Use of taVNS for Painful Diabetic Neuropathy: 12-Week Randomized, Sham-Controlled Trial

NCT06292962 | Completed

• 1 other identifier: SH-34988389
• Study Type: interventional
• Target: 185
• Locations: 1 country
• Sites: 1

Brief Summary

This 12-week, randomized, double-blind, sham-controlled, parallel-group trial will evaluate the analgesic and mechanistic effects of home-based transcutaneous auricular vagus nerve stimulation (taVNS) in adults with painful diabetic peripheral neuropathy (DPN). To increase the likelihood of detecting a biological signal, enrollment is biomarker-enriched for low-grade systemic inflammation and autonomic imbalance (e.g., elevated high-sensitivity C-reactive protein/interleukin-6 or reduced heart-rate variability \\\[HRV\]). Participants are randomized 1:1 to active taVNS (ear-clip stimulation, twice daily) or an indistinguishable sham device for 12 weeks; background diabetes and pain therapies are kept stable where possible. Adherence and daily pain ratings are captured via a smartphone application. The primary outcome is change in average daily pain intensity (11-point Numeric Rating Scale) from baseline to Weeks 10-12. Secondary outcomes assess proposed mechanisms of action and include HRV indices, inflammatory biomarkers (interleukin-6, tumor necrosis factor-α, high-sensitivity C-reactive protein), serum neurofilament light (sNfL) measured from finger-prick dried-spot samples, and corneal confocal microscopy (CCM) metrics of small-fiber integrity (corneal nerve fiber length/density). Additional outcomes include sleep interference, DN4 score, Patient Global Impression of Change, responder rate (≥2-point pain reduction), and safety. The study is multicenter in Pakistan and is designed to test whether taVNS reduces painful symptoms and favorably shifts objective autonomic, inflammatory, and nerve-injury biomarkers, providing scalable evidence relevant to low- and middle-income settings.

Conditions

Diabetes Mellitus; Diabetic Neuropathies; Type2diabetes; Neuropathic Pain

Keywords

diabetes mellitus; neuropathy; pain

Outcome Measures

Primary Outcomes (1)

• Change in average daily pain intensity (11-point Numeric Rating Scale, NRS 0-10)

  Mean change in daily pain intensity from baseline to Weeks 10-12. Daily ratings are captured via e-diary/app; the primary analysis uses the mean of daily values during Weeks 10-12 minus the mean of the 7-day baseline run-in. Higher scores indicate worse pain; negative change indicates improvement.

  Baseline to Week 12 (primary window = Weeks 10-12)

Secondary Outcomes (9)

• Heart-rate variability (HRV) indices

  Baseline, Week 6, Week 12

• Inflammatory biomarkers

  Baseline, Week 6, Week 12

• Serum neurofilament light (sNfL)

  Baseline, Week 12

• Change in Corneal Nerve Fiber Length

  Baseline, Week 12

• Sleep interference score (0-10)

  Baseline, Week 6, Week 12

Other Outcomes (2)

• Device adherence

  Baseline to week 12

• Adverse events and device-related events

  Throughout the 12-week treatment period

Study Arms (2)

Group VTG

EXPERIMENTAL

Group VTG will receive active non-invasive transcutaneous vagal nerve stimulation (tVNS)

Device: non-invasive transcutaneous vagal nerve stimulation (tVNS)

Group STG

SHAM COMPARATOR

Group STG will receive Inactive sham stimulation

Device: Sham device

Interventions

non-invasive transcutaneous vagal nerve stimulation (tVNS) DEVICE

The device is used stimulate the vagus nerve

Also known as: tVNS device

Group VTG

Sham device DEVICE

Sham device that does not stimulate the vagus nerve

Also known as: SD

Group STG

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 30-70 years. Type 2 diabetes mellitus diagnosed ≥ 1 year.
• Painful distal symmetric polyneuropathy ≥ 3 months, meeting all:
• DN4 score ≥4; Average daily pain NRS ≥4 during a 7-day run-in; Clinical examination consistent with DPN (e.g., reduced vibration or abnormal monofilament, or neuropathy disability score \>0).
• Stable antidiabetic regimen and neuropathic-pain medications for ≥4 weeks before randomization, with no planned changes during the 12-week treatment unless medically necessary.
• Biomarker enrichment: at least one of the following at screening:
• hs-CRP ≥2.0 mg/L or IL-6 above laboratory median; or Reduced heart-rate variability (e.g., RMSSD at or below the age/sex-adjusted 25th percentile) on standardized 5-minute ECG.
• Able to use the ear-clip device and the study smartphone app (or willing to use a study phone), and to attend baseline, Week 6 and Week 12 visits (including corneal confocal microscopy and finger-prick sampling).
• Provides written informed consent

You may not qualify if:

• Peripheral neuropathy not due to diabetes (e.g., vitamin B12 deficiency, hypothyroidism, uremia/CKD-related, chemotherapy-induced, HIV, hereditary neuropathies), or predominant radiculopathy/entrapment neuropathy.
• Implanted electronic medical devices (e.g., pacemaker, ICD, deep brain stimulator, cochlear implant) or other contraindication to transcutaneous electrical stimulation.
• History of epilepsy/seizure disorder, clinically significant arrhythmia, or unexplained syncope within 6 months.
• Unstable cardiovascular disease within 3 months (e.g., acute coronary syndrome, decompensated heart failure).
• Severe renal impairment (eGFR \<30 mL/min/1.73 m²) or on dialysis. Active diabetic foot ulcer Grade ≥2, active systemic infection, or dermatologic disease at the ear-clip site.
• Corneal disease precluding CCM (e.g., active keratitis) or inability to undergo CCM imaging.
• Current systemic immunosuppressive therapy (e.g., ≥10 mg/day prednisone equivalent or biologic agents) or expected to start during the trial.
• Uncontrolled psychiatric illness (including active suicidal ideation) or cognitive impairment limiting consent/compliance.
• Initiation/change of neuromodulation treatments for pain within 3 months or prior taVNS use within 3 months.
• Pregnant or breastfeeding, or planning pregnancy during the study. Any condition or circumstance that, in the investigator's judgment, would interfere with safe participation or with study assessments.

Sponsors & Collaborators

• Saima Abass Tahammal: lead
• Al Ain University: collaborator

Study Sites (1)

Shifa Hospital

Lahore, Pakistan

Location

MeSH Terms

Conditions

Diabetes Mellitus; Diabetic Neuropathies; Neuralgia; Pain

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Diabetes Complications; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: a randomized, double-blinded, sham-controlled, parallel group clinical trial
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 24, 2023
• First Posted: March 5, 2024
• Study Start: January 5, 2025
• Primary Completion: May 1, 2025
• Study Completion: June 1, 2025
• Last Updated: June 3, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

PA (1)