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

Transcutaneous Auricular Vagus Nerve Stimulation for Painful Diabetic Peripheral Neuropathy: A 12-Week Randomized, Double-Blind, Sham-Controlled, Parallel-Group Trial With Biomarker Endpoints

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; Diabetic Neuropathies; Neuropathic Pain; Type2diabetes
• Intervention / Treatment: Device: non-invasive transcutaneous vagal nerve stimulation (tVNS); Device: Sham device

Detailed Description

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 enhance biological signal detection, enrollment is biomarker-enriched for low-grade systemic inflammation and autonomic imbalance. Participants will be assigned (1:1) to active taVNS or an indistinguishable sham device. The primary outcome is the change in average daily pain intensity on an 11-point Numeric Rating Scale (NRS), averaged over Weeks 10-12 versus baseline. Secondary outcomes include autonomic function (heart-rate variability), inflammatory biomarkers (IL-6, TNF-α, hs-CRP), serum neurofilament light (sNfL; finger-prick dried-spot sampling), small-fiber structure by AI-assisted corneal confocal microscopy (CCM), sleep interference, quality of life, and safety.

• Study Type: Interventional
• Enrollment (Actual): 185
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Pakistan
  • Lahore, Pakistan
    • Shifa Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Exclusion Criteria:

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group VTG; Group VTG will receive active non-invasive transcutaneous vagal nerve stimulation (tVNS)	Device: non-invasive transcutaneous vagal nerve stimulation (tVNS); The device is used stimulate the vagus nerve; Other Names: tVNS device
Sham Comparator: Group STG; Group STG will receive Inactive sham stimulation	Device: Sham device; Sham device that does not stimulate the vagus nerve; Other Names: SD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart-rate variability (HRV) indices	Change in root mean square of successive differences from standardized 5-minute seated ECG recordings.	Baseline, Week 6, Week 12
Inflammatory biomarkers	Change in high-sensitivity C-reactive protein (hs-CRP) measured by central laboratory immunoassays.	Baseline, Week 6, Week 12
Serum neurofilament light (sNfL)	Change in sNfL concentration measured from finger-prick dried-spot samples using a validated immunoassay (central analysis).	Baseline, Week 12
Change in Corneal Nerve Fiber Length	Change in corneal nerve fiber length measured using corneal confocal microscopy. Images will be acquired at hub sites and analyzed centrally using masked, AI-assisted image analysis pipelines.	Baseline, Week 12
Sleep interference score (0-10)	Change in patient-reported sleep interference due to pain; higher scores indicate more interference.	Baseline, Week 6, Week 12
Change in DN4 Neuropathic Pain Questionnaire Total Score	Change in DN4 neuropathic pain questionnaire total score for neuropathic pain features.	Baseline, week 12
Patient Global Impression of Change (PGIC)	Patient-reported overall improvement/worsening on a 7-point scale.	Week 12
Pain responder rate (≥2-point NRS reduction)	Proportion of participants achieving at least a 2-point decrease from baseline in average daily pain intensity.	Baseline, week 12
Change in SDNN	Change in standard deviation of normal-to-normal intervals from standardized 5-minute seated ECG recordings.	Baseline, Week 6, Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Device adherence	Percentage of prescribed stimulation sessions completed (device/app logs).	Baseline to week 12
Adverse events and device-related events	Number and severity of all adverse events and device-related events.	Throughout the 12-week treatment period

Collaborators and Investigators

• Sponsor: Saima Abass Tahammal
• Collaborators: Al Ain University

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2025
• Primary Completion (Actual): May 1, 2025
• Study Completion (Actual): June 1, 2025

Study Registration Dates

• First Submitted: December 24, 2023
• First Submitted That Met QC Criteria: February 27, 2024
• First Posted (Actual): March 5, 2024

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: pain; diabetes mellitus; neuropathy
• Additional Relevant MeSH Terms: Neurologic Manifestations; Endocrine System Diseases; Nervous System Diseases; Neuromuscular Diseases; Metabolic Diseases; Peripheral Nervous System Diseases; Glucose Metabolism Disorders; Diabetes Complications; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Pain; Diabetes Mellitus; Neuralgia; Diabetic Neuropathies
• Other Study ID Numbers: SH-34988389

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No