A Phase III Trial of e-TNS for the Acute Treatment of Migraine

The main objective of this study is to have Phase III evidences of the efficacy of the Cefaly® Abortive Program device used at home for 2 hours to treat a migraine attack, as triptans are generally used. That is to say having randomized, double-blind, sham-controlled data of the efficacy and safety of the Cefaly® Abortive Program device in the abortive treatment of acute migraine as measured by 2-hour pain freedom, pain relief and migraine-associated symptoms freedom, plus evolution of these measurements for 24 hours after the beginning of the treatment session.

• Verum Cefaly® Abortive Program device (Device): The Cefaly® Abortive Program device is an external cranial neurostimulator designed for supraorbital neurostimulation, also known as external Trigeminal Nerve Stimulation (e-TNS). The Verum Cefaly® Abortive Program device will deliver verum external trigeminal nerve stimulation.
• Sham Cefaly® Abortive Program device (Device): The Cefaly® Abortive Program device is an external cranial neurostimulator designed for supraorbital neurostimulation, also known as external Trigeminal Nerve Stimulation (e-TNS). The Sham Cefaly® Abortive Program device will deliver sham external trigeminal nerve stimulation.

Primary outcomes

• Pain Freedom at 2 Hours [2 hours]: The percentage of patients having a reduction of a moderate or severe migraine headache (Grade 2 or 3) at baseline to no headache (Grade 0) at 2 hours after the beginning of the e-TNS session.
• Most Bothersome Migraine-associated Symptom Freedom at 2 Hours [2 hours]: The percentage of patients with absence, at 2 hours after the beginning of the e-TNS session, of the most bothersome migraine-associated symptom identified at baseline.

Secondary outcomes

• Pain Relief at 2 Hours [2 hours]: The percentage of patients having a reduction of a moderate or severe migraine headache (Grade 2 or 3) at baseline to a mild headache or to no headache (Grade 1 or 0) at 2 hours after the beginning of the e-TNS session.
• Percentage of Patients With Absence of Photophobia, Phonophobia, Nausea, Vomiting at 2 Hours [2 hours]: The percentage of patients with absence of photophobia, phonophobia, nausea, vomiting at 2 hours after the beginning of the e-TNS session.
• Use of Rescue Medication Between 2 and 24 Hours [2-24 hours]: The percentage of patients who took anti-migraine rescue medication between 2 and 24 hours after the beginning of the e-TNS session.
• Sustained Pain Freedom at 24 Hours [24 hours]: The percentage of patients having no headache (Grade 0) at 2 hours, with no use of anti-migraine rescue medication and no relapse of headache pain within the 24 hours after the beginning of the e-TNS session.
• Sustained Pain Relief at 24 Hours [2-24 hours]: The percentage of patients having mild or no headache (Grade 1 or 0) at 2 hours, with no use of anti-migraine rescue medication and no relapse of headache pain within the 24 hours after the beginning of the e-TNS session.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

1. Age from 18 to 65 on the day of signing the informed consent form
2. ≥ 1-year history of migraine with or without aura according to the diagnostic criteria listed in International Classification of Headache Disorders (ICHD)-3 beta (2013) section 1, migraine, with the exception of aura without headache, hemiplegic migraine and brainstem aura migraine
3. Migraine onset before the age of 50
4. Having between 2 and 8 moderate or severe migraine attacks (Grade 2 or 3) per month in each of the two months prior to screening
5. Patient understands the study procedures, alternative treatments available, and voluntarily agrees to participate in the study by giving written informed consent
6. Patient is able to read and understand the written information (instruction sheet, paper diary and Adverse Events reporting form)

Exclusion Criteria:

1. Patient has difficulty distinguishing his/her migraine attacks from tension-type headaches
2. Patient has more than 15 headache days per month
3. Patient having received supraorbital nerve blocks in the prior 4 months
4. Patient having received Botox treatment in the prior 4 months
5. Modification of a migraine prophylaxis treatment in the previous 3 months
6. Diagnosis of other primary headache disorders, except rare (< 4) tension-type headaches per month
7. Diagnosis of secondary headache disorders including Medication Overuse Headache (MOH)
8. Patient abusing opioids or user of recreational or illicit drugs or having had a recent history (within the last year) of drug or alcohol abuse or dependence
9. Implanted metallic or electronic device in the head
10. Cardiac pacemaker or implanted or wearable defibrillator
11. Patient having had a previous experience with the Cefaly® device
12. Migraine Aura without headache
13. Patient is currently participating or has participated in a study with an investigational compound or device in the last 30 days before the screening visit (Visit 1)
14. Patient not having the ability to use appropriately the device and/or to perform himself/herself or bear the first 20-minute stimulation session during the training test session at the study site

Participant flow

Outcome results

• Pain Freedom at 2 Hours (Primary), Count of participants, Participants: Verum 66; Sham 51
• Most Bothersome Migraine-associated Symptom Freedom at 2 Hours (Primary), Count of participants, Participants: Verum 146; Sham 118
• Pain Relief at 2 Hours (Secondary), Count of participants, Participants: Verum 180; Sham 154
• Percentage of Patients With Absence of Photophobia, Phonophobia, Nausea, Vomiting at 2 Hours (Secondary), Count of participants, Participants: Verum 110; Sham 95
• Use of Rescue Medication Between 2 and 24 Hours (Secondary), Count of participants, Participants: Verum 82; Sham 105
• Sustained Pain Freedom at 24 Hours (Secondary), Count of participants, Participants: Verum 59; Sham 44
• Sustained Pain Relief at 24 Hours (Secondary), Count of participants, Participants: Verum 119; Sham 96 (p <0.05)

Adverse events

Time frame: The data was collected during the 24 hours following the beginning of the treatment

Serious adverse events by term

Other adverse events by term

• Results publication: Johnson MAL, Panza G, Kuruvilla DE. Migraine phases and treatment response: a post hoc analysis of participants with migraine with aura from the TEAM study. BMC Neurol. 2026 Jun 3. doi: 10.1186/s12883-026-05028-8. Online ahead of print. PMID 42231198
• Results publication: Kuruvilla DE, Mann JI, Tepper SJ, Starling AJ, Panza G, Johnson MAL. Phase 3 randomized, double-blind, sham-controlled Trial of e-TNS for the Acute treatment of Migraine (TEAM). Sci Rep. 2022 Mar 24;12(1):5110. doi: 10.1038/s41598-022-09071-6. PMID 35332216

• Study Protocol and Statistical Analysis Plan (PDF, 2018-02-26)

• Deena Kuruvilla, M.D., Principal investigator, Yale University