glomerulosclerosis. They must be in remission and have responded to steroids before. Kids can't join if they've taken steroids recently, are on other immunosuppressants, have electronic implants, are pregnant, or have certain heart diseases or inflammatory conditions.

Inclusion Criteria

I am between 3 and 17 years old.

I have been diagnosed with MCD or FSGS.

Informed consent from the parent or guardian and assent from a minor of ≥ 7 years

Exclusion Criteria

Pregnancy

You have an implanted electronic device.

I have an inflammatory condition like lupus.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

up to 8 weeks

Randomized Control Period

Participants are randomized to either taVNS or sham treatment and perform daily therapy for 26 weeks

26 weeks

In-person visits at Weeks 8, 16, and 26; virtual visits at Weeks 4, 12, and 20

Follow-up

Participants are monitored for clinical status and nephrotic syndrome relapses after the randomized period

26 weeks

In-person or telehealth visits every 8 weeks

Open-label Extension (optional)

Participants may opt to receive active taVNS treatment after the randomized period

What Are the Treatments Tested in This Trial?

Interventions

• Sham device
• Transcutaneous auricular vagus nerve stimulation

Trial Overview The study tests transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive treatment that might regulate the immune system without drugs' side effects. Children will be randomly assigned to either real taVNS therapy or a sham device to compare effectiveness and impact on inflammation markers.

How Is the Trial Designed?

Group I: Intervention Group Experimental Treatment 1 Intervention

The intensity setting for pulse amplitude will be adjusted to the participant's tolerance (if a sensation is felt) to a maximum level of 3 on the dial indicator. The remaining settings will be stored in the device and will not need to be set for each treatment. Participants and guardians will be instructed to adjust intensity to highest level of tolerance each time the device is used and level will be logged.

Group II: Sham Group Placebo Group 1 Intervention

The sham device will be disabled internally so that electrical stimulation is not delivered, but the device will appear to function. Externally, the sham device will look identical to the taVNS device. The participant will be told to increase the intensity until tolerated if a sensation is felt, but will be asked to stop at a maximum level of 3. This inactive sham method was chosen because previous studies have shown that stimulation with placement of the ear clip on other parts of the ear such as the earlobe, although not innervated by the vagus nerve, results in some vagus nerve activity. Inactive sham methodology has been used in previous studies.

Who Is Running the Clinical Trial?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

In a pilot study involving 7 children with frequently relapsing nephrotic syndrome (FRNS) and steroid-resistant nephrotic syndrome (SRNS), transcutaneous auricular vagus nerve stimulation (taVNS) showed promising results, with FRNS participants remaining relapse-free and some SRNS participants experiencing a significant reduction in proteinuria.

taVNS was well-tolerated with no reported adverse events, suggesting it could be a safe alternative or complementary therapy for managing nephrotic syndrome in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of pediatric nephrotic syndrome: a pilot study. Merchant, K., Zanos, S., Datta-Chaudhuri, T., et al.[2022]

In a study of 47 children aged 5 to 20 requiring permanent vascular access for hemodialysis, the construction of autogenous arteriovenous access (AAVA) was successful, achieving a primary patency rate of 100% at 1 year and 96% at 2 years.

The use of preoperative vein mapping and an operating microscope allowed for successful AAVA construction, even in cases where upper extremity access was not feasible, demonstrating that AAVA can be effectively created in most pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience with autogenous arteriovenous access for hemodialysis in children and adolescents. Gradman, WS., Lerner, G., Mentser, M., et al.[2017]

In a study of 42 pediatric patients undergoing staged basilic vein transposition (BVT) for hemodialysis access, 93% achieved functional maturation, demonstrating the procedure's high efficacy in creating reliable vascular access.

The primary patency rates for BVT were 78% at 2 years and 72% at 4 years, indicating that while some patients experienced thrombosis, the procedure remains a durable option for children with inadequate cephalic veins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes of staged basilic vein transposition for hemodialysis access in children. Kfoury, E., Demaree, CJ., Poi, MJ., et al.[2018]

In a study of 87 children with steroid-dependent nephrotic syndrome, mycophenolate mofetil (MMF) therapy achieved remission in 83% of patients, demonstrating its efficacy as an alternative treatment.

