## Protocol Section
### Identification Module
**NCT ID:** NCT06415591

**Brief Title:** Auricular Neuromodulation in Veterans With Fibromyalgia

**Official Title:** Auricular Neuromodulation in Veterans With Fibromyalgia: A Randomized, Sham-Controlled Study

#### Organization Study ID Info
**ID:** F5050-R
#### Organization
**Class:** FED
**Full Name:** VA Office of Research and Development
#### Secondary ID Infos
**Domain:** VA RR&D
**ID:** I01RX005050
**Type:** OTHER_GRANT
### Status Module
#### Completion Date
**Date:** 2028-10-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-22

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-21

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2028-09-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-10-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-16
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-08
**Study First Submit QC Date:** 2024-05-09
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** FED

**Name:** VA Office of Research and Development

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** True

**Is FDA Regulated Drug:** False

**Is US Export:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** PENFS (percutaneous electrical nerve field stimulation) is an FDA-approved acupuncture-like therapy applied to the external ear targeting several cranial nerve branches including the auricular branch of the vagus nerve to improve pain, physical function, and reduce symptoms of opioid withdrawal. PENFS has been previously shown to provide improvements in fibromyalgia, a difficult to treat chronic pain syndrome, which correlate with changes observed using a special kind of MRI called resting state functional connectivity MRI (rs-fcMRI) that evaluates brain activity at rest. The goals of this study are to rigorously test the initial promising results of PENFS in a much larger group of Veterans suffering from fibromyalgia and to identify potential mechanisms of PENFS effects. Further developing non-pharmacologic therapies for pain can help to improve quality of life and function for those suffering from fibromyalgia and decrease reliance on opioids and other drugs that have numerous side effects for individuals suffering from chronic pain.

**Detailed Description:** BACKGROUND: In the setting of the opioid epidemic, it is crucial to develop and assess non-pharmacologic treatments for pain and understand underlying mechanisms. In the present investigation, the investigators assess a novel non-pharmacologic approach to chronic pain treatment in Veterans suffering from fibromyalgia (a notoriously difficult to treat pain syndrome that affects 5-10 million Americans and disproportionately affects those returning from the Gulf War), utilizing brain imaging as a biomarker and heart rate variability (HRV) to assess a vagal mechanism. Preliminary results from prior VA-funded feasibility study reveal a trend towards improved pain and function with a FDA-approved, non-pharmacologic therapy - auricular percutaneous electrical nerve field stimulation (PENFS) - over standard therapy control for Veterans suffering from fibromyalgia, correlating to altered network connectivity on rs-fcMRI (resting state functional connectivity MRI). PENFS-related improvements continued through 12 weeks following the completion of treatment and correlated to changes in cross-network connectivity, which differed between groups. Based on the preliminary data, the investigators now intend to rigorously assess the treatment effects of PENFS in a large, double-blind, randomized, sham-controlled study.

OBJECTIVE: The proposed Merit, a randomized, sham-controlled trial of auricular PENFS, evaluates the clinical utility of PENFS for fibromyalgia as compared to sham placebo control, acute and longitudinal PENFS-related neural changes visualized on rs-fcMRI and effects of PENFS on HRV as a potential vagal mechanism of pain relief.

HYPOTHESIS: True PENFS results in non-placebo-related short-and long-term pain and physical function improvements that can be correlated with altered connectivity and HRV.

METHODS: For Aim 1, 240 total participants meeting 2016 diagnostic criteria for fibromyalgia (male and female, age 18-60 years old) will be randomized to either true (n=120) or sham (n=120) auricular PENFS.

Neuroimaging data, self-reported pain, and physical function will be assessed at baseline and at 1- and 12- weeks post-treatment to evaluate neural correlates of PENFS-related treatment. Participants who meet study criteria will be randomized to either true or sham PENFS (series of 4, weekly) treatments and assessed for rsfcMRI and functional changes at 1- and 12-weeks post-treatment. Baseline and follow-up rs-fcMRI will be utilized to identify biomarkers of fibromyalgia and PENFS treatment effects for Aim 2 in a subset of 62 participants from Aim 1 who qualify for MRI procedures. Cardiopulmonary data will be simultaneously collected during rs-fcMRI and utilized for the exploratory Aim 3 to evaluate potential PENFS effects on HRV as an outcome measure for vagal effects. In the initial phase preliminary analytical validation will be accomplished in the first 30 participants following IRB approval, hiring and training of staff, and establishment of an image processing pipeline. If initial milestones are met, the rigorous, double-blind, sham-controlled study in a larger group of Veterans will continue. Veterans who are initially assigned to sham placebo PENFS and are not identified as placebo-responders will be offered the opportunity to test the true PENFS device. This study addresses the critical need to clinically evaluate non-pharmacologic therapies for chronic pain.

### Conditions Module

**Conditions:**

- Fibromyalgia

**Keywords:**

- Pain

- Fibromyalgia

- Magnetic Resonance Imaging

- Veterans

- Percutaneous Electrical Nerve Field Stimulation

- Vagus Nerve

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** Participants will be randomized 1:1 to either true or sham PENFS using the auricular device (series of 4, weekly placement with ongoing 5 day (M-F) stimulation - manufacturer recommended) treatments, then assessed for changes in pain and function at 12 and 24 weeks post-treatment. The 12-week time point is chosen to evaluate longer-term neural changes as an indicator of neural plasticity, given the continued improvements seen in the investigators' PENFS group based on preliminary data. The 24- week timepoint is chosen to evaluate longer term (6 months) pain outcomes related to PENFS.

##### Masking Info

**Masking:** QUADRUPLE

**Masking Description:** Double-blind, sham placebo controlled. Randomization will be performed by a research coordinator, who will assign each participant a study number and keep a record of whether they are receiving true or sham PENFS, thus maintaining blinding of the participant, the study physicians, the research assistant, and the data analysis team including the P.I. (A.W.) until completion of the follow-up period and data analyses can be performed.

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 240

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Percutaneous electrical nerve stimulation applied to the ear x 4 over a 4 week period. The device is placed over the area of the ear and worn home continuously for a 5-day period, during which time it stimulates at a pre-set on/off duty cycle. At each in-person visit, the device is replaced until the device has been placed 4 times. The stimulation delivered is below the threshold of sensory perception.

**Intervention Names:**

- Device: Percutaneous electrical nerve field stimulation

**Label:** True PENFS

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** A device is placed at the same points for the same amount of time and at the same intervals as the true device. This device will not deliver electrical stimulation.

**Intervention Names:**

- Device: Percutaneous electrical nerve field stimulation

**Label:** Sham PENFS

**Type:** SHAM_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Sham PENFS

- True PENFS

**Description:** FDA-approved acupuncture-like therapy applied to the external ear targeting several cranial nerve branches including the auricular branch of the vagus nerve to improve pain, physical function, and reduce symptoms of opioid withdrawal.

**Name:** Percutaneous electrical nerve field stimulation

**Other Names:**

- PENFS

**Type:** DEVICE

### Outcomes Module

#### Primary Outcomes

**Description:** The investigators will assess whether pain and functional improvements occur with the application of PENFS. Clinical pain, as measured by the Defense Veterans Pain Rating Scale (DVPRS), will be our primary outcome. This measure is rated on a scale of 0 to 10, with 0 being "no pain" and 10 being "as bad as it could be, nothing else matters". Assessments will be administered at baseline, immediately pre- and post-treatment (the device is replaced every 5 days for a total of 4 device applications), 12 weeks post-treatment, and 24 weeks post-treatment.

**Measure:** Improvements in Clinical Pain (DVPRS)

**Time Frame:** Through study completion, an average of 1 year

**Description:** The investigators will assess whether pain and functional improvements occur with the application of PENFS. Changes in clinical pain will also be assessed for this outcomes via self-reported analgesic consumption. This measure is not rated on a scale - it is self-reported use. Assessments will be administered at baseline, immediately pre- and post-treatment (the device is replaced every 5 days for a total of 4 device applications), 12 weeks post-treatment, and 24 weeks post-treatment.

**Measure:** Improvements in Clinical Pain (Self-reported analgesic consumption)

**Time Frame:** Through study completion, an average of 1 year

#### Secondary Outcomes

**Description:** Resting state functional connectivity magnetic resonance imaging (rs-fcMRI) will be performed at baseline and 12 weeks post-treatment to assess changes in cross-network connectivity with the default mode network (DMN) and sensorimotor network (SMN) as well as connectivity within the salience network (SN).

**Measure:** rs-fcMRI as a biomarker of treatment response

**Time Frame:** Baseline, 12 weeks post-treatment

**Description:** Heart rate variability (HRV) will be assessed at the MRI scans at baseline and 12 weeks post-treatment with an MR-compatible pulse oximeter to evaluate the effects of PENFS on parasympathetic tone.

**Measure:** PENFS effects on parasympathetic tone as measured by heart rate variability (HRV)

**Time Frame:** Baseline, 12 weeks post-treatment

**Description:** Fibromyalgia severity will be assessed via the Fibromyalgia Impact Questionnaire (FIQ-R). Each question is rated on a scale of 1 to 10 with 1 being the least impact/severity and 10 being the most impact/severity. Assessments will be administered at baseline, immediate post-treatment, 12 weeks post-treatment, and 24 weeks post-treatment.

**Measure:** Changes in Fibromyalgia Severity (FIQ-R)

**Time Frame:** Through study completion, an average of 1 year

**Description:** Functional improvements will be assessed using the arm curl test. Assessments will be administered at baseline, immediate post-treatment, 12 weeks post-treatment, and 24 weeks post-treatment.

**Measure:** Functional Improvements (Arm curls)

**Time Frame:** Through study completion, an average of 1 year

**Description:** Fibromyalgia severity will be assessed via the Polysymptomatic Distress Scale (PSD). This measure ranges from scores of 0 to 31, with 0 being the least severe and 31 being the most severe. Assessments will be administered at baseline, immediate post-treatment, 12 weeks post-treatment, and 24 weeks post-treatment.

**Measure:** Changes in Fibromyalgia Severity (PSD)

**Time Frame:** Through study completion, an average of 1 year

**Description:** Functional improvements will be assessed using the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) measures ("physical function," "anxiety," "depression," "fatigue," "sleep disturbance," "social function," "pain interference," "global health"). PROMIS measures are rated on a scale of 1 to 5 with 1 being the least intense ("Never") and 5 being the most intense ("Always"). There are a few questions (i.e. PROMIS "global health" measure, item 07r) rated on different scales, such as from 1 to 10, with 1 being the least intense and 10 being the most intense. Assessments will be administered at baseline, immediate post-treatment, 12 weeks post-treatment, and 24 weeks post-treatment.

**Measure:** Functional Improvements (PROMIS change)

**Time Frame:** Through study completion, an average of 1 year

**Description:** Functional improvements will be assessed using the 30-s chair stand. Assessments will be administered at baseline, immediate post-treatment, 12 weeks post-treatment, and 24 weeks post-treatment.

**Measure:** Functional Improvements (30-s chair stand)

**Time Frame:** Through study completion, an average of 1 year

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Age 20-60 years old (limit set to minimize brain structural changes due to aging).
* Diagnosis of fibromyalgia by the American College of Rheumatology 2016 criteria.71
* Right-handedness, to provide consistency in brain structure and function.
* Pain score of 4 or greater on DVPRS53 in the 3 months prior to enrollment.
* Intact skin in area of PENFS treatment
* For those who elect to participate in the MRI portion, the ability to safely tolerate MRI

Exclusion Criteria:

Exclusion criteria include:

* pregnancy
* history of seizures or neurologic conditions that alter the brain
* claustrophobia
* MRI-incompatible implants, or other conditions incompatible with MRI (only for those who elect to perform MRI)
* history of uncontrolled psychiatric illness
* autoimmune disease that leads to pain
* skin conditions that can increase risk of infection at PENFS site

**Maximum Age:** 60 Years

**Minimum Age:** 20 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** Anna.Woodbury@va.gov

**Name:** Anna Woodbury, MD

**Phone:** (404) 321-6111

**Phone Ext:** 6939

**Role:** CONTACT

**Contact 2:**

**Email:** anna.ree@va.gov

**Name:** Anna M Ree, BA

**Phone:** (404) 321-6111

**Phone Ext:** 202561

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Decatur

**Contacts:**

***Contact 1:***

- **Email:** Anna.Woodbury@va.gov

- **Name:** Anna Woodbury, MD

- **Phone:** 404-321-6111

- **Phone Ext:** 6939

- **Role:** CONTACT

***Contact 2:***

- **Name:** Anna Woodbury, MD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** United States

**Facility:** Atlanta VA Medical and Rehab Center, Decatur, GA

**State:** Georgia

**Zip:** 30033-4004

#### Overall Officials

**Official 1:**

**Affiliation:** Atlanta VA Medical and Rehab Center, Decatur, GA

**Name:** Anna Woodbury, MD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### See Also Links

**Label:** Woodbury PAIN Lab Page

**URL:** https://www.woodburypainlab.com/

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000009135

- Term: Muscular Diseases

- ID: D000009140

- Term: Musculoskeletal Diseases

- ID: D000012216

- Term: Rheumatic Diseases

- ID: D000009468

- Term: Neuromuscular Diseases

- ID: D000009422

- Term: Nervous System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC05

- Name: Musculoskeletal Diseases

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

### Condition Browse Module - Browse Leaves

- ID: M13066

- Name: Pain

- Relevance: LOW

- As Found: Unknown

- ID: M8486

- Name: Fibromyalgia

- Relevance: HIGH

- As Found: Fibromyalgia

- ID: M12161

- Name: Myofascial Pain Syndromes

- Relevance: HIGH

- As Found: Fibromyalgia

- ID: M16355

- Name: Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M12092

- Name: Muscular Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12097

- Name: Musculoskeletal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M15045

- Name: Rheumatic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M6323

- Name: Collagen Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12411

- Name: Neuromuscular Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000005356

- Term: Fibromyalgia

- ID: D000009209

- Term: Myofascial Pain Syndromes

### Intervention Browse Module - Browse Branches

- Abbrev: Analg

- Name: Analgesics

- Abbrev: CNSDep

- Name: Central Nervous System Depressants

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M4033

- Name: Analgesics, Opioid

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
