The FreMRI Study: Advanced MRI on Migraine Patients Treated With Fremanezumab (FreMRI)

A Prospective Structural, Diffusion and Connectomics MRI Study on Migraine Patients Treated With Fremanezumab: The FreMRI Study

The goal of this open-label, single-blind, controlled-trial is to evaluate brain changes evaluated with diffusion Magnetic Resonance Imaging (MRI) and functional MRI in patients with high-frequency episodic migraine and chronic migraine that will be treated with Fremanezumab, 12 weeks after the treatment onset, compared with the baseline.

Type of study: Phase IV clinical trial Participant population: high-frequency episodic migraine and chronic migraine. Participants will be treated with Fremanezumab.

Study Overview

• Status: Recruiting
• Conditions: Brain Diseases; Migraine Disorders; Migraine Without Aura; Migraine With Aura
• Intervention / Treatment: Drug: Fremanezumab Prefilled Syringe

Detailed Description

Fremanezumab is a monoclonal antibody targeting calcitonin C-reactive peptide (CGRP) that has proven to be effective in the treatment of episodic and chronic migraine. Due to the molecular weight of the drug, it is not supposed to cross the blood-brain barrier, acting peripherally.

Patients with migraine have shown gray and white matter changes that can be evaluated by magnetic resonance imaging (MRI).

In the present study, we aim to evaluate the presence of MRI changes in patients treated with Fremanezumab, 12 weeks after the treatment onset, compared with the baseline.

Number of Subjects: 87 patients. Study Duration per Subject Study duration per patient will be 8 months.

Study procedures:

In the first visit, the screening visit, patients will receive a detailed explanation of the study and will sign informed consent form. Inclusion-exclusion criteria will be reviewed and evaluation of vital signs, general and neurological examination will be done. Patients will receive a headache diary and will be trained in its use.

First MRI scan will be acquired within 0-14 days, prior to Fremanezumab injection.

Patients will do four monthly additional hospital visits. During each visit, occurrence of any adverse event will be interrogated; clinical situation will be analyzed and Fremanezumab will be administered. Visits will be performed at weeks 0, 4 and 8. Last visit will be performed after 12 weeks, without Fremanezumab injection.

The second MRI will be acquired at 12 ± 1 weeks after the first Fremanezumab injection.

Intervention:

MRI acquisition Images will be acquired during interictal periods, defined as at least 24 hours from last migraine attack. High-resolution 3D T1-weighted, diffusion-weighted and resting-state functional MRI data will be acquired using a Philips Achieva 3T MRI unit (Philips Healthcare, Best, The Netherlands) with a 32-channel head coil in the MRI facility at the Universidad de Valladolid (Valladolid, Spain).

For the anatomical T1-weighted images, the following acquisition parameters will be used: Turbo Field Echo (TFE) sequence, repetition time (TR) = 8.1 ms, echo time (TE) = 3.7 ms, flip angle = 8º, 256 x 256 matrix size, 1 x 1 x 1 mm3 of spatial resolution and 170 sagittal slices covering the whole brain.

Diffusion-weighted images (DWI) will be obtained using the next parameters: TR = 9000 ms, TE = 86 ms, flip angle = 90º, 61 gradient directions, two baseline volumes with opposite phase encoding direction, b-value = 1000 s/mm2, 128 x 128 matrix size, 2 x 2 x 2 mm3 of spatial resolution and 66 axial slices covering the whole brain.

Resting-state functional MRI (rs-fMRI) will be acquired with the following parameters: TR = 3000 ms, TE = 30 ms, flip angle = 80º, 80 x 80 matrix size, 3 x 3 x 4 mm3 of spatial resolution, 35 axial slices covering the whole brain and 197 volumes. During this acquisition, the patient will close the eyes but remain awake.

All the scans will be acquired during the same session, starting with the T1-weighted scan, followed by the diffusion-weighted scan and ending with the rs-fMRI scan. Total acquisition time for a single subject is approximately 28 minutes, divided in the following periods of time: six minutes for the T1-weighted scan, 12 minutes for the diffusion-weighted scan and 10 minutes for the rs-fMRI scan. If we consider patient preparation, obtainment of documents and informed consent form, the whole process will take about 50-70 minutes.

