Migraine DisordersSPHERA_WP1_2NCT06562413
Searching for Novel Biological Phenotypes in Migraine Patients Resistant to Treatments
An observational study of Migraine Disorders and Chronic Migraine, run by IRCCS National Neurological Institute "C. Mondino" Foundation at 1 site in Italy.
Trial summary
The investigators aim to define the neurofunctional phenotype of migraine patients who did not respond to at least 3 preventive treatments, including monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) pathway (NON-responders). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Migraine Disorders, Chronic Migraine, Episodic Migraine
- What is being tested?
- MAbs
- How many people
- 100 participants
- Where
- 1 siteItaly
- Study dates
- 10 May 2023to May 2026
- How long will I take part?
- 6 Months
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- Adult, Older adult
Study population: Subjects with chronic and high frequency episodic migraine attending the outpatient clinic of the Headache Science \& Neurorehabilitation Unit of the IRCCS Mondino Foundation (Pavia, Italy) and the Neurology Department of the University of L'Aquila (Avezzano, Italy).
Who may be able to join
- male and female patients aged 18 to 75 years
- diagnosis of episodic migraine or chronic migraine according to ICHD-3 criteria
- for episodic migraine: 8-14 monthly migraine days in the previous 3 months
- diagnosis of resistant migraine, defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating monthly headache days for at least 3 consecutive months
- patients naive to CGRP targeting treatments
Who cannot join
- history of major psychiatric or other neurological conditions
- diagnosis of other primary or secondary headache disorders (only sporadic tension-type headache is allowed if the patients can clearly differentiate between the 2 types of headaches)
- changes in ongoing preventive treatment (if any) in the previous 3 months
- clinically significant medical conditions
- chronic pain conditions
- alcohol and/or drug abuse
- pregnancy or lactation
Trial locations and contacts
1 site in 1 country.
Italy1 site, 1 recruiting
- Recruiting
Headache Science & Neurorehabilitation Unit
Pavia, 27100
Roberto De Icco, Prof, 00382380425, roberto.deicco@mondino.it
About this study
Official title: Unraveling the Spectrum of Migraine Resistant to Treatments: Searching for Novel Biological PHEnotypes and theRApeutic Approaches (SPHERA Project)
The investigators aim to define the neurofunctional phenotype of migraine patients who did not respond to at least 3 preventive treatments, including monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) pathway (NON-responders).
Primary aim will be to assess and compare changes in functional resting-state connectivity at baseline and after three months of mAbs treatment between patients who will achieve a reduction of monthly migraine days >/= than 50% (namely Responders) and those who will not (namely Responders).
The 2 groups will undergo a neurofunctional profile by means of High Density-electroencephalogram (HD-EEG) and functional-magnetic resonance imaging (fMRI).
Read the detailed description
High Density-electroencephalogram (HD-EEG) and functional-magnetic resonance imaging (fMRI) are widely available as powerful means to non-invasively study brain connectivity features in migraine patients.
They both enables to record brain activity with high spatial resolution. HD-EEG also contributes to high temporal resolution, while fMRI contributes to precise evaluation of deep cortical and subcortical areas, relevant in migraine pathophysiology.
Aim of the study is to evaluate changes in resting-state functional connectivity in patients undergoing preventive mAbs treatment using HD- EEG and fMRI. These findings will allow the identification of a multibiomarkers panel signature of migraine patients resisting to specifically targeted preventive treatments and potentially unveiling other molecular targets for therapeutic approaches.
STUDY DESIGN:
This study is part of the SPHERA project receiving funding from the Italian Ministry of Health (GR-2021-12372429). Patients will be enrolled from those attending the outpatient clinic of IRCCS Mondino Institute (Pavia) and Neurology Department of the University of L'Aquila (Avezzano).
The investigators will collect clinical data and perform neurofunctional profiling of migraine patients at baseline (T0) and after three months of mAbs treatment (T3).
METHODS:
All patients will undergo a resting-state functional evaluation through high density-EEG and subset of 40 patients will also be studied in parallel with fMRI at baseline.
- HD-EEG: the investigators will randomly acquire 4 recordings (6 minutes each) in resting-state condition, 2 with opened eyes, and 2 with closed eyes. The investigators will consider the following frequency bands: delta (1-4 Hz), theta (4-8 Hz), alfa (8-13 Hz), beta (13-30 Hz), gamma (30-80 Hz).
Acquisition parameters will be: High-Pass: 0.5 Hz; Low-Pass: 100 Hz; Notch: 50 Hz. For analysis of HD-EEG data, the investigators will use a tailored analysis pipe-line that was previously developed and validated to reconstruct neural sources from cortical/subcortical gray matter (Semprini, 2021). EEG signals will be band-pass filtered (1-80 Hz) and down-sampled at 250 Hz. Biological artifacts will be rejected using Independent Component Analysis (ICA). EEG signals will be referenced with a customized version of the Reference Electrode Standardization Technique (REST) (Mantini, 2007). A matrix will estimate the relationship between the measured scalp potentials and the dipoles corresponding to brain sources. Sources reconstruction will be performed with the exact low-resolution brain electromagnetic tomography (eLORETA) algorithm.
- Resting state fMRI: ICA will be applied to resting state-fMRI to characterize the RSNs. For each subject and for each identified RSN, the mean functional connectivity will be calculated. A seed based component analysis will be applied in order to obtain a whole brain map to describe the strength of the connectivity of each voxel of the brain image with the region of interest (seed). The region of interests selection will be based on available literature and previous experience.
- Conditions
- Migraine Disorders, Chronic Migraine, Episodic Migraine
- Being tested
- MAbs
- Keywords
- migraine, anti CGRP mABs, calcitonin gene related peptide, HD EEG, functional MRI, brain connectivity
- Medical subject headings
- Migraine Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MAbsDrug
Also called Monoclonal antibody targeting the CGRP pathway (ligand or receptor) (mAbs)
Monthly or quarterly mAbs administration
| Study group | Role | What they receive |
|---|---|---|
| Responders | Patients with high frequency episodic or chronic migraine undergoing treatment with monoclonal antibodies directed against calcitonin gene related peptide pathway (mAbs) who obtained a reduction in monthly migraine days equal or higher than 50% compared to pre-treatment values. Receives: Drug: MAbs | |
| NON-Responders | Patients with high frequency episodic or chronic migraine undergoing mAbs treatment who obtained a reduction in monthly migraine days < 50% compared to pre-treatment values. Receives: Drug: MAbs |
What is being measured
The primary outcome is the main question the study is designed to answer.
RSN-FC assessed through HD-EEG
Resting state functional connectivity assessed through HD-EEG (continuous variable, without unit of measurement)
Measured: Baseline (T0), and three months of mAbs treatment (T1)
RSN-FC assessed through MRI
Resting state functional connectivity assessed through MRI (continuous variable, without unit of measurement)
Measured: Baseline (T0)
Secondary outcomes (2)
Comparison between baseline RSN-FC assessed through HD-EEG
Comparison between RSN-FC changes assessed through HD-EEG (continuous variable, without unit of measurement)
Measured: Baseline (T0)
Comparison between baseline RSN-FC assessed through MRI
Comparison between RSN-FC changes assessed through MRI (continuous variable, without unit of measurement)
Measured: Baseline (T0)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Aug 2024
- Study start10 May 2023
- Primary completionFeb 2026 (estimated)
- Study completionMay 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Migraine DisordersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 100 participants (estimated)
- Target duration
- 6 Months
Sponsor and investigators
- Lead sponsor
- IRCCS National Neurological Institute "C. Mondino" Foundation
- Sponsor type
- University, hospital or other
- Collaborators
- University of L'Aquila
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06562413
- Sponsor's protocol ID
- SPHERA-functional
- Acronym
- SPHERA_WP1_2
- Status last verified
- Aug 2024
- First submitted
- 8 Aug 2024
- Last updated
- 20 Aug 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Mantini D, Franciotti R, Romani GL, Pizzella V. Improving MEG source localizations: an automated method for complete artifact removal based on independent component analysis. Neuroimage. 2008 Mar 1;40(1):160-73. doi: 10.1016/j.neuroimage.2007.11.022. Epub 2007 Dec 3.
PubMed 18155928Gao W, Walther A, Wekenborg M, Penz M, Kirschbaum C. Determination of endocannabinoids and N-acylethanolamines in human hair with LC-MS/MS and their relation to symptoms of depression, burnout, and anxiety. Talanta. 2020 Sep 1;217:121006. doi: 10.1016/j.talanta.2020.121006. Epub 2020 Apr 9.
PubMed 32498885Fuertig R, Ceci A, Camus SM, Bezard E, Luippold AH, Hengerer B. LC-MS/MS-based quantification of kynurenine metabolites, tryptophan, monoamines and neopterin in plasma, cerebrospinal fluid and brain. Bioanalysis. 2016 Sep;8(18):1903-17. doi: 10.4155/bio-2016-0111. Epub 2016 Aug 15.
PubMed 27524289Curto M, Lionetto L, Negro A, Capi M, Fazio F, Giamberardino MA, Simmaco M, Nicoletti F, Martelletti P. Altered kynurenine pathway metabolites in serum of chronic migraine patients. J Headache Pain. 2015;17:47. doi: 10.1186/s10194-016-0638-5. Epub 2016 Apr 29.
PubMed 27130315Greco R, Demartini C, Zanaboni AM, Tumelero E, Icco R, Sances G, Allena M, Tassorelli C. Peripheral changes of endocannabinoid system components in episodic and chronic migraine patients: A pilot study. Cephalalgia. 2021 Feb;41(2):185-196. doi: 10.1177/0333102420949201. Epub 2020 Sep 23.
PubMed 32967434De Icco R, Greco R, Demartini C, Vergobbi P, Zanaboni A, Tumelero E, Reggiani A, Realini N, Sances G, Grillo V, Allena M, Tassorelli C. Spinal nociceptive sensitization and plasma palmitoylethanolamide levels during experimentally induced migraine attacks. Pain. 2021 Sep 1;162(9):2376-2385. doi: 10.1097/j.pain.0000000000002223.
PubMed 33587406
Study at a glance
From the registry record, last updated by the sponsor on 20 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Unraveling the Spectrum of Migraine Resistant to Treatments: Searching for Novel Biological PHEnotypes and theRApeutic Approaches (SPHERA Project)
- ClinicalTrials.gov ID
- NCT06562413
- Acronym / sponsor ID
- SPHERA_WP1_2 / SPHERA-functional
- Conditions
- Migraine Disorders, Chronic Migraine, Episodic Migraine
- Keywords
- migraine, anti CGRP mABs, calcitonin gene related peptide, HD EEG, functional MRI, brain connectivity
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- IRCCS National Neurological Institute "C. Mondino" FoundationUniversity, hospital or other
- Collaborators
- University of L'Aquila
- Study start
- 10 May 2023 (actual)
- Primary completion
- Feb 2026 (estimated)
- Study completion
- May 2026 (estimated)
- First posted
- 20 Aug 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The investigators aim to define the neurofunctional phenotype of migraine patients who did not respond to at least 3 preventive treatments, including monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) pathway (NON-responders).
Primary aim will be to assess and compare changes in functional resting-state connectivity at baseline and after three months of mAbs treatment between patients who will achieve a reduction of monthly migraine days >/= than 50% (namely Responders) and those who will not (namely Responders).
The 2 groups will undergo a neurofunctional profile by means of High Density-electroencephalogram (HD-EEG) and functional-magnetic resonance imaging (fMRI).
