nVNS for the Prevention and Treatment of Primary Headache

Cluster Headache Clinical Trial

Official title:

Noninvasive Vagus Nerve Stimulation for the Prevention and Treatment of Primary Headache: a Randomized, Double-blind, Single-center Clinical Trial.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06277063
• Other study ID #: NFEC-2024-057
• Status: Not yet recruiting
• Phase: N/A
• Start date: March 10, 2024
• Est. completion date: December 30, 2026

Study information

• Verified date: March 2024
• Source: Nanfang Hospital, Southern Medical University
• Contact: Xiao XueZhen, PhD
• Phone: +8613425122570
• Email: xuezhenxiao[@]brainclos.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a single-center, randomized, double-blind controlled study. Patients will be randomly assigned to two groups by envelope drawing. The subjects will be divided into two groups: the acute intervention group and the preventive intervention group. In each group, the subjects will be randomly divided into the experimental group and the control group by means of envelope extraction.

Children and adolescents (7-20 years old) with migraine who met the inclusion criteria will be enrolled as subjects in the experimental group, and the changes in headache scores before and after the intervention will be compared. The intervention method is as follows: ictal intervention, in which subjects will be evaluated for headache improvement after a short intervention during an acute exacerbation. By wearing a vagus stimulator, the stimulating electrode will be located in the concha region rich in vagus nerve fiber endings, and the appropriate stimulation intensity will be adjusted for stimulation. Therefore, this study will verify the effect of nVNS on the acute attack and preventive treatment of primary headache in children and adolescents. Based on the electrocardiogram and electromyography indicators during the intervention process of nVNS, an objective evaluation system for the improvement of headache by nVNS is established, and the role of stimulation parameters on the effect is further explored to realize the optimization of parameters.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 288
• Est. completion date: December 30, 2026
• Est. primary completion date: August 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Years to 20 Years

Eligibility

Inclusion Criteria:

1. Patients with migraine, cluster headache and tension-type headache were diagnosed according to Chinese Guidelines for the diagnosis and Treatment of Migraine (2022 edition) and Chinese Guidelines for the diagnosis and treatment of cluster headache (2022 edition).

2. Age >=7 years old, <=20 years old;

3. Patients have experienced headache on 3-15 days per month in the past;

4. Maintain a stable dose and frequency of medication and do not take new drugs during the course of participating in the trial;

5. They volunteered to participate in the trial and signed informed consent.

Exclusion Criteria:

1. History of secondary headache, aneurysm, intracranial hemorrhage, brain tumor, severe head trauma, drug abuse, addiction, syncope, or seizures;

2. prior migraine-preventive surgery, cervical vagotomy, or implantation of an electronic or neurostimulator device;

3. Simultaneous use of other devices (e.g., TENS devices, muscle stimulators);

4. An implantable medical device in use, such as a pacemaker, hearing aid, or any implantable electronic device;

5. underwent head and neck nerve block within the past 2 months;

6. Opioid use (more than 2 days per month); Use of analgesics alone or non-steroidal anti-inflammatory drugs (more than 15 days per month); Or tamoxifen, ergots or combination analgesics (more than 10 days per month);

7. Patients who underwent cervical vagotomy (cervical vagotomy);

8. Pediatric patients (under 6 years old); Pregnant women;

9. Patients with clinically significant hypertension, hypotension, bradycardia or tachycardia;

10. Patients with congenital heart disease;

11. Mental/cognitive disorders, etc.

Related Conditions & MeSH terms

• Cluster Headache
• Headache
• Migraine Disorders
• Migraine in Adolescence
• Migraine in Children
• Primary Headache
• Tension Headache
• Tension-Type Headache

Intervention

Device:
• Transcutaneous auricular vagus nerve stimulation
The vagus nerve's auricular branch is primarily distributed in the tragus, tragus sulcus, and concha cavity. It can activate the nucleus tractus solitarius through the vagus afferent fibers, thereby activating various areas of the vagus nerve in the central nervous system. This stimulation technique involves applying a constant current of around 2-3mA to the epidermal terminals of the ear using an electrode. It aims to regulate the vagus nerve, modulate the autonomic nervous system, release neurotransmitters, improve cerebral blood flow, and alleviate headache symptoms. In the implementation, non-invasive transcutaneous vagus nerve stimulation was performed by having the subject wear a vagus stimulator and adjusting the appropriate stimulation intensity.
• Sham transcutaneous auricular vagus nerve stimulation
The subjects in the sham stimulation group will wera a stimulator with the same appearance as the experimental group. However, the electrode of the stimulator will be located near the auricle and earlobe, and the intensity of the stimulator will be adjusted.

Locations

Country	Name	City	State
China	Nanfang Hospital, Southern Medical University	Guangzhou	Guangdong

Sponsors (3)

Lead Sponsor	Collaborator
Nanfang Hospital, Southern Medical University	BrainClos Co., LTD., Zhuhai Fudan Innovation Institute

Country where clinical trial is conducted

China, 

References & Publications (4)

Cao J, Zhang Y, Li H, Yan Z, Liu X, Hou X, Chen W, Hodges S, Kong J, Liu B. Different modulation effects of 1 Hz and 20 Hz transcutaneous auricular vagus nerve stimulation on the functional connectivity of the periaqueductal gray in patients with migraine. J Transl Med. 2021 Aug 17;19(1):354. doi: 10.1186/s12967-021-03024-9. — View Citation

Diener HC, Goadsby PJ, Ashina M, Al-Karagholi MA, Sinclair A, Mitsikostas D, Magis D, Pozo-Rosich P, Irimia Sieira P, Lainez MJ, Gaul C, Silver N, Hoffmann J, Marin J, Liebler E, Ferrari MD. Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial. Cephalalgia. 2019 Oct;39(12):1475-1487. doi: 10.1177/0333102419876920. Epub 2019 Sep 15. — View Citation

Lai YH, Huang YC, Huang LT, Chen RM, Chen C. Cervical Noninvasive Vagus Nerve Stimulation for Migraine and Cluster Headache: A Systematic Review and Meta-Analysis. Neuromodulation. 2020 Aug;23(6):721-731. doi: 10.1111/ner.13122. Epub 2020 Mar 12. — View Citation

Martelletti P, Barbanti P, Grazzi L, Pierangeli G, Rainero I, Geppetti P, Ambrosini A, Sarchielli P, Tassorelli C, Liebler E, de Tommaso M; PRESTO Study Group. Correction to: Consistent effects of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: additional findings from the randomized, sham-controlled, double-blind PRESTO trial. J Headache Pain. 2018 Dec 18;19(1):120. doi: 10.1186/s10194-018-0949-9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Visual analogue scales(VAS)-actue period	The visual analogue scale (VAS) was used to evaluate the pain. It is widely used in clinical practice in China. The basic method is to use a swimming ruler of about 10cm in length, marked with 10 scales on one side, and "0" and "10" scales on both ends.	VAS pain intensity was assessed at the onset of headache, and within 20 minutes of the onset, patients received nVNS for half an hour and were assessed immediately, 2 hours, 8-12 hours, 24 hours, and 36-48 hours after the end of treatment
Primary	Visual analogue scales(VAS)-prevention period	The visual analogue scale (VAS) was used to evaluate the pain. It is widely used in clinical practice in China. The basic method is to use a swimming ruler of about 10cm in length, marked with 10 scales on one side, and "0" and "10" scales on both ends.	4 weeks of baseline, intervention period (5-12 weeks) and post-intervention period (13-20 weeks).
Secondary	Heart rate variability(HRV)	A 20-minute closed-loop ECG assessment test was performed before and after the intervention. The test consisted of 5 minutes of rest (i.e., no vagal stimulation), 10 minutes of vagal stimulation, 5 minutes of rest, and a total of 20 minutes of electrocard	before and after the intervention. The test consisted of 5 mins of rest (i.e., no vagal stimulation), 10 mins of vagal stimulation, 5 mins of rest, and a total of 20 minutes of electrocard
Secondary	Electromyography(EMG)	A 20-minute closed-loop evaluation test of neck electromyography was performed before and after the intervention. The testing process consisted of 5 minutes of rest (i.e., no vagal stimulation), 10 minutes of vagal stimulation, 5 minutes of rest, and a total of 20 minutes of electrocard	before and after the intervention. The test consisted of 5 mins of rest (i.e., no vagal stimulation), 10 mins of vagal stimulation, 5 mins of rest, and a total of 20 minutes of electrocard