Diabetes MellitusPAK-VAGUSNCT06292962
Use of taVNS for Painful Diabetic Neuropathy: 12-Week Randomized, Sham-Controlled Trial
A study testing non-invasive transcutaneous vagal nerve stimulation (tVNS) in people with Diabetes Mellitus and Diabetic Neuropathies, run by Saima Abass Tahammal at 1 site in Pakistan.
Trial 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). Read more about this study
- Who is it for?
- Ages 30 to 70 years
- Conditions the study is for
- Diabetes Mellitus, Diabetic Neuropathies, Type2diabetes
- What is being tested?
- non-invasive transcutaneous vagal nerve stimulation (tVNS)
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 185 participants
- Where
- 1 sitePakistan
- Study dates
- 5 Jan 2025to 1 Jun 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Being tested
- non-invasive transcutaneous vagal nerve stimulation (tVNS), Sham device
- Keywords
- diabetes mellitus, neuropathy, pain
- Medical subject headings
- Diabetes Mellitus, Diabetic Neuropathies, Neuralgia, Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
non-invasive transcutaneous vagal nerve stimulation (tVNS)Device
Also called tVNS device
The device is used stimulate the vagus nerve
Sham deviceDevice
Also called SD
Sham device that does not stimulate the vagus nerve
| Study group | Role | What they receive |
|---|---|---|
| Group VTG | Experimental | Group VTG will receive active non-invasive transcutaneous vagal nerve stimulation (tVNS) Receives: Device: non-invasive transcutaneous vagal nerve stimulation (tVNS) |
| Group STG | Sham comparator | Group STG will receive Inactive sham stimulation Receives: Device: Sham device |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline to Week 12 (primary window = Weeks 10-12)
Secondary outcomes (9)
Heart-rate variability (HRV) indices
Change in root mean square of successive differences from standardized 5-minute seated ECG recordings.
Measured: Baseline, Week 6, Week 12
Inflammatory biomarkers
Change in high-sensitivity C-reactive protein (hs-CRP) measured by central laboratory immunoassays.
Measured: 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).
Measured: 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.
Measured: Baseline, Week 12
Sleep interference score (0-10)
Change in patient-reported sleep interference due to pain; higher scores indicate more interference.
Measured: 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.
Measured: Baseline, week 12
Patient Global Impression of Change (PGIC)
Patient-reported overall improvement/worsening on a 7-point scale.
Measured: 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.
Measured: Baseline, week 12
Change in SDNN
Change in standard deviation of normal-to-normal intervals from standardized 5-minute seated ECG recordings.
Measured: Baseline, Week 6, Week 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Mar 2024
- Study start5 Jan 2025
- Primary completion1 May 2025
- Study completion1 Jun 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Diabetes MellitusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 185 participants (actual)
Sponsor and investigators
- Lead sponsor
- Saima Abass Tahammal
- Sponsor type
- University, hospital or other
- Collaborators
- Al Ain University
- Responsible party
- Sponsor-investigator, Saima Abass Tahammal, Shifa International Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06292962
- Sponsor's protocol ID
- SH-34988389
- Acronym
- PAK-VAGUS
- Status last verified
- May 2026
- First submitted
- 24 Dec 2023
- Last updated
- 3 Jun 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Transcutaneous Auricular Vagus Nerve Stimulation for Painful Diabetic Peripheral Neuropathy: A 12-Week Randomized, Double-Blind, Sham-Controlled, Parallel-Group Trial With Biomarker Endpoints
- ClinicalTrials.gov ID
- NCT06292962
- Acronym / sponsor ID
- PAK-VAGUS / SH-34988389
- Keywords
- diabetes mellitus, neuropathy, pain
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 185 participants (actual)
- Lead sponsor
- Saima Abass TahammalUniversity, hospital or other
- Collaborators
- Al Ain University
- Study start
- 5 Jan 2025 (actual)
- Primary completion
- 1 May 2025 (actual)
- Study completion
- 1 Jun 2025 (actual)
- First posted
- 5 Mar 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group VTG | Experimental | Device: non-invasive transcutaneous vagal nerve stimulation (tVNS)Group VTG will receive active non-invasive transcutaneous vagal nerve stimulation (tVNS) |
| Group STG | Sham comparator | Device: Sham deviceGroup STG will receive Inactive sham stimulation |
Who may qualify
- Ages
- 30 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Age 30-70 years. Type 2 diabetes mellitus diagnosed ≥ 1 year.
- 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.
- 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).
Key exclusion criteria (10 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| non-invasive transcutaneous vagal nerve stimulation (tVNS)Also: tVNS deviceThe device is used stimulate the vagus nerve | Device | Group VTG |
| Sham deviceAlso: SDSham device that does not stimulate the vagus nerve | Device | Group STG |
Primary outcome
Change in average daily pain intensity (11-point Numeric Rating Scale, NRS 0-10)
Time frame: 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.
9 secondary outcomes
Heart-rate variability (HRV) indices
Time frame: Baseline, Week 6, Week 12
Inflammatory biomarkers
Time frame: Baseline, Week 6, Week 12
Serum neurofilament light (sNfL)
Time frame: Baseline, Week 12
Change in Corneal Nerve Fiber Length
Time frame: Baseline, Week 12
Sleep interference score (0-10)
Time frame: Baseline, Week 6, Week 12
Change in DN4 Neuropathic Pain Questionnaire Total Score
Time frame: Baseline, week 12
Patient Global Impression of Change (PGIC)
Time frame: Week 12
Pain responder rate (≥2-point NRS reduction)
Time frame: Baseline, week 12
Change in SDNN
Time frame: Baseline, Week 6, Week 12
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jun 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing non-invasive transcutaneous vagal nerve stimulation (tVNS) in people with Diabetes Mellitus and Diabetic Neuropathies, run by Saima Abass Tahammal at 1 site in Pakistan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Pakistan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in average daily pain intensity (11-point Numeric Rating Scale, NRS 0-10) (time frame: Baseline to Week 12 (primary window = Weeks 10-12)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jun 2026.