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

Saima Abass Tahammal185 enrolled

Overview

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.

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

Eligibility

Sex: ALLMin age: 30 YearsMax age: 70 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

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

Secondary Outcomes

Heart-rate variability (HRV) indices

Change in root mean square of successive differences from standardized 5-minute seated ECG recordings.

Time frame: Baseline, Week 6, Week 12

Inflammatory biomarkers

Change in high-sensitivity C-reactive protein (hs-CRP) measured by central laboratory immunoassays.

Time frame: 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).

Time frame: 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.

Time frame: Baseline, Week 12

Sleep interference score (0-10)

Change in patient-reported sleep interference due to pain; higher scores indicate more interference.

Time frame: 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.

Time frame: Baseline, week 12

Patient Global Impression of Change (PGIC)

Patient-reported overall improvement/worsening on a 7-point scale.

Time frame: 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.

Time frame: Baseline, week 12

Change in SDNN

Change in standard deviation of normal-to-normal intervals from standardized 5-minute seated ECG recordings.

Time frame: Baseline, Week 6, Week 12

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes