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NCT Number: NCT07681466

Chronology and Sequence of Premonitory Symptoms

The purpose of this study is to prospectively investigate the temporal sequence of premonitory symptoms across multiple migraine attacks.

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Key information

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Sapienza University of Rome, Polo Pontino, centro cefalee, ICOT

Latina, Italy, 04100

Location status: Recruiting

Location contact

Gabriele Sebastianelli, MD

CONTACT

[email protected]

+393926337082

Gabriele Sebastianelli, MD

SUB_INVESTIGATOR

Gianluca Coppola, MD, PhD, Prof.

CONTACT

[email protected]

+393396066924

Gianluca Coppola, MD, PhD, Prof.

PRINCIPAL_INVESTIGATOR

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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.

Exclusion criteria

  • 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.

Treatment and study plan

Primary outcomes

  1. 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.

Secondary outcomes

  1. Time from onset of each premonitory symptom to headache onset (categorical intervals)

    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 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.

  2. Time from onset of each premonitory symptom to headache onset (minutes)

    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 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).

  3. Intra-subject consistency of premonitory symptoms across attacks

    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. 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).

  4. Evolution and persistence of premonitory symptoms during the headache phase

    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 evolution and persistence after headache onset, recorded via a structured electronic diary.

  5. Patient-level agreement between clinically reported and prospectively recorded presence of premonitory symptoms

    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. 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.

  6. Symptom-level concordance between baseline-reported and attack-recorded premonitory symptoms

    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. 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.

  7. Premonitory-phase disability and the symptom responsible

    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 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.

Other outcomes

  1. Patterns of premonitory symptom transition and clustering

    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. Identification of recurrent patterns in the transition between premonitory symptoms and in their co-occurrence (clustering), across all recorded attacks. Symptom sequences are recorded via a structured electronic diary and analysed using sequence analysis and probabilistic modelling approaches (e.g., transition probabilities between symptoms and identification of symptom clusters).

Study contacts

Contact information is provided by the study sponsor or research team.

Gabriele Sebastianelli, MD

CONTACT

[email protected]

+393926337082

Sponsors and collaborators

Lead sponsor

University of Roma La Sapienza

Other

Collaborators

  • Azienda Ospedaliera Universitaria Mater Domini, Catanzaro
  • Azienda Ospedaliero Universitaria Policlinico Modena
  • Azienda Ospedaliero-Universitaria Careggi
  • Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari
  • Azienda USL Ferrara
  • Campus Bio-Medico University
  • Carlo Besta Neurological Institute
  • Cliniche Humanitas Gavazzeni
  • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • IRCCS National Neurological Institute "C. Mondino" Foundation
  • Ospedale di Piove di Sacco
  • University of Bari
  • University of Florence
  • University of Modena and Reggio Emilia

Registry information

Official study title

Chronology and Sequence of Premonitory Symptoms to Understand How Migraine Attack Starts: the CHRONOpS Study

Acronym: CHRONOpS

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Jul 2, 2026
Registry last updated
Jul 2, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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