Imaging the Migraine Brain Pre- and Post-Erenumab

Imaging the Migraine Brain Pre- and Post-Erenumab: an MRI Study to Identify Functional and Structural Changes That Correlate With Patient Improvement

Researchers are trying to determine if there is a difference between brain images of subjects that do respond to treatment with erenumab and subjects who do not respond to treatment with erenumab using Magnetic Resonance Imaging (MRI).

Study Overview

• Status: Completed
• Conditions: Migraine
• Intervention / Treatment: Drug: Erenumab

Detailed Description

The study will include 50 participants with migraine aged 18-65 years who have 10-25 migraine days per month at baseline. Following a 4-week headache diary run-in phase, participants will receive two treatments with once monthly subcutaneous injections of erenumab 140 mg. Questionnaires, structured interviews, cognitive tests, quantitative sensory testing and brain imaging will be performed prior to and following erenumab treatment. These data will be collected at early time points after the first treatment as well as at eight weeks following the first treatment to allow for identification of early and late effects of erenumab on clinical, physiologic, and imaging outcomes and to determine if early physiologic and imaging outcomes predict clinical outcomes at eight weeks. Physiologic and imaging data will be compared to already collected data from healthy controls so as to interpret changes that are seen following treatment with erenumab.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• 18-65 years of age
• Episodic migraine (with or without aura) or chronic migraine according to the diagnostic criteria included within the International Classification of Headache Disorders 3 (ICHD-3)
• 6-25 migraine days per month on average over the 3 months prior to screening, confirmed by run-in phase prospective data collection
• Duration since migraine onset of at least 12 months prior to screening based on medical records and/or patient self-report

Exclusion Criteria

• Older than 50 years of age at migraine onset
• History of cluster headache or hemiplegic migraine
• Continuous headache pain (i.e. no pain-free periods of any duration during the one month before screening)
• Opioid- or butalbital-containing analgesics on 6 or more days per month during the 2 months prior to the start of the baseline phase
• 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
• No therapeutic response in migraine prevention after an adequate therapeutic trial of 4 or more of the following medication categories: Category 1- divalproex sodium, sodium valproate; Category 2- topiramate; Category 3- beta-blockers; Category 4- tricyclic antidepressants; Category 5- venlafaxine or desvenlafaxine, duloxetine or milnacipran; Category 6- flunarizine, verapamil; Category 7- lisinopril, candesartan; Category 8- botulinum toxin. No therapeutic response is defined as no reduction in headache frequency, duration, or severity after administration of the medication for at least 6 weeks at the generally accepted therapeutic dose(s) based on the investigator's assessment. Lack of sustained response to a medication and failure to tolerate a therapeutic dose are not considered to be "no therapeutic response".
• Concomitant use of 3 or more of the following medications for migraine prevention within 2 months before the start of the baseline phase or throughout the study: divalproex sodium, sodium valproate, topiramate, carbamazepine, gabapentin, beta-blockers, tricyclic antidepressants, venlafaxine, desvenlafaxine, duloxetine, milnacipran, flunarizine, verapamil, lomerizine, lisinopril, candesartan, clonidine, guanfacine, cyproheptadine, methysergide, pizotifen, butterbur, feverfew, magnesium (at least 600 mg per day), riboflavin (at least 100 mg per day). Use of up to two medications is permitted as long as the dose has been stable for at least 2 months before the start of the run-in phase and during the study.
• Botulinum toxin (in the head and/or neck region) within 4 months before the start of the baseline phase and throughout the study
• Ergotamine derivatives, steroids, and triptans used for migraine prophylaxis within 2 months before the start of the baseline phase and throughout the study
• Procedures (e.g. nerve blocks) used for migraine prophylaxis within 2 months before the start of the baseline phase and throughout the study
• History of myocardial infarction, stroke, transient ischemic attack, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening.
• Contraindications to MRI including, but not limited to: Metal implants, aneurysm clips, severe claustrophobia, implanted electronic devices, insulin or infusion pump, cochlear/otologic/ear implant, non-removable prosthesis, implanted shunts/catheters, certain intrauterine devices, tattooed makeup, body piercings that cannot be removed, metal fragments, wire sutures or metal staples.
• Factors that Reduce MR Image Quality and Interpretability: dental braces or other non-removable devices (e.g. retainers); prior brain surgery; 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)
• Pregnancy
• Lactation
• 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: 1) is post-menopausal by history, defined as: a) At least 55 years of age with cessation of menses for 12 or more months, OR b) Younger than 55 years of age but no spontaneous menses for at least 2 years, OR c)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 d) Underwent bilateral oophorectomy, OR e) Underwent hysterectomy, OR f) Underwent bilateral salpingectomy
• Currently receiving treatment in another drug study or an investigational device study, or less than 90 days prior to screening since ending treatment on another investigational device or drug study(-ies)
• Has received calcitonin gene-related peptide (CGRP) monoclonal antibody within 4 months of the start of the run-in phase
• Active chronic pain condition that in the investigator's opinion is unrelated to migraine (e.g. chronic pelvic pain)
• Acute pain condition that in the investigator's opinion is unrelated to migraine (e.g. post-surgical pain)
• Unable to provide informed consent
• Less than 80% compliance with providing headache diary data during the run-in phase (i.e. provides data on less than 80% of days)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Erenumab; All participants receive erenumab 140mg by subcutaneous injection at baseline and again 4 weeks later.	Drug: Erenumab; Erenumab will be used per label instructions.; Other Names: Aimovig