Detailed description
High Density-electroencephalogram (HD-EEG) and functional-magnetic resonance imaging (fMRI) are widely available as powerful means to non-invasively study brain connectivity features in migraine patients.
They both enables to record brain activity with high spatial resolution. HD-EEG also contributes to high temporal resolution, while fMRI contributes to precise evaluation of deep cortical and subcortical areas, relevant in migraine pathophysiology.
Aim of the study is to evaluate changes in resting-state functional connectivity in patients undergoing preventive mAbs treatment using HD- EEG and fMRI. These findings will allow the identification of a multibiomarkers panel signature of migraine patients resisting to specifically targeted preventive treatments and potentially unveiling other molecular targets for therapeutic approaches.
STUDY DESIGN:
This study is part of the SPHERA project receiving funding from the Italian Ministry of Health (GR-2021-12372429). Patients will be enrolled from those attending the outpatient clinic of IRCCS Mondino Institute (Pavia) and Neurology Department of the University of L'Aquila (Avezzano).
The investigators will collect clinical data and perform neurofunctional profiling of migraine patients at baseline (T0) and after three months of mAbs treatment (T3).
METHODS:
All patients will undergo a resting-state functional evaluation through high density-EEG and subset of 40 patients will also be studied in parallel with fMRI at baseline.
- HD-EEG: the investigators will randomly acquire 4 recordings (6 minutes each) in resting-state condition, 2 with opened eyes, and 2 with closed eyes. The investigators will consider the following frequency bands: delta (1-4 Hz), theta (4-8 Hz), alfa (8-13 Hz), beta (13-30 Hz), gamma (30-80 Hz).
Acquisition parameters will be: High-Pass: 0.5 Hz; Low-Pass: 100 Hz; Notch: 50 Hz. For analysis of HD-EEG data, the investigators will use a tailored analysis pipe-line that was previously developed and validated to reconstruct neural sources from cortical/subcortical gray matter (Semprini, 2021). EEG signals will be band-pass filtered (1-80 Hz) and down-sampled at 250 Hz. Biological artifacts will be rejected using Independent Component Analysis (ICA). EEG signals will be referenced with a customized version of the Reference Electrode Standardization Technique (REST) (Mantini, 2007). A matrix will estimate the relationship between the measured scalp potentials and the dipoles corresponding to brain sources. Sources reconstruction will be performed with the exact low-resolution brain electromagnetic tomography (eLORETA) algorithm.
- Resting state fMRI: ICA will be applied to resting state-fMRI to characterize the RSNs. For each subject and for each identified RSN, the mean functional connectivity will be calculated. A seed based component analysis will be applied in order to obtain a whole brain map to describe the strength of the connectivity of each voxel of the brain image with the region of interest (seed). The region of interests selection will be based on available literature and previous experience.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Target follow-up
- 6 Months
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Responders | – | Drug: MAbsPatients with high frequency episodic or chronic migraine undergoing treatment with monoclonal antibodies directed against calcitonin gene related peptide pathway (mAbs) who obtained a reduction in monthly migraine days equal or higher than 50% compared to pre-treatment values. |
| NON-Responders | – | Drug: MAbsPatients with high frequency episodic or chronic migraine undergoing mAbs treatment who obtained a reduction in monthly migraine days < 50% compared to pre-treatment values. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Age groups
- Adult, Older adult
- Study population
- Subjects with chronic and high frequency episodic migraine attending the outpatient clinic of the Headache Science \& Neurorehabilitation Unit of the IRCCS Mondino Foundation (Pavia, Italy) and the Neurology Department of the University of L'Aquila (Avezzano, Italy).
