nVNS, CBD, and SoC for Persistent Post-Traumatic Headache

A Phase 2 Randomized, Multicenter Study of Non-Invasive Vagus Nerve Stimulation (nVNS), Cannabidiol, and Standard of Care for the Treatment of Persistent Post-Traumatic Headache in Elite Athletes

Do cannabidiol (CBD) or vagus nerve stimulation reduce the frequency of persistent post-traumatic headache more than traditional oral headache medications?

Study Overview

• Status: Not yet recruiting
• Conditions: Persistent Post Traumatic Headache
• Intervention / Treatment: Device: Non-Invasive Vagus Nerve Stimulation; Drug: Cannabidiol; Drug: Standard of Care

Detailed Description

In this randomized, open-label clinical trial, athletes with persistent post-traumatic headache will be treated with either non-invasive vagal nerve stimulation, cannabidiol, or standard of care oral pharmacotherapy for 12 weeks.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Nathaniel M Schuster, MD; Phone Number: (858) 249-3800; Email: nmschuster@health.ucsd.edu
• Study Contact Backup: Name: Erika A Petersen; Phone Number: 501-686-5270; Email: eapetersen@uams.edu

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85054
      • Mayo Clinic
      • Contact: Natalie Strand, MD; Email: Strand.Natalie@mayo.edu
      • Principal Investigator: Natalie Strand, MD
  • California
    • Los Angeles, California, United States, 90045
      • Kerlan-Jobe Orthopaedic Institute
      • Contact: Vernon Williams, MD; Email: vernon.williams@cskerlanjobe.org
      • Principal Investigator: Vernon Williams, MD
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20006
      • International Spine, Pain & Performance Center
      • Principal Investigator: Mehul Desai, MD
      • Contact: Mary Meg Valentine, BS; Phone Number: 202-849-8333; Email: mvalentine@isppcenter.com
  • Florida
    • Tampa, Florida, United States, 33614
      • Florida Spine & Pain Specialists
      • Principal Investigator: Nomen Azeem, MD
      • Contact: Nomen Azeem, MD; Email: azeemnx@gmail.com
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University Of Kansas Medical Center
      • Principal Investigator: Dawood Sayed, MD
      • Contact: Dawood Sayed, MD; Email: dsayed1@yahoo.com
  • New Jersey
    • Shrewsbury, New Jersey, United States, 07702
      • Premier Pain Center
      • Principal Investigator: Sean Li, MD
      • Contact: Katie Gee; Phone Number: 65509 732-380-0200; Email: kgee@treatingpain.com
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
      • Contact: Melinda Lawrence, MD; Email: melinda.lawrence@uhhospitals.org
      • Principal Investigator: Melinda Lawrence, MD
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
      • Principal Investigator: Boyle Cheng, PhD
      • Principal Investigator: Patrick DeMeo, MD
      • Contact: Boyle Cheng, PhD; Email: boyle.cheng@ahn.org
      • Sub-Investigator: Praveer Vyas, PhD

Participation Criteria

Eligibility Criteria

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

Description

INCLUSION CRITERIA

1. Between the ages of 18 and 75 years inclusive
2. Participated in competitive sports at high school level or beyond or, in the case of sports without interscholastic competition, as per investigator
3. Persistent headache attributed to traumatic injury to the head in accordance with the ICHD-3 criteria (including "Headache persists for >3 months after its onset")
4. Experiences 4-25 (inclusive) headaches days per month (during the 28-day baseline period), with at least 4 of them being moderate or severe in intensity
5. Completed at least 80% (23 of 28 days) on 28-day baseline headache diary
6. Agrees to refrain from initiating or changing the type, dosage, or frequency of any preventive headache medications whether for headache prevention or for indications other than headache that, in the opinion of the clinician may interfere with the study objectives (e.g., antidepressants, anticonvulsants, beta-adrenergic blockers, etc.)
7. Agrees to be randomized to nVNS, CBD or SoC
8. Agrees to use nVNS, CBD, or SoC as intended, follow all of the requirements of the study including Follow-up Visit requirements, and record required study data in the subject e-diary
9. Able to provide written informed consent

EXCLUSION CRITERIA

1. Body weight at screening of less than 40 kg
2. Other severe pain condition (e.g., cancer pain or trigeminal neuralgia) that, in the discretion of the investigator, may confound the study assessments
3. Known or suspected severe cardiac disease (e.g., symptomatic coronary artery disease, prior myocardial infarction, congestive heart failure), neurologic disease (history of intracranial aneurysm, intracranial hemorrhage, or brain tumor), moderate to severe hepatic impairment, history of cervical surgery (e.g. cervical vagotomy) that in the judgment of the investigator would interfere with the study, or other major medical problems at the discretion of the investigator
4. Psychiatric, substance abuse, or cognitive disorder and/or behavioral problems that, in the opinion of the investigator, may interfere with the study.
5. Belongs to a vulnerable population (e.g., developmentally disabled, prisoner) or has any condition such that his or her ability to provide informed consent, comply with the follow-up requirements, or provide self-assessments is compromised at the discretion of the investigator
6. Currently takes prescription opioids more than 4 days per month for any indication
7. Patients receiving PREEMPT protocol onabotulinumtoxin injections, nerve blocks (occipital or other), steroid injections, radiofrequency ablations, and/or trigger point injections in the head or neck injections within the prior 12 weeks must continue receiving this procedure on a regular schedule at the discretion of the investigator during the course of the study. Patients who experience "wear-off" effects or increases in headache days during the last two weeks of their procedural cycles will be excluded from the study
8. Currently implanted with a cardiac defibrillator
9. Allergy to CBD or other components of Cannabis sativa L. (including hemp or cannabis)
10. Previously used gammaCore or high-dose CBD (>100mg/day) for PPTH
11. Used medical marijuana, cannabis, hemp or CBD-based product within 30 days prior to the study
12. Unwilling to discontinue use of medical marijuana, cannabis, hemp or CBD-based product during the study
13. Patients using medications that can interact with the study drug and/or its safety profile throughout the study and for at least five half-lives after the last dose of investigational product, including clobazam and valproic acid and other drugs according to the drug-drug interaction (DDI) risks as described in the Epidiolex USPI.
14. Patients who are pregnant, breastfeeding, or not using acceptable methods of contraception during the course of the study and for three months thereafter.
15. Male patient's partner is of childbearing potential; unless willing to ensure that they (male patients) or their partner(s) are using acceptable methods of contraception during the course of the study and for three months thereafter.
16. Participating in any other therapeutic clinical investigation or has participated in a clinical trial in the preceding 30 days
17. A relative of or an employee of the Investigator or the clinical study site
18. Presence of any implantable device that may interfere or interact with gammaCore, any history of cardiac arrhythmias or conduction defects, and any other medical history that, in the opinion of the investigator and/or based on the labeling of gammaCore, may increase the risk of using the gammaCore device.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cannabidiol	Drug: Cannabidiol; Dosage titrated as per schedule; Other Names: BRC-003
Experimental: Non-Invasive Vagus Nerve Stimulation	Device: Non-Invasive Vagus Nerve Stimulation; Two treatments to the cervical vagus nerve twice daily; Other Names: gammaCore
Experimental: Standard of Care	Drug: Standard of Care; Oral pharmacotherapy as selected by site investigator and participant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Moderate-severe headache days	Mean reduction from baseline in number of moderate or severe headache days per 28 days during weeks 9-12	Weeks 9-12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
50% Responder Rate	Percentage of participants who report at least a 50% reduction in the number of moderate or severe headache days per 28 days during the last 4 weeks versus the 4 week baseline period	Weeks 9-12
Headache days	Mean reduction from baseline in number of headache days per 28 days during weeks 9-12	Weeks 9-12
Acute headache medication days	Mean reduction from baseline in number of days that acute medication was used per 28 days during weeks 9-12	Weeks 9-12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent reduction in moderate or severe headache days	Mean percent reduction from baseline in moderate or severe headache days per 28 days during weeks 9-12	Weeks 9-12
HIT-6	Change from baseline in Headache Impact Test-6	Weeks 9-12
EQ-5D-5L	Change from baseline in EQ-5D-5L	Weeks 9-12
PGIC	Patient Global Impression of Change	Weeks 9-12
PROMIS-29	Change from baseline in PROMIS-29	Week 12
Moderate-severe headache days	Mean reduction from baseline in number of moderate or severe headache days per 28 days during weeks 1-4	1-4
Moderate-severe headache days	Mean reduction from baseline in number of moderate or severe headache days per 28 days during weeks 5-8	5-8

Collaborators and Investigators

• Sponsor: American Society of Pain and Neuroscience, Inc.
• Collaborators: National Football League
• Investigators: Principal Investigator: Nathaniel M Schuster, MD, University of California, San Diego; Principal Investigator: Erika A Petersen, MD, University of Arkansas

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: May 29, 2026
• First Submitted That Met QC Criteria: May 29, 2026
• First Posted (Actual): June 3, 2026

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: Persistent Post-Traumatic Headache, Vagus Nerve, Neuromodulation, Cannabidiol
• Additional Relevant MeSH Terms: Health Services Administration; Health Care Quality, Access, and Evaluation; Organic Chemicals; Hydrocarbons; Terpenes; Quality of Health Care; Quality Indicators, Health Care; Cannabinoids; Cannabidiol; Standard of Care
• Other Study ID Numbers: ASPN-NFL-US-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes