Noninvasive Vagus Nerve Stimulation for the Prevention and Treatment of Primary Headache: a Single-arm Single-center Clinical Trial.
Phase: NA
Conditions: Primary Headache, Migraine in Adolescence, Migraine in Children, Cluster Headache, Tension Headache
Sponsor: Nanfang Hospital, Southern Medical University

Version number: 4.0; Version date: 2024.01.04
Research unit: Southern Medical University Southern Hospital
Study protocol
Title
Noninvasive vagus nerve stimulation for the prevention and treatment of primary
headache: a single-arm, single-center clinical study
Application
Department of Neurology, Nanfang Hospital, Southern Medical University
Purpose
1) Main objectives: This study will validate the efficacy of nVNS in the acute and
preventive treatment of primary headache in children and adolescents and
establish an objective evaluation system for the improvement of headache based
on the electrocardiogram (ECG) and electromyography (EMG) parameters during
nVNS intervention.
2) Secondary objectives: This study will further explore the role of stimulation
parameters on the effect and realize the optimization of parameters.
Research
hypothesis
1) Transcutaneous auricular vagus stimulation can prevent acute primary
headache in adolescents;
2) Heart rate variability changes significantly during acute attack of primary
headache.
Design and
procedure
This study was a single-arm, single-center, open-label study. Children and
adolescents (7-20 years old) with migraine who met the inclusion criteria were
enrolled as subjects, and the changes in headache scores before and after
intervention were compared. The intervention method was as follows: ictal
intervention, in which subjects were evaluated for headache improvement after a
short intervention during an acute exacerbation. By wearing a vagus stimulator,
the stimulating electrode was located in the concha region rich in vagus nerve
fiber endings, and the appropriate stimulation intensity was adjusted for
stimulation.
Sample size
Sample size estimation calculation method, referring to the statistical effect size
in the trial of Cao et al., (2021), according to the change in headache score before
and after intervention in the experimental group was significantly greater than
zero, by n = 2*[(Zα+Zβ)σ/d]2 (sample size was estimated using statistical effect
analysis software G*Power3.1), α = 0.05, β = 0.80, the sample size of the
experimental group was 15.
Eligibility
Inclusion Criteria:
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).
Age >=7 years old, <=20 years old;
Patients have experienced headache on 3-15 days per month in the past;
Maintain a stable dose and frequency of medication and do not take new drugs
during the course of participating in the trial;
They volunteered to participate in the trial and signed informed consent.
Exclusion Criteria:
History of secondary headache, aneurysm, intracranial hemorrhage, brain
tumor, severe head trauma, drug abuse, addiction, syncope, or seizures;
prior migraine-preventive surgery, cervical vagotomy, or implantation of an
electronic or neurostimulator device;
Simultaneous use of other devices (e.g., TENS devices, muscle stimulators);
An implantable medical device in use, such as a pacemaker, hearing aid, or
any implantable electronic device;
underwent head and neck nerve block within the past 2 months;
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);
Patients who underwent cervical vagotomy (cervical vagotomy);
Pediatric patients (under 6 years old); Pregnant women;
Patients with clinically significant hypertension, hypotension, bradycardia or
tachycardia;

Version number: 4.0; Version date: 2024.01.04
Research unit: Southern Medical University Southern Hospital
Patients with congenital heart disease;
Mental/cognitive disorders, etc.
Evaluating
Indicator
The primary outcome : VAS score of headache.
The secondary efficacy indexes : electromyography and electrocardiogram
characteristics
Statistical
method
Data from all participants conforming to the protocol set were included in the
statistical analysis. Paired sample t test and mixed linear model were used to
analyze the primary and secondary indicators.