Key inclusion criteria (5 listed)
- male and female patients aged 18 to 75 years
- diagnosis of episodic migraine or chronic migraine according to ICHD-3 criteria
- for episodic migraine: 8-14 monthly migraine days in the previous 3 months
- diagnosis of resistant migraine, defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating monthly headache days for at least 3 consecutive months
- patients naive to CGRP targeting treatments
Key exclusion criteria (7 listed)
- history of major psychiatric or other neurological conditions
- diagnosis of other primary or secondary headache disorders (only sporadic tension-type headache is allowed if the patients can clearly differentiate between the 2 types of headaches)
- changes in ongoing preventive treatment (if any) in the previous 3 months
- clinically significant medical conditions
- chronic pain conditions
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MAbsAlso: Monoclonal antibody targeting the CGRP pathway (ligand or receptor) (mAbs)Monthly or quarterly mAbs administration | Drug | NON-Responders, Responders |
Primary outcome
RSN-FC assessed through HD-EEG
Time frame: Baseline (T0), and three months of mAbs treatment (T1)
Resting state functional connectivity assessed through HD-EEG (continuous variable, without unit of measurement)
RSN-FC assessed through MRI
Time frame: Baseline (T0)
Resting state functional connectivity assessed through MRI (continuous variable, without unit of measurement)
2 secondary outcomes
Comparison between baseline RSN-FC assessed through HD-EEG
Time frame: Baseline (T0)
Comparison between baseline RSN-FC assessed through MRI
Time frame: Baseline (T0)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Aug 2024.
- Background: PubMed 18155928Mantini D, Franciotti R, Romani GL, Pizzella V. Improving MEG source localizations: an automated method for complete artifact removal based on independent component analysis. Neuroimage. 2008 Mar 1;40(1):160-73. doi: 10.1016/j.neuroimage.2007.11.022. Epub 2007 Dec 3.
- Background: PubMed 32498885Gao W, Walther A, Wekenborg M, Penz M, Kirschbaum C. Determination of endocannabinoids and N-acylethanolamines in human hair with LC-MS/MS and their relation to symptoms of depression, burnout, and anxiety. Talanta. 2020 Sep 1;217:121006. doi: 10.1016/j.talanta.2020.121006. Epub 2020 Apr 9.
- Background: PubMed 27524289Fuertig R, Ceci A, Camus SM, Bezard E, Luippold AH, Hengerer B. LC-MS/MS-based quantification of kynurenine metabolites, tryptophan, monoamines and neopterin in plasma, cerebrospinal fluid and brain. Bioanalysis. 2016 Sep;8(18):1903-17. doi: 10.4155/bio-2016-0111. Epub 2016 Aug 15.
- Background: PubMed 27130315Curto M, Lionetto L, Negro A, Capi M, Fazio F, Giamberardino MA, Simmaco M, Nicoletti F, Martelletti P. Altered kynurenine pathway metabolites in serum of chronic migraine patients. J Headache Pain. 2015;17:47. doi: 10.1186/s10194-016-0638-5. Epub 2016 Apr 29.
- Background: PubMed 32967434Greco R, Demartini C, Zanaboni AM, Tumelero E, Icco R, Sances G, Allena M, Tassorelli C. Peripheral changes of endocannabinoid system components in episodic and chronic migraine patients: A pilot study. Cephalalgia. 2021 Feb;41(2):185-196. doi: 10.1177/0333102420949201. Epub 2020 Sep 23.
- Background: PubMed 33587406De Icco R, Greco R, Demartini C, Vergobbi P, Zanaboni A, Tumelero E, Reggiani A, Realini N, Sances G, Grillo V, Allena M, Tassorelli C. Spinal nociceptive sensitization and plasma palmitoylethanolamide levels during experimentally induced migraine attacks. Pain. 2021 Sep 1;162(9):2376-2385. doi: 10.1097/j.pain.0000000000002223.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Migraine Disorders and Chronic Migraine, run by IRCCS National Neurological Institute "C. Mondino" Foundation at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 20 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Roberto De Icco (00390382380425, roberto.deicco@mondino.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
RSN-FC assessed through HD-EEG (time frame: Baseline (T0), and three months of mAbs treatment (T1)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06562413, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Aug 2024.