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NCT Number: NCT07081685

Efficacy of Non-Invasive Neuromodulation on Pain in Migraine

This is a prospective clinical study evaluating the analgesic efficacy of a non-medicated treatment: repeated transcranial magnetic stimulation (rTMS) of the primary motor cortex in chronic migraine (> 7 headache days per month and failure of at least 3 drug treatments).

To this end, the study involves a double-blind, randomized, comparative experimental protocol against a sham control condition via 2 parallel groups comprising 60 patients each (N= 120 in total). Randomized block design with stratification by center and type of migraine (episodic or chronic).

5 rTMS sessions will be performed, with one stimulation session every 2 weeks. One group will receive active stimulation at each session (high-frequency stimulation of the left primary motor cortex, 2000 pulses per session, 80% of resting motor threshold) and the other group placebo stimulation (sham).

Depending on the randomization group, rTMS sessions will be carried out by trained experimenters in the investigating center where the patient has been included. The study is multicentric, with five centers, four of which are in the Auvergne-Rhône-Alpes region. Data will be centralized at the Clermont-Ferrand University Hospital, and statistical analysis will be carried out by the Clermont-Ferrand University Hospital's Clinical Research and Innovation Department. Principal difference analysis (active vs sham) performed in ITT; missing data processed by multiple imputation.

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Key information

Conditions

rTMS Stimulation Brain Diseases Central Nervous System Diseases Headache Disorders Headache Disorders, Primary Migraine Migraine Disorders Nervous System Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

CHU Clermont-Ferrand

Clermont-Ferrand, France

Location contact

Lise LACLAUTRE

CONTACT

[email protected]

0473754963

Xavier Moisset

PRINCIPAL_INVESTIGATOR

Who can participate

Healthy volunteers accepted: No

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

Inclusion criteria

  • Age greater than or equal to 18 years ;
  • Frequent episodic or chronic migraine: migraine more than 8 days per month for more than 3 months;
  • Maximum 26 headache days / 28 ;
  • Failure (ineffectiveness, intolerance or contraindication) to at least 3 background drug treatments;
  • Analgesic treatment stable for at least one month and will not need to be modified for the duration of the study;
  • Patient can be followed throughout the study;
  • Information letter read and understood;
  • Signed informed consent;
  • Affiliation with a social security scheme.

Exclusion criteria

  • Contraindication to rTMS (patient with conductive/sensitive material to magnetic fields implanted in the skull or less than 30 cm from the coil, implanted material controlled by physiological signals, history of epilepsy or unexplained seizures, drug treatment lowering the epileptic threshold, brain lesions in relation to the stimulation zone [of vascular, traumatic, tumoral, infectious or metabolic origin], sleep deprivation, alcoholism, treatment with electroconvulsive therapy in the previous month, uncontrolled intracranial hypertension,
  • Contraindication to MRI (ferromagnetic material not compatible with MRI including: intracerebral metal clip, pacemaker, insulin pump, intrathecal pump, metal prosthesis; severe claustrophobia)§ drug or psychoactive substance abuse
  • Presence of other pain more severe than that justifying inclusion
  • Patients under guardianship or deprived of liberty.
  • Pregnant or breast-feeding women
  • Patients participating in another research protocol involving a drug in the 30 days prior to inclusion.
  • Subject having already benefited from rTMS sessions in the past (to maintain the blind)

Treatment and study plan

Repetitive transcranial magnetic stimulation (rTMS)

Device

robot-guided high-frequency rTMS treatment (10hz - 5 sessions) of the primary motor cortex

sham repetitive Magnetic Transcranial Stimulation (rTMS)

Device

sham robot-guided high-frequency rTMS treatment (10hz - 5 sessions) of the primary motor cortex

Primary outcomes

  1. Variation of headaches days number per month

    Time frame: difference between the 4 weeks prior to initiation of treatment and the last 4 weeks post-treatment

Secondary outcomes

  1. variation in the number of headache (days per month) of at least 50%

    Time frame: between the 4 weeks prior to initiation of treatment and the last 4 weeks post-treatment

  2. variation in the number of headache (days per month) of at least 30%.

    Time frame: between the 4 weeks prior to initiation of treatment and the last 4 weeks post-treatment

  3. Patient Global Impression of Change (PGIC)

    Time frame: at week 12

    The score varies from 1 to 7 . A score of 1 means a better outcome and a score of 7 means a worse outcome

Other outcomes

  1. Bang blinding index

    Time frame: week 0, week 2, week 4, week 6, week 8, week 12

    The patient will be asked what he thinks he received after the treatment, rTMS neuromodulation or sham neuromodulation

  2. Variation of blood cytokine levels

    Time frame: Before (Week 0) and after treatment (Weeks 8 and 12)

    Following cytokines levels will be assessed : IL-6, IL-10, IL-17, IL-18, IL-1α, IL-1β, IL-21, IL-22, IL-23, IL-33, IL-35, CCL-20, IL-36β, IL-37, IL-38, IL-1Ra, TNFa, TGFβ, IL-2, INF-γ

  3. Variation of headaches days number per month

    Time frame: Every each 4-week period post-treatment, compared to 4 weeks before treatment initiation

  4. Migraine Hypersensitivity Assessment Questionnaire (MHQ-8 scale, ex-MIGAL) score

    Time frame: Pre-treatment period (inclusion visit at W0 - 4) and at week 12

    This scale assesses the frequency and intensity of disturbances related to noise, light, skin stimulation, and odors during migraines

  5. Improvement in Quality of life by migraine rescue medication intakes

    Time frame: Week0 - 4 to week0 -1 period compared to Week 9 - week 12 period

    Improvement in quality of life will be assessed by use of migraine rescue medication before and after neurostimulation

  6. Improvement in Quality of life by European Quality of Life 5 dimensions (EQ- 5D) scale score

    Time frame: At week 0, week 8 and week 12

    Improvement in quality of life will be assessed by the change of EQ-5D score

  7. Improvement in Quality of life by relief subjective rate

    Time frame: At Week 2, week 4, week 6, week 8 and week 12

    A relief subjective rate since last neurostimulation will be asked to patient before each new neurostimulation session . A rate of 0% means "no relief" and 100% means a complete relief .

  8. Improvement in Quality of life by anxiety and depression scores

    Time frame: At screening visit (Week 0 - 4) and week 12

    Anxiety and depression will be assessed by Hospital Anxiety and Depression Scale (HADS)

  9. Improvement in Quality of life by resilience score

    Time frame: At screening visit (Week 0-4) and week 12

    Resilience score will be assessed by Connor-Davidson Resilience Scale (CD-RISC) in 25 items. The score ranges from 0 to 100 and a higher score means a higher resilience

  10. Improvement in Quality of life by catastrophizing score

    Time frame: At screening visit (Week 0-4) and week 12

    Catastrophism will be assessed by Pain Catastrophizing Scale (PCS) . Score ranges from 0 to 52. A higher score indicates a higher level of catastrophizing of pain.

  11. Improvement in Quality of life by intensity and emotional experience of pain

    Time frame: At screening visit (week 0- 4) and week 12

    A visual analogue scale (VAS) ranging from 0 to 100 for pain intensity and affective experience will be used.

  12. Brain activity (resting-state fMRI)

    Time frame: At screening visit (week 0- 4) and week 12

    MRI recording is routinely carried out before any rTMS session. This involves acquiring a 3D image of the participants' brains, which is necessary for targeting cortical area stimulated by rTMS using a neuronavigation system. Functional imaging (fMRI) in a resting state (i.e., without a 'resting-state' task) will allow to measure the basal state of activity and connectivity in the participants' brains.

  13. Cortical excitability

    Time frame: At week 0 and week 12

    measured during rTMS motor threshold with paired pulse stimulation measurements

  14. Evaluation of side effects

    Time frame: up to 4 weeks post-treatment (at week 12)

  15. Changes in prognostic markers of response

    Time frame: At week 0, week 8 and week 12

    Following blood parameters will be assessed : Blood count, CRP, Venous glycemia, Insulin, prolactin, estradiol, FSH, LH, progesterone, testosterone, β-hCG, CGRP, VIP, PACAP-38, IL-6, IL-10, IL-17, IL-18, IL-1α, IL-1β, IL-21, IL-22, IL-23, IL-33, IL-35, CCL-20, IL-36β, IL-37, IL-38, IL-1Ra, TNFa, TGFβ, IL-2, INF-γ, T lymphocyte immunophenotyping (CD3, CD4, CD25, FoxP3, CTLA-4, ICOS, TNFR2, CD45, CD45RA, CD8, CD14, 4-1-BB, NKp46, CD19, CD197, CD39, CD73, GITR, TCRaβ, CD127, CD56, CD62L)

  16. Patient Global Impression of Change (PGIC)

    Time frame: week 2, week 4, week 6, week 8

    The score ranges from 1 to 7. A score of 1 means a better outcome and a score of 7 means a worse outcome

Study contacts

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

Lise LACLAUTRE

CONTACT

[email protected]

04.73.75.49.63

Sponsors and collaborators

Lead sponsor

University Hospital, Clermont-Ferrand

Other

Registry information

Acronym: ENDIM

Important dates

Study start
2025
Primary completion
2028
Study completion
2028
First posted
Jul 23, 2025
Registry last updated
Jul 23, 2025

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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