Diabetes Mellitus, Diabetic Neuropathies, Neuropathic Pain, Type2diabetes
Conditions
Keywords
diabetes mellitus, neuropathy, pain
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.
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.
Interventions
DEVICEnon-invasive transcutaneous vagal nerve stimulation (tVNS)
The device is used stimulate the vagus nerve
DEVICESham device
Sham device that does not stimulate the vagus nerve
Sponsors
Saima Abass Tahammal
Al Ain University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
a randomized, double-blinded, sham-controlled, parallel group clinical trial
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in average daily pain intensity (11-point Numeric Rating Scale, NRS 0-10) | Baseline to Week 12 (primary window = Weeks 10-12) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Heart-rate variability (HRV) indices | Baseline, Week 6, Week 12 | Change in root mean square of successive differences from standardized 5-minute seated ECG recordings. |
| Inflammatory biomarkers | Baseline, Week 6, Week 12 | Change in high-sensitivity C-reactive protein (hs-CRP) measured by central laboratory immunoassays. |
| Serum neurofilament light (sNfL) | Baseline, Week 12 | Change in sNfL concentration measured from finger-prick dried-spot samples using a validated immunoassay (central analysis). |
| Change in Corneal Nerve Fiber Length | Baseline, Week 12 | 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. |
| Sleep interference score (0-10) | Baseline, Week 6, Week 12 | Change in patient-reported sleep interference due to pain; higher scores indicate more interference. |
| Change in DN4 Neuropathic Pain Questionnaire Total Score | Baseline, week 12 | Change in DN4 neuropathic pain questionnaire total score for neuropathic pain features. |
| Patient Global Impression of Change (PGIC) | Week 12 | Patient-reported overall improvement/worsening on a 7-point scale. |
| Pain responder rate (≥2-point NRS reduction) | Baseline, week 12 | Proportion of participants achieving at least a 2-point decrease from baseline in average daily pain intensity. |
| Change in SDNN | Baseline, Week 6, Week 12 | Change in standard deviation of normal-to-normal intervals from standardized 5-minute seated ECG recordings. |
Countries
Pakistan
Outcome results
None listed