MMF was well tolerated, with only 22% of patients experiencing adverse events, and discontinuation of MMF led to a 100% relapse rate, highlighting its importance in maintaining remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of mycophenolate mofetil in children and adolescents with steroid-dependent nephrotic syndrome: a single-centre study. Karunamoorthy, S., Thanigachalam, D., Jeyachandran, D., et al.[2022]

Transcutaneous auricular vagus nerve stimulation (TaVNS) effectively normalized gastric dysrhythmias in healthy individuals during a water-load test, indicating its potential as a treatment for gastric symptoms.

The study found that TaVNS at 40 Hz improved heart rate variability and reduced bloating, suggesting it positively influences both parasympathetic and sympathetic nervous system pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Auricular Vagus Nerve Stimulation Normalizes Induced Gastric Myoelectrical Dysrhythmias in Controls Assessed by Body-Surface Gastric Mapping. Du, P., Maharjan, A., Calder, S., et al.[2023]

Noninvasive transcutaneous stimulation of the auricular branch of the vagus nerve (AB-VNS) significantly reduces spontaneous ventricular arrhythmias in beagle dogs after myocardial infarction, indicating its potential as an antiarrhythmic treatment.

AB-VNS enhances ventricular electrical stability and reduces ventricular interstitial fibrosis, although it does not improve overall cardiac function or reverse structural changes in the heart after 4 weeks of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation reduces ventricular arrhythmias and increases ventricular electrical stability. Nasi-Er, BG., Wenhui, Z., HuaXin, S., et al.[2019]

In a study of 1,284 children on hemodialysis, 59% were using vascular catheters instead of arteriovenous fistulas (AVFs) or grafts (AVGs), highlighting a high prevalence of catheter use in this population.

The study found that while small body size was a common reason for catheter use, only one-third of children with catheters underwent transplantation within a year, suggesting a need for targeted interventions to promote the use of AVFs/AVGs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns of use of vascular catheters for hemodialysis in children in the United States. Fadrowski, JJ., Hwang, W., Neu, AM., et al.[2018]

Central venous lines (CVLs) in children with end-stage kidney disease (ESKD) are associated with higher rates of infections and access dysfunction compared to arteriovenous fistulas (AVFs), which are considered superior despite being used in only about 25% of pediatric patients on hemodialysis.

The European Society for Paediatric Nephrology has developed recommendations emphasizing the importance of choosing the right type of vascular access for children, highlighting the need for venous preservation and tailored approaches based on individual patient circumstances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vascular access in children requiring maintenance haemodialysis: a consensus document by the European Society for Paediatric Nephrology Dialysis Working Group. Shroff, R., Calder, F., Bakkaloğlu, S., et al.[2021]

A 4-year-old boy with nephritic syndrome developed serious complications, including bilateral sixth-nerve palsy and lethargy due to cerebral sinus thrombosis, highlighting the potential neurological risks associated with this condition.

Despite challenges in achieving effective anticoagulation, the boy received treatment with heparin and other therapies, ultimately leading to a complete neurological recovery, demonstrating the potential for positive outcomes even in severe cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebral venous thrombosis in the nephrotic syndrome. Al Fakeeh, KN., Al Rasheed, SA.[2008]

Transcutaneous vagus nerve stimulation (tVNS) significantly reduced postural tachycardia in patients with POTS, showing a mean heart rate increase of 17.6 beats/min in the active group compared to 31.7 beats/min in the sham group after 2 months.

tVNS also led to lower levels of antiadrenergic autoantibodies and inflammatory cytokines, along with improved heart rate variability, indicating its potential as a safe and effective noninvasive treatment for POTS without any reported side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial. Stavrakis, S., Chakraborty, P., Farhat, K., et al.[2023]

Transcutaneous vagus nerve stimulation (tVNS) is a promising non-invasive alternative to traditional vagus nerve stimulation (VNS) for treating conditions like epilepsy and depression, which can be invasive and have side effects.

