Transcranial Direct Current Stimulation Plus Monoclonal Antibodies Acting on the CGRP Pathway for Migraine

Effectiveness of tDCS and Monoclonals Antibodies Anti-CGRP as a Combined Treatment for Migraine: a Randomized, Double-blind, Sham-controlled Trial

Electrophysiological changes that occur in the brains of migraine patients, lead to the activation of nociceptive centers, including a peripheral neural structure, the trigeminal ganglion (TG), which releases pain-inducing peptides and mostly calcitonin gene-related peptide (CGRP). Monoclonal antibodies acting on the CGRP pathway (CGRP-MAbs) are the first drugs specifically designed for migraine, they inhibit CGRP release from the TG without entering the brain. Not all patients experience benefit from CGRP-MAbs treatment. For this reason, associating these drugs with a non-pharmacological treatment that acts centrally, such as transcranial direct current stimulation, could be effective.

The aim of the study is investigating how the migraine preventive treatment with CGRP-MAbs in association with tDCS, is effective to reduce headache days, days of disabling headache, intensity of pain and consumption of acute treatments. Migraine-related disability, quality of life, sleep disturbance and psychological aspects will also be evaluated. Patients will be randomized into two groups, one will receive active tDCS and one sham tDCS. Both patients and investigators will be blind to the treatment administered (double-blind).

Furthermore, will be evalutated the cortical mechanisms involved in migraine by directly modulating brain physiology via repetitive tDCS in patients with migraine on treatment with CGRP-MAbs. To fulfill this aim, we will assess the EEG correlates of the actual effects of the stimulation in a sham-controlled study, providing the EEG indexes linked to the altered and potentially restored cortical dynamics in migraine.

Study Overview

• Status: Completed
• Conditions: Migraine
• Intervention / Treatment: Device: Cathodal transcranial direct current stimulation; Device: Sham cathodal transcranial direct current stimulation

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • L'Aquila, Italy, 67100
    • University of L'Aquila

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• male or female patients, aged between 40 and 70 years, referring to the Headache Center of the University of L'Aquila;
• a diagnosis of migraine with or without aura according to the International Classification of Headache Disorders, 3rd Edition (ICHD-3; https://ichd-3.org/);
• age at onset of migraine <50 years;
• migraine must have been present for at least ≥ 12 months;
• treated with CGRP-MAbs (erenumab, fremanezumab or galcanezumab) according to clinical practice criteria for 90-180 days since the first subcutaneous administration (this time range was chosen to ensure a stable CGRP pathway inhibition);
• reporting >4 monthly migraine days in the last 30 days of observation despite treatment with CGRP-MAbs;
• able to discriminate between migraine and tension-type headaches;
• written informed consent to participate in the study

Exclusion Criteria:

• any migraine preventive medication other than CGRP-MAbs;
• secondary migraine;
• epilepsy or any other neurologic condition that may be worsened by transcranial electrical stimulation;
• metallic head implants, cardiac pacemaker or any other device that could malfunction or be displaced by electrical stimulation;
• pregnancy or lactation.

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
Active Comparator: Cathodal transcranial direct current stimulation	Device: Cathodal transcranial direct current stimulation; The cathodal transcranial direct current stimulation protocol will consist in five daily sessions, each lasting 20 min. The montage will provide a bilateral stimulation on occipital areas, with the reference anodal electrodes positioned on the M1 areas. The stimulation will be applied via 4 conductive-rubber square electrodes (5x5 cm) placed in sponges saturated with high conductivity gel and connected to a battery-operated stimulator system. Direct current with maximal intensity of 1.5 mA with be provided for 20 minutes.
Sham Comparator: Sham transcranial direct current stimulation	Device: Sham cathodal transcranial direct current stimulation; Sham stimulation will be performed by the same protocol as active stimulation; however, the device will be switched off 30 seconds after the beginning of stimulation. This way, the patient will experience the same sensations as with active stimulation without receiving actual stimulation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Decrease in headache days	Difference between the active tDCS treated group and the sham tDCS treated group	4 weeks
Decrease in disabling headache days	Difference between the active tDCS treated group and the sham tDCS treated group	4 weeks
Decrease in mean 10-point Visual Analog Scale	Difference between the active tDCS treated group and the sham tDCS treated group in the 10-point Visual Analog Scale (0 to 10 points, where 0 means "no pain at all" and 10 "maximum conceivable pain")	4 weeks
Decrease in doses of acute treatment	Difference between the active tDCS treated group and the sham tDCS treated group	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Decrease in mean modified Migraine Disability Assessment Scale (mMIDAS) score	Difference between the active tDCS treated group and the sham tDCS treated group in the modified Migraine Disability Assessment Scale (mMIDAS). mMIDAS is a self-administered questionnaire that contains five questions about the headache a patient had in the previous month, assessing the impact of migraine on three domains of daily activity: two questions for paid work or schoolwork, two questions for household work, and one question for family, social and leisure activities. The two questions for each of the first two groups assess, respectively, the number of days off due to headache, and the number of days in which the productivity was reduced by half or more. mMIDAS index is derived from the sum of the answers on the first five questions. This score defines patients in four categories of headache disability: little/none disability if the score is between 0 and 5; mild disability if between 6 and 10; moderate disability if between 11 and 20; and severe disability if greater than 20.	4 weeks
Decrease in mean Headache Impact Test-6 (HIT-6) score	Difference between the active tDCS treated group and the sham tDCS treated group	4 weeks
Decrease in mean Short Form Health Survey (SF-36) score	Difference between the active tDCS treated group and the sham tDCS treated group	4 weeks
Decrease in mean Pittsburgh Sleep Quality Index (PSQI) score	Difference between the active tDCS treated group and the sham tDCS treated group	4 weeks
Decrease in mean Hospital Anxiety and Depression Scale (HADS) score	Difference between the active tDCS treated group and the sham tDCS treated group. HADS is a scale based upon 14 questions. A score from 0 to 21 is given to both anxiety and depression, where 0-7 scores are normal, 8-10 borderline, and 11-21 abnormal.	4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in occipital electroencephalographic (EEG) signal power at 8-13 Hz frequency after vs before tDCS	Difference between the active tDCS treated group and the sham tDCS treated group	4 weeks

Collaborators and Investigators

• Sponsor: University of L'Aquila

Publications and helpful links

General Publications

• Ornello R, Rosignoli C, Caponnetto V, Pistoia F, Ferrara M, D'Atri A, Sacco S. Effectiveness of Transcranial Direct Current Stimulation and Monoclonal Antibodies Acting on the CGRP as a Combined Treatment for Migraine (TACTIC): Protocol for a Randomized, Double-Blind, Sham-Controlled Trial. Front Neurol. 2022 May 10;13:890364. doi: 10.3389/fneur.2022.890364. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2022
• Primary Completion (Actual): January 16, 2023
• Study Completion (Actual): April 16, 2023

Study Registration Dates

• First Submitted: December 3, 2021
• First Submitted That Met QC Criteria: December 3, 2021
• First Posted (Actual): December 17, 2021

Study Record Updates

• Last Update Posted (Estimated): December 5, 2024
• Last Update Submitted That Met QC Criteria: December 4, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders
• Other Study ID Numbers: 201722 ID INT 193/21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No