Multidisciplinary Translational Approach to Investigate Mechanisms Predictors & Prevention of Persistent PTH

A Multidisciplinary Translational Approach to Investigate the Mechanisms, Predictors, and Prevention of Persistent Post-Traumatic Headache

This is a United States Department of Defense funded Focused Program study that aims to identify mechanisms and predictors for persistent of post-traumatic headache attributed to mild traumatic brain injury, and identify methods of preventing post-traumatic headache persistence.

The objective of the clinical trial component of the Focused Program is to determine whether intervention with erenumab is an effective treatment for PTH attributed to mTBI.

Study Overview

• Status: Recruiting
• Conditions: Post-Traumatic Headache
• Intervention / Treatment: Other: Placebo; Drug: Erenumab

Detailed Description

The human studies component of this Focused Program includes clinical phenotyping, neurophysiology, molecular and genetic biomarker discovery, brain imaging, and a clinical trial.These data will be utilized to characterize post-traumatic headache and build univariate and multivariate predictive models for post-traumatic headache persistence and for the response to post-traumatic headache treatment. These studies are described in more detail within a separate clinicaltrials.gov record.

The clinical trial is a double-blind, randomized, placebo-controlled investigation of erenumab for the treatment of post-traumatic headache. Participants will be randomized when PTH has been present for 35-56 days. Follow-up questionnaires, headache diary data, pain threshold results, and brain imaging data will be collected longitudinally during the clinical trial to assess for changes over time and associations of such changes with post-traumatic headache treatment outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 112
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Dani Smith; Phone Number: 480-342-6524; Email: smith.dani@mayo.edu

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Recruiting
      • Mayo Clinic
      • Principal Investigator: Todd Schwedt, MD
      • Contact: Dani Smith; Phone Number: 480-342-6524; Email: smith.dani@mayo.edu
    • Phoenix, Arizona, United States, 85012
      • Recruiting
      • Phoenix VA Health Care System
      • Contact: Katherine Ross, PhD; Phone Number: 7982 602-277-5551; Email: Katherine.Ross3@va.gov
    • Scottsdale, Arizona, United States, 85259
      • Recruiting
      • Mayo Clinic in Arizona
      • Principal Investigator: Todd Schwedt, MD
      • Contact: Dani Smith; Phone Number: 480-342-6524; Email: smith.dani@mayo.edu
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Not yet recruiting
      • Mayo Clinic
      • Contact: Dylan Wood; Phone Number: 904-953-9774; Email: wood.dylan@mayo.edu
      • Principal Investigator: Kevin Barrett, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55901
      • Recruiting
      • Mayo Clinic
      • Principal Investigator: Dmitry Esterov, DO
      • Contact: Zachary Pohlkamp; Phone Number: 507-422-0140; Email: pohlkamp.zachary@mayo.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Have a diagnosis of acute PTH attributed to mild traumatic injury to the head as defined by the International Classification of Headache Disorders (ICHD-3).
• PTH onset 7-56 days prior to the time of enrollment
• Adults 18-70 years of age
• Willing to be randomized to either of the two clinical trial treatment arms
• Willing to maintain a headache diary
• Willing and able to return for follow-up visits
• 5 or more moderate or severe headache days during the 4-week run-in phase and an increase of at least 2 moderate to severe headache days compared to pre-TBI and at least a 30% increase
• At least 80% compliant with diary keeping during the 4-week run-in phase (i.e., provides data on at least 80% of days)

Exclusion Criteria:

• Episodic tension-type headache, migraine, or other headaches with at least 4 headache days/month on average over the 6 months prior to the mTBI resulting in PTH
• Chronic headache (i.e., at least 15 headache days/month for more than 3 months) within 12 months prior to the mTBI that led to the current PTH, including PPTH, chronic migraine, medication overuse headache, new daily persistent headache, hemicrania continua, chronic tension-type headache
• Diminished decision-making capacity that in the investigator's opinion would interfere with the person's ability to provide informed consent and complete study procedures
• Started or changed dose of a headache preventive medication within the 3 months prior to screening
• Use of onabotulinumtoxinA in the head, neck or face region within 6 months of screening
• During the 6 months before screening, use of opioids or barbiturates on an average of at least 4 days per month
• Subjects who underwent an intervention or used a device (e.g., nerve blocks, transcranial magnetic stimulation, vagal nerve stimulation, or electrical trigeminal nerve stimulation) for headache
• History of major psychiatric disorder such as schizophrenia and bipolar disorder
• History or evidence of any unstable or clinically significant medical condition, that in the opinion of the investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion
• History of positive neuroimaging findings that indicate a moderate or severe TBI

• Contraindications to magnetic resonance imaging, including, but not limited to (only an exclusion for patients participating in the brain MRI portion of this research):

  1. Metal implants
  2. Aneurysm clips
  3. Severe claustrophobia
  4. Implanted electronic device
  5. Insulin or infusion pump
  6. Cochlear/otologic/ear implant
  7. Non-removable prosthesis
  8. Implanted shunts/catheters
  9. Certain intrauterine devices
  10. Tattooed makeup
  11. Body piercings that cannot be removed
  12. Metal fragments
  13. Wire sutures or metal staples

• Factors that reduce MR image quality and interpretability (only an exclusion for patients participating in the brain MRI portion of this research):

  1. Dental braces or other non-removable devices (e.g., retainers)
  2. Prior brain surgery
  3. Known brain MRI abnormality that in the investigator's opinion will significantly impact MRI data
• Sensory disorders that in the investigator's opinion might affect perception of cutaneous thermal stimuli (e.g., peripheral neuropathy) (only an exclusion for patients participating in the neurophysiology studies)
• Pregnancy
• Breastfeeding
• History of myocardial infarction, stroke, transient ischemic attack, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening.

• Not willing to use a reliable form of contraception (for women of childbearing potential) through 16 weeks after the last dose of erenumab. Acceptable methods of birth control include not having intercourse, hormonal birth control methods, intrauterine devices, surgical contraceptive methods, or two barrier methods (each partner must use a barrier method) with spermicide. A reliable form of contraception must be started prior to or at the time of starting the run-in phase. Not being of childbearing potential is defined as any woman who is post-menopausal by history, defined as:

  1. At least 55 years of age with cessation of menses for 12 or more months; OR
  2. Younger than 55 years of age but no spontaneous menses for at least 2 years; OR
  3. Younger than 55 years of age and spontaneous menses within the past 1 year, but currently amenorrheic (e.g., spontaneous or secondary to hysterectomy), AND with postmenopausal gonadotropin levels (luteinizing hormone and follicle-stimulating hormone levels at least 40 IU/L) or postmenopausal estradiol level (less than 5 ng/dL) or according to the definition of "postmenopausal range" for the laboratory involved; OR
  4. Underwent bilateral oophorectomy; OR
  5. Underwent hysterectomy; OR
  6. Underwent bilateral salpingectomy.
• Currently or within 90 days prior to screening: received treatment in another drug study or an investigational device study
• Has previously received any CGRP ligand or receptor targeted monoclonal antibody

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; placebo comparator	Other: Placebo; Placebo
Experimental: Erenumab; 140 mg erenumab	Drug: Erenumab; a CGRP receptor monoclonal antibody; Other Names: Aimovig

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Moderate-to-severe headache day frequency	Moderate-to-severe headache day frequency measured at weeks 9-12 after administration of first dose of erenumab 140mg or placebo vs. frequency of moderate-to-severe headache days during the 4-week baseline phase (BP).	9-12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Responder rate	Percentage of patients with at least a 50% reduction in headache days during weeks 9-12 after administration of first dose of erenumab 140 mg or placebo compared to baseline phase.	9-12 weeks
Chronic headache	Percentage of patients with chronic headache, defined as at least 15 headache days, during weeks 9-12 after administration of first dose of erenumab 140 mg or placebo compared to baseline phase.	9-12 weeks
Headache Impact Test (HIT-6)	Headache Impact Test (HIT-6) score at weeks 9-12 after administration of first dose of erenumab 140 mg or placebo compared to baseline phase.	9-12 weeks
Treatment day frequency	Acute treatment day frequency measured at weeks 9-12 after administration of first dose of erenumab 140mg or placebo compared to baseline phase. Acute treatment day is any day on which analgesic, triptan, or ergotamine containing medication is taken, or device neuromodulation [e.g. vagal or trigeminal nerve electrical stimulation or single pulse transcranial magnetic stimulation] is administered to relieve headache.	9-12 weeks

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: United States Department of Defense; Amgen; Arizona State University; University of Arizona; Translational Genomics Research Institute; Phoenix VA Health Care System
• Investigators: Principal Investigator: Todd Schwedt, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2021
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: September 19, 2019
• First Submitted That Met QC Criteria: September 19, 2019
• First Posted (Actual): September 23, 2019

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 17, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: headache; post-traumatic headache
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Headache Disorders; Headache Disorders, Secondary; Headache; Post-Traumatic Headache; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Calcitonin Gene-Related Peptide Receptor Antagonists; Erenumab
• Other Study ID Numbers: 19-003200

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes