Vagus Nerve Stimulation for Nephrotic Syndrome

(kidNEY-VNS Trial)

Recruiting at 1 trial location

Overseen By Suzanne Vento, RN

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: Northwell Health

Must be taking: Immunosuppressants, ACE inhibitors

Disqualifiers: Genetic defects, Cardiac disease, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 20

10 Participants Needed

Trial Summary

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

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should have a stable immunosuppression and ACE inhibitor/angiotensin receptor blocker treatment regimen for at least three months, which suggests you may need to continue your current medications.

What data supports the effectiveness of the treatment Vagus Nerve Stimulation for Nephrotic Syndrome?

Research shows that transcutaneous auricular vagus nerve stimulation (taVNS) can help with heart rate regulation and has anti-inflammatory effects, which might be beneficial for conditions like nephrotic syndrome that involve inflammation. ^{1 2 3 4 5}

Is transcutaneous auricular vagus nerve stimulation (taVNS) safe for humans?

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally considered safe, with mild and temporary side effects like ear pain, headache, and tingling. A large review found no serious adverse events linked to taVNS, making it a safe option for clinical use. ^{5 6 7 8 9}

How is the treatment taVNS different from other treatments for nephrotic syndrome?

taVNS (Transcutaneous Auricular Vagus Nerve Stimulation) is unique because it involves stimulating the vagus nerve through the skin of the ear, which is a non-invasive method, unlike traditional treatments that often involve medications like corticosteroids or immunosuppressants. This approach may offer a novel way to manage symptoms without the side effects associated with drugs. ^{10 11 12 13 14}

What is the purpose of this trial?

Children with steroid resistant nephrotic syndrome (SRNS) are exposed to prolonged courses of immunosuppressant medications. Given the adverse side effect profiles and variable efficacy of these medications, there is an urgent need to identify novel and safe therapies to treat nephrotic syndrome in children. Stimulation of the vagus nerve, which can be activated noninvasively by transcutaneous auricular vagus nerve stimulation (taVNS), has immunomodulatory effects mediated by the inflammatory reflex and spleen. taVNS has become a therapy of interest for treating chronic immune mediated illnesses. The aims of the study are (1) To determine the feasibility of protocol implementation and tolerability of taVNS in the treatment of nephrotic syndrome in children (2) To establish proof-of-concept and generate statistical estimates of variance parameters and effect sizes for treatment response outcomes in children with nephrotic syndrome randomized to taVNS therapy compared with sham therapy (3) To investigate the effects of taVNS on inflammatory markers in children with nephrotic syndrome.

Eligibility Criteria

This trial is for children aged 3-17 with steroid-resistant nephrotic syndrome, specifically those diagnosed with MCD or FSGS via biopsy. Participants must have stable medication regimens and no history of cardiac disease, skin issues at the stimulation site, secondary causes of nephrotic syndrome like genetic conditions, or any implantable electronic devices.

Inclusion Criteria

My B cells have returned to normal after rituximab treatment.

I am between 3 and 17 years old.

My immunosuppression and blood pressure medication have been stable for 3 months.

Exclusion Criteria

I have a known inflammatory condition.

My kidney condition improves with steroid treatment.

Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

up to 8 weeks

1 visit (in-person)

Randomized Control Period

Participants are randomized to either taVNS or sham treatment and use the intervention device for 5 minutes per day for 26 weeks

26 weeks

3 visits (in-person), 3 visits (virtual)

Follow-up

Participants are monitored for clinical status and safety for an additional 26 weeks

26 weeks

Every 8 weeks (in-person or virtual)

Open-label extension (optional)

Participants may opt into continuation of active taVNS treatment after the randomized period

Long-term

Every 8 weeks (in-person)

Treatment Details

Interventions

• Sham device
• taVNS

Trial Overview The study tests transcutaneous auricular vagus nerve stimulation (taVNS) against a sham device to see if it's a feasible and tolerable treatment for children's nephrotic syndrome. It also aims to understand taVNS's effects on inflammatory markers in these patients.

Participant Groups

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.

Group II: Sham Group Placebo Group 1 Intervention

The sham device will be altered 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.

taVNS is already approved in United States, European Union for the following indications:

Approved in United States as Transcutaneous Auricular Vagus Nerve Stimulation for:

• Epilepsy
• Depression
• Obesity

Approved in European Union as Transcutaneous Auricular Vagus Nerve Stimulation for:

• Epilepsy
• Depression

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+

Findings from Research

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 auricular vagus nerve stimulation (taVNS) using specific parameters (500μs pulse width at 10Hz and 25Hz) was found to significantly decrease heart rate (HR) in healthy individuals, indicating its potential efficacy in modulating HR.

The study demonstrated that taVNS is safe, with no adverse effects reported, and it effectively attenuated sympathetic HR rebound after stimulation, suggesting a beneficial impact on autonomic regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate. Badran, BW., Mithoefer, OJ., Summer, CE., et al.[2020]

A systematic review of 261 studies revealed significant confusion in the nomenclature for transcutaneous stimulation of the auricular branch of the vagus nerve (ABVN), with 67 full and 27 abbreviated terms identified, highlighting the need for standardization.

The most commonly used terms were 'transcutaneous vagus nerve stimulation' and 'tVNS', but there was no consistent one-to-one relationship between full and abbreviated names, indicating a lack of uniformity in terminology across different research teams.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toward Diverse or Standardized: A Systematic Review Identifying Transcutaneous Stimulation of Auricular Branch of the Vagus Nerve in Nomenclature. Wang, Y., Li, L., Li, S., et al.[2023]

Transcutaneous electrical stimulation of the auricular branch of the vagus nerve (taVNS) was found to improve heart rate variability in heart failure patients, indicating a better balance in the autonomic nervous system, with significant improvements in rMSSD and SDNN measurements.

The study, involving 43 patients in a double-blind, randomized design, suggests that taVNS is a safe and well-tolerated intervention that may offer therapeutic benefits for heart failure, although further research with larger sample sizes is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Auricular Vagal Neuromodulation and its Application in Patients with Heart Failure and Reduced Ejection Fraction. Couceiro, SM., Sant'Anna, LB., Sant'Anna, MB., et al.[2023]

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]

This study will investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on 15 patients with a minimally conscious state, using five different frequencies (1, 10, 25, 50, and 100 Hz) to determine the optimal stimulation parameters.

The goal is to achieve stable improvements in consciousness levels in patients with disorders of consciousness by optimizing the taVNS neuromodulation technique, with results measured through the coma recovery scale-revised (CRS-R) and resting EEG assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the modulation paradigm of transcutaneous auricular vagus nerve stimulation in patients with disorders of consciousness: A prospective exploratory pilot study protocol. Zhai, W., Jiao, H., Zhuang, Y., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally safe, with a low incidence of mild and transient adverse effects, such as ear pain, headache, and tingling, reported in only 24.86% of the studies analyzed.

In a systematic review of 177 studies involving 6322 subjects, there was no significant difference in the risk of adverse events between taVNS and control groups, indicating that taVNS is a feasible option for clinical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Kim, AY., Marduy, A., de Melo, PS., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) significantly improves depression symptoms, as evidenced by reduced scores on the Hamilton Depression Scale in a review of 12 studies involving 838 participants.

taVNS shows comparable response rates to traditional antidepressants and has fewer side effects, suggesting it could be a safe alternative or complementary treatment for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: A systematic review and meta-analysis of randomized controlled trials. Tan, C., Qiao, M., Ma, Y., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive and cost-effective method for modulating the vagus nerve, making it a promising alternative to traditional surgical vagus nerve stimulation.

taVNS allows for easy and safe administration, with considerations for proper electrode placement and individual dosing based on perception thresholds, which enhances its potential for treating various central and peripheral diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. Badran, BW., Yu, AB., Adair, D., et al.[2020]

This case series study of 5 patients with nephrotic syndrome (NS) revealed that NS can be a significant cause of cerebral venous sinus thrombosis (CVST), with all patients initially presenting with headaches and diagnosed via magnetic resonance venography.

