MigraineCHRONOpSNCT07681466
Chronology and Sequence of Premonitory Symptoms
An observational study of Migraine, run by University of Roma La Sapienza at 1 site in Italy.
Trial summary
The purpose of this study is to prospectively investigate the temporal sequence of premonitory symptoms across multiple migraine attacks. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Migraine
- How many people
- 500 participants
- Where
- 1 siteItaly
- Study dates
- 17 Mar 2026to Sep 2027
- How long will I take part?
- 6 Months
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
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 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Prospective, longitudinal, multicentric study on patients with migraine attending the outpatient clinic of Italian Headache centres who will meet the inclusion and exclusion criteria.
Who may be able to join
- Diagnosis of episodic (EM) or chronic migraine (CM) or CM with medication overuse headache (MOH) according to ICHD-III criteria;
- Age between 18 and 65 years;
- At least 2 migraine days (MMD) in the month preceding the inclusion;
- Migraine history of at least 12 months prior to inclusion
- Signed written informed consent.
Who cannot join
- History or current diagnosis of secondary headache disorders as defined by ICHD-III;
- History of other neurological comorbidities or major psychiatric disorders;
- History of migraine for < 12 months prior to the inclusion;
- Opioid overuse according to the ICHD-III criteria;
- Pregnancy or breastfeeding.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site, 1 recruiting
- Recruiting
Sapienza University of Rome, Polo Pontino, centro cefalee, ICOT
Latina, Italy, 04100
Gabriele Sebastianelli, MD, +393926337082, gabriele.sebastianelli@uniroma1.it
Gianluca Coppola, MD, PhD, Prof., +393396066924, gianluca.coppola@uniroma1.it
About this study
Official title: Chronology and Sequence of Premonitory Symptoms to Understand How Migraine Attack Starts: the CHRONOpS Study
The purpose of this study is to prospectively investigate the temporal sequence of premonitory symptoms across multiple migraine attacks.
Read the detailed description
The premonitory phase marks the transition from the interictal to the headache phase and is considered the beginning of the migraine attack. During this phase, changes in brain activity and network connectivity give rise to non-headache symptoms (premonitory symptoms) that precede pain.
Premonitory symptoms (PSs) are reported by a substantial proportion of individuals with migraine, with prevalence estimates ranging widely across studies, from approximately 29% in population-based to 66% in clinic-based settings, a variability largely dependent on the method of assessment. Although neuroimaging studies have consistently shown hypothalamic activation during the premonitory phase, activation of other areas may also be observed. However, neuroimaging studies have been mostly limited by their reliance on time-based criteria to define the premonitory phase and by insufficient temporal resolution to capture the sequential activation of brain regions within the same phase.
To date, the temporal sequence of events at migraine onset remains unknown and clinical evaluation of symptoms remains the most reliable approach to reconstructing the sequence of events underlying migraine initiation. Recent evidence supports the efficacy of treating the migraine attack during the prodrome. However, the lack of prospective data on the temporal ordering of premonitory symptoms represents a critical gap.
This study will prospectively investigate the temporal sequence of premonitory symptoms across multiple migraine attacks, addressing a critical gap in our understanding of early attack dynamics. By identifying consistent early symptoms and their progression, we aim to define clinically actionable windows for early intervention and provide indirect insight into the sequence of brain network activation underlying migraine onset.
PSs will be collected prospectively. Participants will record premonitory symptoms using a structured electronic diary across a maximum of 5 migraine attacks. They will be instructed to complete the diary at headache onset as early as possible, with timestamped entries to minimise recall bias. Data will be collected using an ad hoc electronic diary developed on the REDCap platform and a standardised case report form (CRF). The diary will collect information on the type, sequence, onset, and duration of PSs experienced before the pain phase.
- Conditions
- Migraine
- Keywords
- premonitory symptoms, sequence, hypothalamus, chronology, disability
- Medical subject headings
- Migraine Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| patients with migraine | episodic migraine or chronic migraine or migraine with aura |
What is being measured
The primary outcome is the main question the study is designed to answer.
Frequency of each symptom as the first premonitory symptom
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each premonitory symptom, the percentage of recorded attacks in which it was reported as the first symptom of the premonitory phase. Symptoms are recorded at headache onset for each attack via a structured electronic diary, capturing the type, sequence, onset, and duration of symptoms preceding the pain phase. The denominator is the number of recorded attacks with a premonitory phase.