Image processing T1-weighted morphometric parameters MRI images will be processed in order to obtain cortical curvature, cortical thickness, gray matter volume and surface area of the different gray matter regions.

Grey matter volume will be obtained for all the 84 grey matter regions from the Desikan-Killiany atlas (Reuter et al., 2012). Also, cortical curvature, cortical thickness and area will be calculated for the 68 regions from the atlas that are cortical regions.

DWI processing DWI will be processed to carry out two types of analysis: Tract-Based Spatial Statistics (TBSS) and structural connectomics.

Prior to the beginning of both processing pipelines, diverse preprocessing procedures will be implemented on the DWI data. Diffusion-weighted images will be denoised, using "dwidenoise" tool from MRtrix (www.mrtrix.org), eddy currents, motion and B0 field inhomogeneity corrected, using "dwipreproc" tool from MRtrix, and B1 field inhomogeneity corrected, using "dwibiascorrect" tool with the "-fast" option from MRtrix.

Four diffusion descriptors from Diffusion Tensor Imaging will be obtained: Fractional Anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD) and Axial Diffusivity (AD). We will also be using measures non based on the diffusion tensor, like the return-to-origin probability (RTOP), which reflects cellularity and restrictions better than MD.

Once the DWI data are preprocessed, a whole brain mask for each image will be generated using "dwi2mask" tool from MRtrix and, next, diffusion tensors at each voxel will be estimated using the "dtifit" tool from FSL, also obtaining FA, MD and AD maps. RD will be manually calculated by obtaining the mean of the second and the third eigenvalues, which will also be previously computed with "dtifit". RTOP will be estimated using the method called "Apparent Measures Using Reduced Acquisitions" (AMURA).

Structural connectomics The analysis of structural connectivity will use the segmentation results from T1-weighted processing pipeline.

Anatomically-Constrained Tractography (ACT) will be implemented. Previously, five-tissue-type (5TT) segmented images for each subject will be obtained from the T1-weighted images using the "5ttgen" tool from MRtrix to have suitable images for ACT. 5TT image and the automated parcellation from FreeSurfer will be inearly registered to the FA image using the FLIRT tool from FSL.

Finally, structural connectivity matrices will be computed from the filtered tractography output and the registered cortical segmentation volumes. 84 × 84 connectivity matrices, corresponding to the 84 cortical and subcortical regions from the Desikan-Killiany atlas, will be obtained using mean FA and the number of streamlines in each connection as connectome metrics. Connectivity matrices constructed in this manner are symmetric, so only a half of each matrix will be employed for further analysis.

Due to the tractography method employed, it is possible that streamlines start and end in different points belonging to the same gray matter region from the Desikan-Killiany atlas. For this reason, these connections ("self-connections") will also be included in the analysis.

fMRI processing The fMRI processing pipeline will be fully implemented in the software CONN. Firstly, some preprocessing steps will be implemented. fMRI volumes will be realigned and unwarpped to estimate and correct subject motion. To identify outliers, ARtifact detection Tools (ART) based outlier detection algorithm will be implemented. Then, fMRI volumes will be directly coregistered to the corresponding structural volumes (T1-weighted images) using a rigid body transformation. T1-weighted images will be segmented to detect different types of tissue, i.e., gray matter, white matter and cerebrospinal fluid (CSF).

Finally, the functional connectivity matrix for each case will be computed considering whole-brain region-to-region connections, using the 84 cortical and subcortical regions from the Desikan-Killiany atlas in each subject as regions of interest. The matrices will contain the Z-values from the Fisher's r-to-z transformation.

Safety Variables Safety and side effects will be evaluated according to reported adverse events, both spontaneously by patients and systematically analyzed during study visits. Vital signs (blood pressure, pulse, temperature and respiratory rate), physical examination and 12-lead electrocardiography will be done prior to the enrollment. Presence of any adverse event or local injection-site reaction will be systematically addressed. Columbia-Suicide Severity Rating Scale will assess suicidal ideation and behavior at baseline.

Statistical Analysis Parameter evolution in time and relationship with change in monthly migraine days for each of the parameters, i.e., morphometric (gray matter) parameters, diffusion descriptors (white matter), structural connectivity and resting-state functional connectivity, longitudinal evolution will be assessed.

n order to analyze the structural connectivity matrices, firstly, the mean number of streamlines in each connection (cell from the connectivity matrix) will be computed for each group. Next, connections with less than 500 streamlines (group mean) will be discarded in order to exclude weak connections, for which results could be unreliable, from further analysis.

In the case of functional resting-state connectivity matrices, a similar rejection of non-important connections will be selected, connections with absolute Z-value lower than 0.1 are excluded, i.e., a Pearson correlation value of r = 0.1 following the Fisher's r-to-z transformation.

In the previous two cases, if the thresholds are too high or too low, i.e., almost all the connections are rejected, or almost no connections are rejected, the thresholds will be changed.

A model will be implemented for each of the four types of analysis described in the document. In each of the models, the significant effect of the covariates and the predictive capability of the model using the lowest number of covariates will be considered. To compare the different models, Akaike's Information Criterion (AIC) will be used (67). In the case of very similar AIC values, the model with a lower number of regressors will be chosen.

For each of the four types of analysis, the predictive model will be computed for a single regressor. Regressors with p-value equal or higher than 0.05 in the singular predictive model will not be further considered to be included in the final model; while the remaining regressors will be considered for the final model of the corresponding type of analysis.

Relationship between MRI parameters evolution and clinical response A linear mixed-effect model will be prepared using the same strategy that was employed for the analysis of change in monthly migraine days and MRI parameters. To evaluate the clinical response to treatment, a dichotomic variable showing positive or negative response to treatment will be used, instead of change in monthly migraine days.

Positive response to treatment is considered as 50% reduction in number of monthly migraine days.

Exploratory variables analysis The final model used in the analysis of the relationship between the diverse MRI parameters and change in monthly migraine days will be used. The variable representing the change in monthly migraine days will be replaced by the change in monthly intense headache days, in monthly days of acute treatment medication.

In the case of response to treatment, the same final model from the analysis of clinical response considered as 50% reduction in number of monthly migraine days will be used. Response to treatment, in this case, will be represented by reduction of 75%, 100% and 30% of monthly migraine days.

Analysis of adverse events Categorical adverse events will be compared using Fisher's exact test. A p-value < 0.05 will be considered as statistically significant.

• Study Type: Interventional
• Enrollment (Estimated): 87
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: David Garcia Azorin, MD, PhD; Phone Number: +34 665872228; Email: davilink@hotmail.com
• Study Contact Backup: Name: Yesica Gonzalez Osorio, MBA; Phone Number: +34 634330426; Email: ygoinvestigacion@outlook.com

Study Locations

• Spain
  • Valladolid, Spain, 47010
    • Recruiting
    • Hospital Clinico Universitario de Valladolid
    • Contact: David Garcia Azorin, MD, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Definite diagnosis of Migraine With Aura or Migraine Without Aura according to the International Classification of Headache Disorders, 3rd version (IHCD-3) (1).
2. Age between 18 and 65 years old.
3. Providing signed informed consent form.
4. Diagnosis of migraine before 50 years old.
5. History of migraine during at least 12 months prior to the study.
6. With eight or more migraine days per month within the last three months

Exclusion Criteria:

1.Presence of other primary headache disorders other than infrequent tension-type headache or medication overuse headache (MOH).

1. Participation of MOH patients will be restricted to a maximum of 50% of the total sample.
2. Prior use of Fremanezumab or another monoclonal antibody targeting CGRP or CGRP receptor.
3. Prior use of less than two or more than four preventive drugs according to the local national guidelines (34), with inadequate response after sufficient doses and enough time or lack of tolerability.
4. Any medical condition that might prevent study completion or interfere with interpretation of results.
5. History of any neurological or neurosurgical condition affecting the brain.
6. History of moderate-severe head trauma.
7. History of other chronic pain syndrome with a frequency of five or more days of pain per month.
8. Presence of daily headache
9. Pregnant or breastfeeding women.
10. Current or recent use of any other prophylactic treatment in the preceding five half-lives prior to the start.
11. Exposure to onabotulinumtoxinA in the preceding four months.
12. Any expected surgery during the study.
13. Use of opioids or barbiturates.
14. Any condition contraindicating an MRI acquisition.
15. Completing headache diary at least 80% of the time during the screening period

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

Experimental: Fremanezumab; Patients will be treated with 225 mg of subcutaneous injections of Fremanezumab per month. Patients will do four monthly additional hospital visits. During each visit, occurrence of any adverse event will be interrogated; clinical situation will be analyzed and Fremanezumab will be administered. Visits will be performed at weeks 0, 4 and 8. Last visit will be performed after 12 weeks, without Fremanezumab injection.