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting State Functional Connectivity	Brain MRI resting state functional connectivity measured as global efficiency percentage. An increase in global efficiency suggests an improvement in the ability of the brain regions to functionally communicate on a global scale. Efficiency relates to the network. In this case, the investigators defined the network to be the pain matrix. Increased efficiency would mean the connectivity within the matrix is increased and more efficient. This has not been attributed to a clinical outcome but is rather a characteristic of the network.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Erenumab Responders	The number of participants who responded to erenumab treatment. Treatment response was defined as at least a 50% reduction in the frequency of migraine days during weeks 5-8 compared to the 4 week pre-treatment run-in phases as recorded in the headache diary.	8 weeks
Iron Accumulation in Periaqueductal Gray Brain Region	Iron accumulation in the periaqueductal gray as measured by magnetic resonance imaging (MRI) transverse relaxation rates (T2*).	8 weeks
Iron Accumulation in Anterior Cingulate Cortex Brain Region	Iron accumulation in the anterior cingulate cortex as measured by magnetic resonance imaging (MRI) transverse relaxation rates (T2*).	8 weeks
Change in the Migraine Disability Assessment Questionnaire (MIDAS)	The MIDAS questionnaire consists of 5 questions that assess the degree of headache related disability. Each question asks the patient to record the number of days in the past 3 months where a headache has impacted various daily life activities. The individual responses to each of the five questions are then added to obtain a total score and level of disability. A total score of 0-5 days reflects little or no disability (Grade I); 6-10 days is mild disability (Grade II); 11-20 days is moderate disability (Grade III) and over 21 days is severe disability (Grade IV). A lower score indicates less disability while a higher score reflects more disability.	Baseline, 8 weeks
ROI-ROI Functional Connectivity of Middle Temporal Left With Supramarginal Gyrus Right Regions of the Brain	Temporal correlations in blood oxygen level dependent (BOLD) signal fluctuations between selected regions of interest (ROIs). The correlation coefficient ( r ) is measured between seed regions. This measurement is bound by the range [ -1 to 1]. In order to perform statistical tests (such as T-tests) we Fisher transform the correlation coefficient from [-1 1] to a real number [ -infinity infinity] Mathematically it is: z=atanh( r ). The Z-score themselves are functional connectivity between the regions and do not serve as clinical biomarkers. The difference, and longitudinal changes are of greater interest as they indicate alterations to normal pain processing. A more efficient pain processing network would suggest that more of these regions are being enlisted and with greater connectivity.	8 weeks
ROI-ROI Functional Connectivity of Temporal Pole Right With Middle Occipital Right	Temporal correlations in blood oxygen level dependent (BOLD) signal fluctuations between selected regions of interest (ROIs). The correlation coefficient ( r ) is measured between seed regions. This measurement is bound by the range [ -1 to 1]. In order to perform statistical tests (such as T-tests) we Fisher transform the correlation coefficient from [-1 1] to a real number [ -infinity infinity] Mathematically it is: z=atanh( r ). The Z-score themselves are functional connectivity between the regions and do not serve as clinical biomarkers. The difference, and longitudinal changes are of greater interest as they indicate alterations to normal pain processing. A more efficient pain processing network would suggest that more of these regions are being enlisted and with greater connectivity.	8 weeks