Measured: Up to 6 months
Secondary outcomes (7)
Time from onset of each premonitory symptom to headache onset (categorical intervals)
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each premonitory symptom, the time of onset relative to headache onset, classified into predefined intervals: simultaneous with pain onset; less than 1 hour before; 1 to 2 hours before; more than 2 to 6 hours before; more than 6 to 12 hours before. Results are reported as the distribution of attacks across intervals for each symptom (percentage of recorded attacks). Onset times are recorded at headache onset for each attack via a structured electronic diary.
Measured: up to 6 months
Time from onset of each premonitory symptom to headache onset (minutes)
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each premonitory symptom, the time interval in minutes between its onset and headache onset, recorded for each attack via a structured electronic diary. Results are summarised per symptom (e.g., median minutes before headache onset).
Measured: Up to 6 months
Intra-subject consistency of premonitory symptoms across attacks
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. The degree of within-subject agreement in the presence and chronology of premonitory symptoms across multiple attacks of the same participant, recorded via a structured electronic diary. Agreement is summarised per participant and reported across the sample (e.g., concordance in symptom presence and chronology).
Measured: Up to 6 months
Evolution and persistence of premonitory symptoms during the headache phase
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each premonitory symptom, the evolution and persistence after headache onset, recorded via a structured electronic diary.
Measured: Up to 6 months
Patient-level agreement between clinically reported and prospectively recorded presence of premonitory symptoms
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. At the patient level, the agreement between whether participants report experiencing premonitory symptoms during clinical assessment (baseline) and whether they actually record premonitory symptoms during prospectively monitored attacks.
Measured: Up to 6 months
Symptom-level concordance between baseline-reported and attack-recorded premonitory symptoms
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. The degree of agreement between premonitory symptoms reported by the participant at baseline and those recorded prospectively at the time of the attack via a structured electronic diary.
Measured: Up to 6 months
Premonitory-phase disability and the symptom responsible
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each attack, (i) whether the premonitory phase caused a reduction in the participant's usual activities (presence or absence of premonitory-phase disability), and (ii) where disability was present, which premonitory symptom the participant identified as primarily responsible for it.
Measured: Up to 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jul 2026
- Study start17 Mar 2026
- Primary completionMar 2027 (estimated)
- Study completionSep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for MigraineStudies of the same condition, open and under way.
- More trials run by University of Roma La SapienzaThe sponsor's other registered studies.
- 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
- Cohort
- Time perspective
- Prospective
- Enrolment
- 500 participants (estimated)
- Target duration
- 6 Months
Sponsor and investigators
- Lead sponsor
- University of Roma La Sapienza
- Sponsor type
- University, hospital or other
- Collaborators
- IRCCS National Neurological Institute "C. Mondino" Foundation, University of Modena and Reggio Emilia, University of Bari, Campus Bio-Medico University, Azienda Ospedaliera Universitaria Mater Domini, Catanzaro, Azienda USL Ferrara, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Azienda Ospedaliero Universitaria Policlinico Modena, ULSS6 - Ospedale di Piove di Sacco, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Cliniche Humanitas Gavazzeni, Carlo Besta Neurological Institute, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
- Responsible party
- Principal investigator, Gabriele Sebastianelli, University of Roma La Sapienza
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07681466
- Sponsor's protocol ID
- CHRONO-PS-26
- Acronym
- CHRONOpS
- Status last verified
- Jun 2026
- First submitted
- 20 Jun 2026
- Last updated
- 2 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Dodick DW, Goadsby PJ, Schwedt TJ, Lipton RB, Liu C, Lu K, Yu SY, Severt L, Finnegan M, Trugman JM. Ubrogepant for the treatment of migraine attacks during the prodrome: a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial in the USA. Lancet. 2023 Dec 16;402(10419):2307-2316. doi: 10.1016/S0140-6736(23)01683-5. Epub 2023 Nov 15.
PubMed 37979595Messina R, Rocca MA, Goadsby PJ, Filippi M. Insights into migraine attacks from neuroimaging. Lancet Neurol. 2023 Sep;22(9):834-846. doi: 10.1016/S1474-4422(23)00152-7. Epub 2023 Jul 18.
PubMed 37478888Karsan N, Goadsby PJ. Neuroimaging in the pre-ictal or premonitory phase of migraine: a narrative review. J Headache Pain. 2023 Aug 11;24(1):106. doi: 10.1186/s10194-023-01617-x.