All patients in the study fully recovered from CVST after treatment, with no relapses reported during a follow-up period averaging 26.6 months, highlighting the effectiveness of standard CVST treatment in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nephrotic Syndrome May Be One of the Important Etiologies of Cerebral Venous Sinus Thrombosis. Wang, Y., Meng, R., Duan, J., et al.[2017]

A 3-year-old child with steroid-dependent nephrotic syndrome developed a rare case of cerebral vessel thrombosis, specifically superior sagittal sinus thrombosis, presenting with drowsiness and left hemiparesis.

The child fully recovered after treatment with low molecular weight heparin (LMWH), suggesting that LMWH may be effective for preventing or treating thrombosis in nephrotic syndrome, although further controlled studies are needed to confirm its safety and efficacy in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Superior sagittal sinus thrombosis and nephrotic syndrome: favorable outcome with low molecular weight heparin]. de Saint-Martin, A., Terzic, J., Christmann, D., et al.[2019]

Adult idiopathic nephrotic syndrome is primarily caused by the loss of plasma proteins in urine, leading to symptoms like low albumin levels, high cholesterol, and swelling, with four main subclasses requiring specific diagnosis through kidney biopsy.

Treatment varies by subclass and may include corticosteroids, cytotoxic agents, and dietary changes, with management focusing on reducing proteinuria and addressing complications like fluid imbalance and high cholesterol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacologic management of adult idiopathic nephrotic syndrome. Alaniz, C., Brosius, FC., Palmieri, J.[2013]

A study of 26 children with minimal change nephrotic syndrome (MCNS) found that their hearing status remained stable during both remission and relapse periods, with no significant changes in pure tone averages or tympanometry results.

The majority of patients exhibited normal tympanometry results (type A) in both periods, indicating that MCNS does not appear to affect hearing in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of the relapse and remission periods on hearing status in children with minimal change nephrotic syndrome. Bayazit, YA., Balat, A., Pakir, HI., et al.[2006]

A 32-month-old boy with steroid-sensitive nephrotic syndrome (SSNS) developed steroid-resistant nephrotic syndrome (SRNS) and cerebral venous sinus thrombosis (CVST), a rare complication, highlighting the serious risks associated with nephrotic syndrome.

The combination of pulse methylprednisolone, IV Rituximab, and Enoxaparin led to significant improvement in the child's condition, demonstrating an effective treatment strategy for this complex case.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Methylprednisolone Pulse Therapy plus Rituximab for Treating a Rare Juvenile Steroid-Resistant Nephrotic Syndrome with Cerebral Venous Sinus Thrombosis: A Case Report. Sakr, HI., Edrees, B., Taher, HO., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Toward Diverse or Standardized: A Systematic Review Identifying Transcutaneous Stimulation of Auricular Branch of the Vagus Nerve in Nomenclature. [2023]

4. Brazil pubmed.ncbi.nlm.nih.gov

Auricular Vagal Neuromodulation and its Application in Patients with Heart Failure and Reduced Ejection Fraction. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Transcutaneous Auricular Vagus Nerve Stimulation Normalizes Induced Gastric Myoelectrical Dysrhythmias in Controls Assessed by Body-Surface Gastric Mapping. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Optimizing the modulation paradigm of transcutaneous auricular vagus nerve stimulation in patients with disorders of consciousness: A prospective exploratory pilot study protocol. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: A systematic review and meta-analysis of randomized controlled trials. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. [2020]

10. United States pubmed.ncbi.nlm.nih.gov

Nephrotic Syndrome May Be One of the Important Etiologies of Cerebral Venous Sinus Thrombosis. [2017]

11. France pubmed.ncbi.nlm.nih.gov

[Superior sagittal sinus thrombosis and nephrotic syndrome: favorable outcome with low molecular weight heparin]. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Pharmacologic management of adult idiopathic nephrotic syndrome. [2013]

13. France pubmed.ncbi.nlm.nih.gov

Influence of the relapse and remission periods on hearing status in children with minimal change nephrotic syndrome. [2006]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Combined Methylprednisolone Pulse Therapy plus Rituximab for Treating a Rare Juvenile Steroid-Resistant Nephrotic Syndrome with Cerebral Venous Sinus Thrombosis: A Case Report. [2022]