ROI-ROI Functional Connectivity of Inferior Lateral Parietal Right With Middle Frontal Left	Temporal correlations in blood oxygen level dependent (BOLD) signal fluctuations between selected regions of interest (ROIs). The correlation coefficient ( r ) is measured between seed regions. This measurement is bound by the range [ -1 to 1]. In order to perform statistical tests (such as T-tests) we Fisher transform the correlation coefficient from [-1 1] to a real number [ -infinity infinity] Mathematically it is: z=atanh( r ). The Z-score themselves are functional connectivity between the regions and do not serve as clinical biomarkers. The difference, and longitudinal changes are of greater interest as they indicate alterations to normal pain processing. A more efficient pain processing network would suggest that more of these regions are being enlisted and with greater connectivity.	8 weeks
ROI-ROI Functional Connectivity of Dorsolateral Prefrontal Cortex Left With Hypothalamus Right	Temporal correlations in blood oxygen level dependent (BOLD) signal fluctuations between selected regions of interest (ROIs). The correlation coefficient ( r ) is measured between seed regions. This measurement is bound by the range [ -1 to 1]. In order to perform statistical tests (such as T-tests) we Fisher transform the correlation coefficient from [-1 1] to a real number [ -infinity infinity] Mathematically it is: z=atanh( r ). The Z-score themselves are functional connectivity between the regions and do not serve as clinical biomarkers. The difference, and longitudinal changes are of greater interest as they indicate alterations to normal pain processing. A more efficient pain processing network would suggest that more of these regions are being enlisted and with greater connectivity.	8 weeks
ROI-ROI Functional Connectivity of Inferior Lateral Parietal Right With Supramarginal Gyrus Right	Temporal correlations in blood oxygen level dependent (BOLD) signal fluctuations between selected regions of interest (ROIs). The correlation coefficient ( r ) is measured between seed regions. This measurement is bound by the range [ -1 to 1]. In order to perform statistical tests (such as T-tests) we Fisher transform the correlation coefficient from [-1 1] to a real number [ -infinity infinity] Mathematically it is: z=atanh( r ). The Z-score themselves are functional connectivity between the regions and do not serve as clinical biomarkers. The difference, and longitudinal changes are of greater interest as they indicate alterations to normal pain processing. A more efficient pain processing network would suggest that more of these regions are being enlisted and with greater connectivity.	8 weeks
ROI-ROI Functional Connectivity of Ventromedial Prefrontal Cortex Left With Pulvinar Right	Temporal correlations in blood oxygen level dependent (BOLD) signal fluctuations between selected regions of interest (ROIs). The correlation coefficient ( r ) is measured between seed regions. This measurement is bound by the range [ -1 to 1]. In order to perform statistical tests (such as T-tests) we Fisher transform the correlation coefficient from [-1 1] to a real number [ -infinity infinity] Mathematically it is: z=atanh( r ). The Z-score themselves are functional connectivity between the regions and do not serve as clinical biomarkers. The difference, and longitudinal changes are of greater interest as they indicate alterations to normal pain processing. A more efficient pain processing network would suggest that more of these regions are being enlisted and with greater connectivity.	8 weeks

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Todd J Schwedt, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2019
• Primary Completion (Actual): June 30, 2022
• Study Completion (Actual): June 30, 2022

Study Registration Dates

• First Submitted: November 27, 2018
• First Submitted That Met QC Criteria: December 10, 2018
• First Posted (Actual): December 12, 2018

Study Record Updates

• Last Update Posted (Actual): January 9, 2024
• Last Update Submitted That Met QC Criteria: December 18, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Migraine; Magnetic Resonance Imaging; Brain Function; Brain Structure
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; 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: 18-001497

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