PubMed 37563570Eigenbrodt AK, Christensen RH, Ashina H, Iljazi A, Christensen CE, Steiner TJ, Lipton RB, Ashina M. Premonitory symptoms in migraine: a systematic review and meta-analysis of observational studies reporting prevalence or relative frequency. J Headache Pain. 2022 Nov 12;23(1):140. doi: 10.1186/s10194-022-01510-z.
PubMed 36371152Sebastianelli G, Atalar AC, Cetta I, Farham F, Fitzek M, Karatas-Kursun H, Kholodova M, Kukumagi KH, Montisano DA, Onan D, Pantovic A, Skarlet J, Sotnikov D, Caronna E, Pozo-Rosich P; International Headache Academy of the International Headache Society (IHS-iHEAD). Insights from triggers and prodromal symptoms on how migraine attacks start: The threshold hypothesis. Cephalalgia. 2024 Oct;44(10):3331024241287224. doi: 10.1177/03331024241287224.
PubMed 39380339
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Chronology and Sequence of Premonitory Symptoms to Understand How Migraine Attack Starts: the CHRONOpS Study
- ClinicalTrials.gov ID
- NCT07681466
- Acronym / sponsor ID
- CHRONOpS / CHRONO-PS-26
- Conditions
- Migraine
- Keywords
- premonitory symptoms, sequence, hypothalamus, chronology, disability
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 500 participants (estimated)
- Lead sponsor
- University of Roma La SapienzaUniversity, hospital or other
- Collaborators
- IRCCS National Neurological Institute "C. Mondino" Foundation, University of Modena and Reggio Emilia, University of Bari, Campus Bio-Medico University, Azienda Ospedaliera Universitaria Mater Domini, Catanzaro, Azienda USL Ferrara, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Azienda Ospedaliero Universitaria Policlinico Modena, ULSS6 - Ospedale di Piove di Sacco, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Cliniche Humanitas Gavazzeni, Carlo Besta Neurological Institute, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
- Study start
- 17 Mar 2026 (actual)
- Primary completion
- Mar 2027 (estimated)
- Study completion
- Sep 2027 (estimated)
- First posted
- 2 Jul 2026 (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 purpose of this study is to prospectively investigate the temporal sequence of premonitory symptoms across multiple migraine attacks.
Detailed description
The premonitory phase marks the transition from the interictal to the headache phase and is considered the beginning of the migraine attack. During this phase, changes in brain activity and network connectivity give rise to non-headache symptoms (premonitory symptoms) that precede pain.
Premonitory symptoms (PSs) are reported by a substantial proportion of individuals with migraine, with prevalence estimates ranging widely across studies, from approximately 29% in population-based to 66% in clinic-based settings, a variability largely dependent on the method of assessment. Although neuroimaging studies have consistently shown hypothalamic activation during the premonitory phase, activation of other areas may also be observed. However, neuroimaging studies have been mostly limited by their reliance on time-based criteria to define the premonitory phase and by insufficient temporal resolution to capture the sequential activation of brain regions within the same phase.
To date, the temporal sequence of events at migraine onset remains unknown and clinical evaluation of symptoms remains the most reliable approach to reconstructing the sequence of events underlying migraine initiation. Recent evidence supports the efficacy of treating the migraine attack during the prodrome. However, the lack of prospective data on the temporal ordering of premonitory symptoms represents a critical gap.
This study will prospectively investigate the temporal sequence of premonitory symptoms across multiple migraine attacks, addressing a critical gap in our understanding of early attack dynamics. By identifying consistent early symptoms and their progression, we aim to define clinically actionable windows for early intervention and provide indirect insight into the sequence of brain network activation underlying migraine onset.
PSs will be collected prospectively. Participants will record premonitory symptoms using a structured electronic diary across a maximum of 5 migraine attacks. They will be instructed to complete the diary at headache onset as early as possible, with timestamped entries to minimise recall bias. Data will be collected using an ad hoc electronic diary developed on the REDCap platform and a standardised case report form (CRF). The diary will collect information on the type, sequence, onset, and duration of PSs experienced before the pain phase.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 6 Months
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| patients with migraine | – | –episodic migraine or chronic migraine or migraine with aura |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Prospective, longitudinal, multicentric study on patients with migraine attending the outpatient clinic of Italian Headache centres who will meet the inclusion and exclusion criteria.