Drug: Fremanezumab Prefilled Syringe; MRI will be scanned prior to the first administration of Fremanezumab, within 0-14 days, prior to Fremanezumab injection. The second MRI will be acquired at 12 ± 1 weeks after the first Fremanezumab injection.Images will be acquired during interictal periods, defined as at least 24 hours from last migraine attack. All the scans will be acquired during the same session, starting with the T1-weighted scan, followed by the diffusion-weighted scan and ending with the rs-fMRI scan. Total acquisition time for a single subject is approximately 28 minutes, divided in the following periods of time: six minutes for the T1-weighted scan, 12 minutes for the diffusion-weighted scan and 10 minutes for the rs-fMRI scan. If we consider patient preparation, obtainment of documents and informed consent form, the whole process will take about 50-70 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Morphometric MRI parameters change from baseline during the 12-week period after the administration of Fremanezumab 1	Cortical curvature	Baseline, week 12-15
Morphometric MRI parameters change from baseline during the 12-week period after the administration of Fremanezumab 2.	Cortical thickness	Baseline, week 12-15
Morphometric MRI parameters change from baseline during the 12-week period after the administration of Fremanezumab 3.	Gray matter volume	Baseline, week 12-15
Morphometric MRI parameters change from baseline during the 12-week period after the administration of Fremanezumab 4.	Surface area,	Baseline, week 12-15
Diffusion MRI descriptors change from baseline during the 12-week period after the administration of Fremanezumab 1.	Fractional anisotropy	Baseline, week 12-15
Diffusion MRI descriptors change from baseline during the 12-week period after the administration of Fremanezumab 2.	Mean diffusivity	Baseline, week 12-15
Diffusion MRI descriptors change from baseline during the 12-week period after the administration of Fremanezumab 3.	Radial diffusivity	Baseline, week 12-15
Diffusion MRI descriptors change from baseline during the 12-week period after the administration of Fremanezumab 4.	Axial diffusivity	Baseline, week 12-15
Structural connectivity change from baseline during the 12-week period after the administration of Fremanezumab 1.	Number of streamlines in the connection between two regions	Baseline, week 12-15
Structural connectivity change from baseline during the 12-week period after the administration of Fremanezumab 2.	Mean fractional anisotropy in the connection between two regions	Baseline, week 12-15
Structural connectivity change from baseline during the 12-week period after the administration of Fremanezumab 3.	Mean axial diffusivity in the connection between two regions	Baseline, week 12-15
Resting-state functional connectivity change from baseline during the 12-week period after the administration of Fremanezumab.	Z-score	Baseline, week 12-15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relationship between morphometric MRI parameters and the change in monthly migraine days 1.	Cortical curvature	Baseline, week 12-15
Relationship between morphometric MRI parameters and the change in monthly migraine days 2.	Cortical thickness	Baseline, week 12-15
Relationship between morphometric MRI parameters and the change in monthly migraine days 3.	Gray matter volume	Baseline, week 12-15
Relationship between morphometric MRI parameters and the change in monthly migraine days 4.	Surface area.	Baseline, week 12-15
Relationship between diffusion descriptors and the change in monthly migraine days 1.	Fractional anisotropy	Baseline, week 12-15
Relationship between diffusion descriptors and the change in monthly migraine days 2.	Mean diffusivity	Baseline, week 12-15
Relationship between diffusion descriptors and the change in monthly migraine days 3.	Radial diffusivity	Baseline, week 12-15
Relationship between diffusion descriptors and the change in monthly migraine days 4.	Axial diffusivity.	Baseline, week 12-15
Relationship between structural connectivity and the change in monthly migraine days 1. [Time Frame: baseline, week 12]	Number of streamlines in the connection between two regions.	Baseline, week 12-15
Relationship between structural connectivity and the change in monthly migraine days 2. [Time Frame: baseline, week 12]	Mean fractional anisotropy in the connection between two regions.	Baseline, week 12-15
Relationship between structural connectivity and the change in monthly migraine days 3. [Time Frame: baseline, week 12]	Mean axial diffusivity in the connection between two regions.	Baseline, week 12-15
Relationship between resting-state functional connectivity and the change in monthly migraine days. [Time Frame: baseline, week 12]	Z-score	Baseline, week 12-15
Baseline morphometric MRI parameters will be assessed as potential predictors of change in monthly migraine days 1.	Cortical curvature	Baseline
Baseline morphometric MRI parameters will be assessed as potential predictors of change in monthly migraine days 2.	Cortical thickness	Baseline
Baseline morphometric MRI parameters will be assessed as potential predictors of change in monthly migraine days 3.	Gray matter volume	Baseline
Baseline morphometric MRI parameters will be assessed as potential predictors of change in monthly migraine days 4.	Surface area.	Baseline
Baseline diffusion MRI descriptors will be assessed as potential predictors of change in monthly migraine headache days 1.	Fractional anisotropy	Baseline
Baseline diffusion MRI descriptors will be assessed as potential predictors of change in monthly migraine headache days 2.	Mean diffusivity	Baseline
Baseline diffusion MRI descriptors will be assessed as potential predictors of change in monthly migraine headache days 3.	Radial diffusivity	Baseline
Baseline diffusion MRI descriptors will be assessed as potential predictors of change in monthly migraine headache days 4.	Axial diffusivity.	Baseline
Baseline structural connectivity will be assessed as potential predictors of change in monthly migraine days.	Number of streamlines in the connection between two regions.	Baseline
Baseline resting-state functional connectivity will be assessed as potential predictors of change in monthly migraine days	Z-score	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relationship between morphometric MRI parameters and the change in monthly intense headache days 1.	Cortical curvature	Baseline, week 12-15
Relationship between morphometric MRI parameters and the change in monthly intense headache days 2.	Cortical thickness	Baseline, week 12-15
Relationship between morphometric MRI parameters and the change in monthly intense headache days 3.	Gray matter volume	Baseline, week 12-15
Relationship between morphometric MRI parameters and the change in monthly intense headache days 4.	Surface area,	Baseline, week 12-15
Difference between clinical response groups in the morphometric parameters, diffusion descriptors, structural connectivity and resting-state functional connectivity	Clinical response assessed as reduction by at least 30%, 50% and 100% reduction in monthly migraine days in the last month compared to baseline.	Baseline, week 12-15

