Neurophysiological and Biomolecular Effects of Atogepant in Episodic Migraine (ATOM)

March 11, 2025 updated by: IRCCS National Neurological Institute "C. Mondino" Foundation

Neurophysiological and Biomolecular Effects of Atogepant in High Frequency Episodic Migraine (ATOM Project)

The investigators aim to assess and compare neurophysiological and biochemical changes induced by a 3-month treatment with atogepant (60 mg daily) in patients with high-frequency episodic migraine (8-14 monthly migraine days). Evaluations will include neurophysiological assessments (High-Density EEG, nociceptive reflexes, and visual evoked potentials) and biomolecular profiling (gene expression of endocannabinoid catabolizing enzymes, CGRP and PACAP plasma levels, and headache-specific microRNAs). Outputs will contribute to defining predictors of atogepant response, elucidating its effects on brain connectivity, excitability, and CGRP/endocannabinoid pathways, and identifying alternative therapeutic targets for non-responders.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

BACKGROUND:

Migraine is a highly prevalent neurological disease associated to a severe burden for patients and society. Despite recent advances, the knowledge of the molecular and biochemical pathways that turn on and off a migraine attack and lead to an increased frequency of attacks is still limited. In addition, the lack of predictors of the therapeutic response is a barrier to access to care and to a personalized approach. In recent years, several migraine-specific drugs have become available for the preventive treatment of the disease, which is aimed at reducing the frequency and the intensity of the attacks. Among the drugs currently available for migraine treatment, there are molecules that directly interfere with the calcitonin gene-related peptide (CGRP) pathway. Gepants, oral drugs that are CGRP receptor antagonists, represent a recently available pharmacological class for the acute and preventive treatment of migraines due to their specific mechanism of action.

The potential mechanism underlying the therapeutic benefit derived from drugs that block CGRP, as well as their impact on various biochemical and functional parameters associated with migraine pathophysiology, remains a topic of debate.

The objective of the ATOM project is to characterize the neurophysiological and biomolecular mechanisms underlying the therapeutic action of Atogepant (ATO), a drug belonging to the new pharmacological class of gepants. ATO has been shown to be effective in the preventive treatment of both chronic and episodic migraine. However, preventive treatment with gepants is still ineffective (reducing the number of monthly migraine days by less than 50%) in 30% of patients. This finding suggests that other biological pathways independent of CGRP may play a role in migraine pathophysiology. Among these, the endocannabinoid system has gained increasing importance over the years.

From a neurofunctional perspective, central sensitization is a significant aspect of migraine pathophysiology. Our group has demonstrated the utility of the nociceptive withdrawal reflex at the lower limb (RIII) in studying central sensitization. A subsequent study showed improvement in RIII reflex parameters in 30% of chronic migraine patients who responded to Erenumab after three months of treatment, suggesting a potential correlation between improved central sensitization and clinical benefit from anti-CGRP antibody treatment.

Additionally, migraine patients exhibit altered responses following repeated cranial stimulation, specifically a deficit in habituation to such stimuli. It has been described that the habituation pattern follows a characteristic course throughout the migraine cycle. The habituation deficit has been demonstrated through various neurophysiological methods, such as the nociceptive blink reflex (nBR) and visual evoked potentials (VEPs). These assessments provide information about the modulation of relevant stations in the trigemino-vascular system, specifically the trigemino-cervical complex and the occipital cortex.

Our study includes an evaluation of brain functional connectivity using High-Density Electroencephalography (HD-EEG). Recently, we analyzed potential variations in functional connectivity within the Resting State Network (RSN) in migraine patients undergoing six months of treatment with monoclonal antibodies targeting the CGRP pathway through serial HD-EEG evaluations (unpublished data). Our findings demonstrate that migraine patients, when compared to healthy controls, exhibit widespread hyperconnectivity in the theta and delta frequency bands, potentially attributable to dysfunction of the generators of these frequency bands, highlighting the importance of the thalamo-cortical dysrhythmia concept in migraine pathophysiology. Conversely, longitudinal comparisons revealed a trend towards normalization of connectivity in patients with a good clinical response to anti-CGRP monoclonal antibodies.

From a biochemical standpoint, our group has demonstrated that the gene expression of endocannabinoid catabolizing enzymes - fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) - is altered in peripheral cells of patients with episodic and chronic migraine and is correlated with migraine severity. Similarly, various literature evidence supports the role of microRNAs in the mechanisms underlying migraines. Elevated expression levels of miR-382-5p and miR-34a-5p, combined with lower levels of miR-30a-5p expression, have been found in migraine patients compared to healthy controls, confirming an epigenetic alteration. In a previous study, we reported that peripheral levels of miR-382-5p and miR-34a-5p in migraine patients were correlated with disease severity, as they were increased in patients with chronic migraine and medication-overuse headache (CM-MOH) compared to episodic migraine (EM) patients, suggesting involvement in chronicization, while not excluding an influence of pharmacological migraine treatments . Elevated levels of miR-155, a microRNA known to modulate inflammation, have been found in peripheral cells of both EM and CM-MOH patients compared to healthy controls, with higher levels in chronic patients.

The overarching aim of this project is the identification of specific neurophysiological and biomolecular signatures that differentiate subjects with migraine who benefit or do not benefit from atogepant treatment. This aim will be achieved via a thorough neurophysiological and biochemical profiling of subjects with high frequency episodic migraine treated with atogepant 60 mg for a period of 3 months.

STUDY DESIGN:

Patients will be enrolled from those attending the outpatient clinic of IRCCS Mondino Institute (Pavia). The investigators will enroll 30 patients with high-frequency episodic migraine (8-14 monthly migraine days) with clinical indications to start atogepant (ATO - 60 mg daily) according to the Italian regulations.

The investigators will collect clinical data and perform biochemical and neurofunctional profiling of migraine patients at baseline (T0) and after three months of atogepant treatment (T1).

METHODS: All patients will undergo at T0 and T1:

  1. Biochemical profiling that will include analysis of:

    • eCBome system: FAAH, MAGL mRNA in PBMCs;
    • plasma levels of CGRP, PACAP, and VIP;
    • miR-382-5p, miR-34a and miR-155 in PBMCs. The investigators will collect biochemical sampling between 9 and 11 a.m. to avoid circadian rhythm influence. All evaluation will be performed in the interictal phase.

    The following collection methods will be adopted: • mRNA and microRNA analysis in PBMCs. Blood samples will be collected within ethylenediamine tetra-acetic acid tubes, the investigators will first isolate PBMCs and total RNA. Ubiquitin C and U6 will act as housekeeping genes for genes coding for the eCBome enzymes and miRNAs. • CGRP alpha, PACAP-38 and VIP levels will be measured using a commercial enzyme linked immunosorbent assay.

  2. Neurofunctional profiling that will include:

    • recording of the Nociceptive Withdrawal Reflex (RIII);
    • recording of the nociceptive Blink Reflex (nBR);
    • recording of High-Density EEG (HD-EEG);
    • recording of Visual Evoked Potentials (VEP). The following methods will be adopted: - Nociceptive Withdrawal Reflex (RIII reflex): The sural nerve will be stimulated via surface electrodes behind the right lateral malleolus. Reflex threshold (≥20 μV, >10 msec) will be determined using the ladder method. Temporal summation threshold (TST) will be assessed by increasing stimulus intensity (5 stimuli at 2 Hz) until facilitation of the reflex response appears. (De Icco et al., 2020).- Nociceptive Blink Reflex (nBR): nBR R2 response will be recorded using a concentric electrode above the supraorbital nerve and surface electrodes at the orbicularis oculi muscle. Habituation will be evaluated with 25 stimuli at varying frequencies, with area under the curve (AUC) calculated for 5 averaged blocks. Habituation index (HI) will reflect percentage change in AUC from the last to the first block. (Perrotta et al., 2017). - Visual Evoked Potentials (VEP) recording: VEP will be recorded during monocular stimulation using black-and-white checkered patterns. Components (N70, P100, N145) will be analyzed, and habituation will be defined as the percentage change in P100 amplitude between the last and first block. (Ambrosini et al., 2017). High Density Electroencephalography recording (HD-EEG): Recordings (128 channels, high-pass: 0.5 Hz, low-pass: 100 Hz) will include four 6-minute resting-state sessions (2 with eyes open, 2 with eyes closed). Frequency bands (delta to gamma) will be analyzed using a validated custom pipeline to reconstruct cortical/subcortical neural sources.

STATISTICAL ANALYSIS: Sample size calculation was performed for the primary outcome of ATOM project (namely compare the TST threshold of the RIII reflex between T0 and T1. From previous papers, preliminary data and experience of our research group, an expected difference between the means at T0 and T1 of 2 mA is inferred, with a standard deviation of 4 mA for both measurements. The comparison will be made by t test for paired data or corresponding nonparametric test (Wilcoxon Signed Rank Test), after performing a preliminary test on the normality of the data (Shapiro test). The investigators will consider a test power of β=0.8 and a 95% confidence. The suggested sample size is n=30. Regarding the co-primary outcome (Aim 2 - gene expression of MAGLs in PBMCs) a power analysis was performed, considering a significant difference between T0 and T1 of 5 RQ (standard deviation 4 and 10 respectively). Assuming a sample size of 30, the expected power is more than 80%.

Study Type

Observational

Enrollment (Estimated)

30

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Pavia, Italy, 27100
        • Recruiting
        • Headache Science & Neurorehabilitation Center
        • Contact:
        • Contact:
        • Contact:
          • Francescantonio Cammarota, MD
        • Contact:
          • Roberto De Icco, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

Subjects with high frequency episodic migraine attending the outpatient clinic of the Headache Science & Neurorehabilitation Center of the IRCCS Mondino Foundation (Pavia, Italy).

Description

Inclusion Criteria:

  • Individuals aged between 18 and 70;
  • Diagnosis of episodic migraine according to ICHD-3 criteria;
  • Monthly migraine days between 8 and 14 (high-frequency episodic migraine pattern) in the 3 months before screening;
  • Individuals naïve to CGRP-targeted treatments;
  • No more than one ongoing migraine preventive treatment with a stable dose for at least 3 months.

Exclusion Criteria:

  • Contraindications to atogepant;
  • History of serious psychiatric conditions;
  • Diagnosis of other primary or secondary headaches (only sporadic tension-type headache is allowed);
  • Medical conditions considered clinically significant by the investigator;
  • Chronic pain conditions that need chronic treatment;
  • Abuse of alcohol and/or drugs;
  • Pregnancy or breastfeeding.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
HFEM group
High-frequency episodic migraine patients (8-14 migraine days per months) undergoing atogepant 60 mg daily for 3 months
Drug: Atogepant 60 mg
Atogepant 60 mg daily for 3 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Temporal summation threshold of the RIII reflex (continuos variable)
Time Frame: Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Temporal summation threshold of the RIII reflex will be used to assess central sensitization after 3 months of treatment with atogepant 60 mg/day compared to baseline.
Baseline (T0) - three months of atogepant 60 mg treatment (T1)
MAGL gene expression (continuos variable)
Time Frame: Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Changes in MAGL gene expression after 3 months of treatment with atogepant 60 mg/day
Baseline (T0) - three months of atogepant 60 mg treatment (T1)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Habituation index of the nociceptive Blink Reflex (continuous variable)
Time Frame: Baseline (T0) - three months of atogepant 60 mg treatment (T1)
"Habituation index" of the nociceptive Blink Reflex will be used to evaluate difference in brainstem habituation after three months of treatment with atogepant 60mg.
Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Habituation of the visual evoked potential (continuous variable)
Time Frame: Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Habituation of the visual evoked potential, assessed through P100 amplitude between the last and first block, will be used to assess changes in cortical habituation after three months of atogepant
Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Functional brain connectivity (continuous variable)
Time Frame: Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Changes in functional brain connectivity, assessed through HD-EEG after 3 months of treatment with atogepant 60 mg/day.
Baseline (T0) - three months of atogepant 60 mg treatment (T1)
FAAH gene expression (continuous variable)
Time Frame: Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Changes in FAAH gene expression after 3 months of treatment with atogepant 60 mg/day.
Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Plasma levels of CGRP (continuous variable)
Time Frame: Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Changes in plasma levels of CGRP after 3 months of treatment with atogepant 60 mg/day.
Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Plasma levels of PACAP (continuous variable)
Time Frame: Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Changes in plasma levels of PACAP after 3 months of treatment with atogepant 60 mg/day.
Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Gene expression of miR-382-5p, miR-34a-5p, and miR-155 (continuous variables)
Time Frame: Baseline (T0) - three months of atogepant 60 mg treatment (T1)
Changes in the gene expression of miR-382-5p, miR-34a-5p, and miR-155 after 3 months of treatment with atogepant 60 mg/day at the level of peripheral polymorphonuclear cells (PBMCs).
Baseline (T0) - three months of atogepant 60 mg treatment (T1)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS National Neurological Institute "C. Mondino" Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2024

Primary Completion (Estimated)

December 1, 2025

Study Completion (Estimated)

April 1, 2026

Study Registration Dates

First Submitted

March 11, 2025

First Submitted That Met QC Criteria

March 11, 2025

First Posted (Actual)

March 25, 2025

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

March 11, 2025

Last Verified

March 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ATOM (Radius Health, Inc.)

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

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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