Key inclusion criteria (5 listed)
- Diagnosis of episodic (EM) or chronic migraine (CM) or CM with medication overuse headache (MOH) according to ICHD-III criteria;
- Age between 18 and 65 years;
- At least 2 migraine days (MMD) in the month preceding the inclusion;
- Migraine history of at least 12 months prior to inclusion
- Signed written informed consent.
Key exclusion criteria (5 listed)
- History or current diagnosis of secondary headache disorders as defined by ICHD-III;
- History of other neurological comorbidities or major psychiatric disorders;
- History of migraine for < 12 months prior to the inclusion;
- Opioid overuse according to the ICHD-III criteria;
- Pregnancy or breastfeeding.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Frequency of each symptom as the first premonitory symptom
Time frame: Up to 6 months
Premonitory symptoms will be recorded at the beginning of each migraine attack for a maximum of 5 migraine attacks per participant. For each premonitory symptom, the percentage of recorded attacks in which it was reported as the first symptom of the premonitory phase. Symptoms are recorded at headache onset for each attack via a structured electronic diary, capturing the type, sequence, onset, and duration of symptoms preceding the pain phase. The denominator is the number of recorded attacks with a premonitory phase.
7 secondary outcomes
Time from onset of each premonitory symptom to headache onset (categorical intervals)
Time frame: up to 6 months
Time from onset of each premonitory symptom to headache onset (minutes)
Time frame: Up to 6 months
Intra-subject consistency of premonitory symptoms across attacks
Time frame: Up to 6 months
Evolution and persistence of premonitory symptoms during the headache phase
Time frame: Up to 6 months
Patient-level agreement between clinically reported and prospectively recorded presence of premonitory symptoms
Time frame: Up to 6 months
Symptom-level concordance between baseline-reported and attack-recorded premonitory symptoms
Time frame: Up to 6 months
Premonitory-phase disability and the symptom responsible
Time frame: Up to 6 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2026.
- Background: PubMed 37979595Dodick DW, Goadsby PJ, Schwedt TJ, Lipton RB, Liu C, Lu K, Yu SY, Severt L, Finnegan M, Trugman JM. Ubrogepant for the treatment of migraine attacks during the prodrome: a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial in the USA. Lancet. 2023 Dec 16;402(10419):2307-2316. doi: 10.1016/S0140-6736(23)01683-5. Epub 2023 Nov 15.
- Background: PubMed 37478888Messina R, Rocca MA, Goadsby PJ, Filippi M. Insights into migraine attacks from neuroimaging. Lancet Neurol. 2023 Sep;22(9):834-846. doi: 10.1016/S1474-4422(23)00152-7. Epub 2023 Jul 18.
- Background: PubMed 37563570Karsan N, Goadsby PJ. Neuroimaging in the pre-ictal or premonitory phase of migraine: a narrative review. J Headache Pain. 2023 Aug 11;24(1):106. doi: 10.1186/s10194-023-01617-x.
- Background: PubMed 36371152Eigenbrodt AK, Christensen RH, Ashina H, Iljazi A, Christensen CE, Steiner TJ, Lipton RB, Ashina M. Premonitory symptoms in migraine: a systematic review and meta-analysis of observational studies reporting prevalence or relative frequency. J Headache Pain. 2022 Nov 12;23(1):140. doi: 10.1186/s10194-022-01510-z.
- Background: PubMed 39380339Sebastianelli G, Atalar AC, Cetta I, Farham F, Fitzek M, Karatas-Kursun H, Kholodova M, Kukumagi KH, Montisano DA, Onan D, Pantovic A, Skarlet J, Sotnikov D, Caronna E, Pozo-Rosich P; International Headache Academy of the International Headache Society (IHS-iHEAD). Insights from triggers and prodromal symptoms on how migraine attacks start: The threshold hypothesis. Cephalalgia. 2024 Oct;44(10):3331024241287224. doi: 10.1177/03331024241287224.
- Individual participant dataSharing planned: Undecided
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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.
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, run by University of Roma La Sapienza 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 5 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: looking for participants now, as of the sponsor's last update on 2 Jul 2026. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Gabriele Sebastianelli, MD (+393926337082, gabriele.sebastianelli@uniroma1.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Frequency of each symptom as the first premonitory symptom (time frame: Up to 6 months). 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 NCT07681466, which also lists 5 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 2 Jul 2026.