Collaborators and Investigators

• Sponsor: Hospital Clínico Universitario de Valladolid
• Collaborators: University of Valladolid; Complejo Asistencial Universitario de Palencia; Complejo Público Asistencial de Zamora
• Investigators: Principal Investigator: Angel L Guerrero Peral, MD, PhD, Sanidad de Castilla y León

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Helpful Links

• Aja-Fernández S, de Luis-García R, Afzali M, Molendowska M, Pieciak T, Tristán-Vega A. Microstructure Diffusion Scalar Measures from Reduced MRI Acquisitions. bioRxiv. 2019. (accessed 2 November 2019)

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2023
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: December 24, 2022
• First Submitted That Met QC Criteria: January 29, 2024
• First Posted (Actual): February 6, 2024

Study Record Updates

• Last Update Posted (Actual): February 6, 2024
• Last Update Submitted That Met QC Criteria: January 29, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Treatment outcomes; Preventive treatment; Brain functional changes; Brain structural changes
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Brain Diseases; Migraine Disorders; Migraine without Aura; Migraine with Aura
• Other Study ID Numbers: CASVE 20-469; 2020-004509-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized data may be shared upon reasonable request to the principal investigator.
• IPD Sharing Time Frame: Up to 5 years after the publication of the study.
• IPD Sharing Access Criteria: Upon request to the corresponding study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

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