There is ongoing research into the best stimulation parameters and sites for tVNS, particularly focusing on stimulation at the outer ear, to optimize its therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation and the realm of its therapeutic hopes and physiologic enigmas. Hilz, MJ., Bolz, A.[2022]

Transcutaneous auricular vagus nerve stimulation (ta-VNS) was found to be effective in reducing symptoms of mild to moderate Crohn's disease and ulcerative colitis in a study of 22 pediatric patients, with 50% of Crohn's patients and 33% of ulcerative colitis patients achieving clinical remission by week 16.

The therapy also led to significant reductions in fecal calprotectin levels, with 64.7% of patients showing at least a 50% decrease, indicating a positive impact on inflammation without any safety concerns reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: a proof-of-concept clinical trial. Sahn, B., Pascuma, K., Kohn, N., et al.[2023]

The NAPRTCS report analyzed data from 3,183 pediatric patients who underwent renal transplants, revealing that chronic rejection is now the leading cause of graft failure, accounting for 34% of failures in the past year.

Early treatment with antithymocyte globulin or similar therapies significantly improved graft survival, particularly in younger patients, highlighting the importance of tailored treatment strategies in pediatric renal transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The 1994 annual report of the North American Pediatric Renal Transplant Cooperative Study. Kohaut, EC., Tejani, A.[2019]

A systematic review of 12 trials involving 868 children with steroid-sensitive nephrotic syndrome (SSNS) found that treating with corticosteroids for at least 3 months significantly reduces the risk of relapse without increasing side effects.

Longer treatment durations were associated with lower relapse rates, indicating that a minimum of 3 months of glucocorticoid therapy is beneficial for children experiencing their first episode of SSNS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Glucocorticoid administration in steroid sensitive nephritic syndrome: a meta-analysis]. Guan, FJ., Yi, ZW., Dang, XQ., et al.[2008]

In a study of 31 children with end-stage renal disease undergoing hemodialysis, arteriovenous fistulas (AVFs) were the preferred vascular access, but they had a primary failure rate of 25.7% and took an average of 4 months to mature.

Non-cuffed central venous catheters (CVCs) were also used, primarily inserted in the jugular vein, with a low incidence of bacteremia (0.9 episodes per 1000 catheter days), making them a viable alternative when AVFs are not suitable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vascular access in children on chronic hemodialysis: a Slovenian experience. Rus, RR., Novljan, G., Buturović-Ponikvar, J., et al.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35078538/

Transcutaneous auricular vagus nerve stimulation (taVNS) ... Conclusions: taVNS was associated with clinical remission in FRNS and moderately reduced proteinuria in non-congenital SRNS. Further study of ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04169776?term=Creatinine%20AND%20NPHS2&viewType=Table&rank=10

Effect of Daily Transcutaneous Auricular Vagus Nerve ... This study evaluates the impact of transcutaneous auricular Vagus Nerve stimulation (taVNS) therapy on the incidence of nephrotic syndrome relapses in ...

3. journals.lww.com journals.lww.com/jasn/fulltext/2021/10001/transcutaneous_auricular_vagus_nerve_stimulation.1835.aspx

Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)... taVNS prevented NS relapses in FRNS, reduced proteinuria in SRNS, and reduced TNF-α levels without any adverse effects, suggesting taVNS as a promising therapy ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8790887/

Transcutaneous auricular vagus nerve stimulation (taVNS) ... taVNS was associated with clinical remission in FRNS and moderately reduced proteinuria in non-congenital SRNS.

5. sciencedirect.com sciencedirect.com/science/article/pii/S1094715922007644

Transcutaneous Auricular Vagus Nerve Stimulation in ... In this study, we focus on auricular tVNS because it was shown that cervical tVNS can make selective transcutaneous stimulation of vagus nerve fibers difficult ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05588063?term=AREA%5BConditionSearch%5D(Nephrotic%20Syndrome)%20AND%20AREA%5BOverallStatus%5D(RECRUITING)%20AND%20AREA%5BStdAge%5D(CHILD)%20AND%20AREA%5BFunderTypeSearch%5D(NIH%20OR%20FED)&rank=4

Study Details | NCT05588063 | taVNS for FRNS in Children A Pilot Randomized Clinical Trial of Transcutaneous Auricular Vagus Nerve Stimulation for the Treatment of Frequently Relapsing Nephrotic Syndrome in Children.