Efficacy of Non-Invasive Neuromodulation on Pain in Migraine (ENDIM)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Migraine; rTMS Stimulation
• Intervention / Treatment: Device: repetitive Transcranial Magnetic Stimulation (rTMS); Device: sham repetitive Magnetic Transcranial Stimulation (rTMS)

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lise Laclautre; Phone Number: 04.73.75.49.63; Email: promo_interne_drci@chu-clermontferrand.fr

Study Locations

• France
  • Clermont-Ferrand, France
    • CHU Clermont-Ferrand
    • Principal Investigator: Xavier MOISSET
    • Contact: Lise Laclautre; Phone Number: 0473754963; Email: promo_interne_drci@chu-clermontferrand.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: rTMS stimulation	Device: repetitive Transcranial Magnetic Stimulation (rTMS); robot-guided high-frequency rTMS treatment (10hz - 5 sessions) of the primary motor cortex
Sham Comparator: sham rTMS stimulation	Device: sham repetitive Magnetic Transcranial Stimulation (rTMS); sham robot-guided high-frequency rTMS treatment (10hz - 5 sessions) of the primary motor cortex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Variation of headaches days number per month	difference between the 4 weeks prior to initiation of treatment and the last 4 weeks post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
variation in the number of headache (days per month) of at least 50%		between the 4 weeks prior to initiation of treatment and the last 4 weeks post-treatment
variation in the number of headache (days per month) of at least 30%.		between the 4 weeks prior to initiation of treatment and the last 4 weeks post-treatment
Patient Global Impression of Change (PGIC)	The score varies from 1 to 7 . A score of 1 means a better outcome and a score of 7 means a worse outcome	at week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bang blinding index	The patient will be asked what he thinks he received after the treatment, rTMS neuromodulation or sham neuromodulation	week 0, week 2, week 4, week 6, week 8, week 12
Variation of blood cytokine levels	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	Before (Week 0) and after treatment (Weeks 8 and 12)
Variation of headaches days number per month		Every each 4-week period post-treatment, compared to 4 weeks before treatment initiation
Migraine Hypersensitivity Assessment Questionnaire (MHQ-8 scale, ex-MIGAL) score	This scale assesses the frequency and intensity of disturbances related to noise, light, skin stimulation, and odors during migraines	Pre-treatment period (inclusion visit at W0 - 4) and at week 12
Improvement in Quality of life by migraine rescue medication intakes	Improvement in quality of life will be assessed by use of migraine rescue medication before and after neurostimulation	Week0 - 4 to week0 -1 period compared to Week 9 - week 12 period
Improvement in Quality of life by European Quality of Life 5 dimensions (EQ- 5D) scale score	Improvement in quality of life will be assessed by the change of EQ-5D score	At week 0, week 8 and week 12
Improvement in Quality of life by relief subjective rate	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 .	At Week 2, week 4, week 6, week 8 and week 12
Improvement in Quality of life by anxiety and depression scores	Anxiety and depression will be assessed by Hospital Anxiety and Depression Scale (HADS)	At screening visit (Week 0 - 4) and week 12
Improvement in Quality of life by resilience score	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	At screening visit (Week 0-4) and week 12
Improvement in Quality of life by catastrophizing score	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.	At screening visit (Week 0-4) and week 12
Improvement in Quality of life by intensity and emotional experience of pain	A visual analogue scale (VAS) ranging from 0 to 100 for pain intensity and affective experience will be used.	At screening visit (week 0- 4) and week 12
Brain activity (resting-state fMRI)	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.	At screening visit (week 0- 4) and week 12
Cortical excitability	measured during rTMS motor threshold with paired pulse stimulation measurements	At week 0 and week 12
Evaluation of side effects		up to 4 weeks post-treatment (at week 12)
Changes in prognostic markers of response	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)	At week 0, week 8 and week 12
Patient Global Impression of Change (PGIC)	The score ranges from 1 to 7. A score of 1 means a better outcome and a score of 7 means a worse outcome	week 2, week 4, week 6, week 8

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand

Study record dates

Study Major Dates

• Study Start (Estimated): July 31, 2025
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2028

Study Registration Dates

• First Submitted: May 27, 2025
• First Submitted That Met QC Criteria: July 16, 2025
• First Posted (Actual): July 23, 2025

Study Record Updates

• Last Update Posted (Actual): July 23, 2025
• Last Update Submitted That Met QC Criteria: July 16, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: rTMS neurostimulation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders
• Other Study ID Numbers: PHRC I 2023 MOISSET; 2024-A01985-42 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No