Vagus nerve stimulation for treatment-resistant depression: protocol for a pilot self-controlled trial
Jing-jing Zhou1, Jian Yang1, Xiao-hua Zhang2, Gang Wang M.D. 1
1 National Research Center for Mental and Psychological Diseases, Beijing Anding Hospital, Capital Medical University, Beijing, China
2 Xuanwu Hospital, Capital Medical University, Beijing, China
|Date of Web Publication||8-Mar-2018|
National Research Center for Mental and Psychological Diseases, Beijing Anding Hospital, Capital Medical University, Beijing
Source of Support: None, Conflict of Interest: None
Background and objectives: Patients with treatment-resistant depression (TRD) show no improvement after treatment with a series of drugs. Previous reports have described positive effects of vagus nerve stimulation (VNS) on the emotional states of patients with epilepsy. VNS for TRD has not been explored in China. We will investigate the efficacy and safety of VNS for the treatment of TRD in a Chinese cohort.
Design: A pilot self-controlled trial.
Methods: The study population will comprise 10 consecutive patients with TRD admitted to Beijing Anding Hospital at Capital Medical University in Beijing, China. The patients will receive routine treatment supplemented with VNS starting at 2 weeks after surgery. Follow-up evaluations will be performed at 1, 2, 3, 6, and 12 months of nerve stimulation.
Outcome measures: The primary outcome measure will be the change in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score from baseline to 12 months of nerve stimulation. The secondary outcome measures will include the proportion of patients who achieve ≥ 50% reduction from baseline in the HAMD-17 total score, complete remission rate, and the Quick Inventory of Depression Symptomatology-Self Report, 7-item Generalized Anxiety Disorder Scale, Global Assessment of Function, Clinical Global Impression-severity, Clinical Global Impression-improvement, Hamilton Rating Scale for Anxiety, Young Mania Rating Scale, Patient Health Questionaire-15, Sheehan Disability Scale, Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form, Perceived Deficits Questionnaire-Depression, Frequency, Intensity and Burden of Side Effects Rating, and Columbia-Suicide Severity Rating Scale scores.
Discussion: The trial will provide objective data on the potential of the clinical implementation of VNS as a treatment for TRD in China.
Ethics and dissemination: This study protocol was approved by the Institution Review Board of Beijing Anding Hospital of Capital Medical University in China (approval No. 201775FS-2) at October 2017. Design of the study was finished in August 2017, participant recruitment was started at December 2017, and data analysis will be completed until December 2021. The results of the study will be disseminated through presentations at peer-reviewed publications.
Trial registration: This trial was registered in the Chinese Clinical Trial Registry with registration No. ChiCTR-ONC-174013430 (version 2.0) in November 2017.
Keywords: vagus nerve stimulation; treatment-resistant depression; adjuvant therapy; 17-item Hamilton Rating Scale for Depression; quality of life and social function; clinical trials
|How to cite this article:|
Zhou Jj, Yang J, Zhang Xh, Wang G. Vagus nerve stimulation for treatment-resistant depression: protocol for a pilot self-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:22-30
|How to cite this URL:|
Zhou Jj, Yang J, Zhang Xh, Wang G. Vagus nerve stimulation for treatment-resistant depression: protocol for a pilot self-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2018 Sep 19];3:22-30. Available from: http://www.actnjournal.com/text.asp?2018/3/1/22/226186
| Introduction|| |
Major depressive disorder (MDD) is a group of mood or affective disorders with depression as the main symptom, caused by a variety of factors. The average annual prevalence rate of MDD is about 4%, and approximately 15% of people develop depression in their lifetimes (Richards, 2011). The proportion of the global population living with depression is estimated to be 322 million people—4.4% of the world's population according to a new report (Friedrich, 2017). The World Health Organization (WHO) predicts that by 2020, MDD will impose an enormous economic burden secondary only to that of cardiovascular diseases (Lopez and Murray, 1998). It is worrisome that the incidence of MDD is likely to continue to rise with the development of society, growing stress of modern everyday living, and increasing work pressure. Antidepressants are the first-line treatment for MDD; however, only 60–70% of MDD patients respond to antidepressant therapies (Arroll et al., 2005). MDD cases that cannot achieve full remission after treatment with at least two antidepressants are described as treatment-resistant depression (TRD), accounting for 20–30% of all MDD cases. Therefore, a safe and reliable treatment for TRD is urgently needed.
Current treatments for TRD can be divided into pharmacological and non-pharmacological categories. Three main strategies are used for TRD treatment: incremental, combination, and synergistic (Shelton et al., 2010). Incremental therapy is based on continually increasing the drug dosage once the current dosage becomes ineffective. Patients following this approach are prone to developing serious adverse reactions and show poor treatment compliance. Combination therapy aims to achieve the cumulative effect of simultaneously using at least two types of antidepressants. However, patients undergoing this treatment are also prone to adverse reactions, and the prudence and effectiveness of combining different antidepressant classes are hotly debated. The synergistic strategy involves supplementation of routine antidepressant medication with lithium salts, thyroid hormones, or atypical antipsychotics. In particular, multiple studies have reported that adding atypical antipsychotics to an antidepressant regimen can produce positive effects (Hassan et al., 2016). Treatment with selective serotonin reuptake inhibitors combined with olanzapine, risperidone, or quetiapine achieves good outcomes in some cases of TRD (Philip et al., 2010). However, the long-term use of atypical antipsychotic drugs is associated with multiple side effects.
Despite the multiple strategies, it is still difficult to effectively alleviate the symptoms of TRD in some patients. Therefore, attempts have been underway to develop non-pharmacological treatments for depression. Vagus nerve stimulation (VNS) is used to create sustained stimulation to the vagus nerve by a neurostimulator implanted into the left armpit and connected to the left vagus nerve with a bipolar electrode. The vagus nerve is a mixed nerve that carries motor parasympathetic fibers, including general efferent fibers, special visceral efferent fibers, general somatic afferent fibers, and general visceral afferent fibers. The vagus nerve innervates various organs and conveys sensory information about the states of the organs to the central nervous system through afferent nerves. The central branches of the vagus nerve mostly end in the solitary tract nucleus, and a small part terminate in the medulla oblongata, cerebellum, and wedge-shaped nucleus. Fibers arising from the solitary tract nucleus project onto the amygdala of the hypothalamus and the anterior part of the brain. Fibers descending from the lateral part of the hypothalamus and forebrain also have associations with the cerebral cortex and can transmit impulses to the cerebral cortex. Innervation by the left and right vagus nerves is different. The left vagus nerve contributes to the atrioventricular node, which is responsible for myocardial contractility and has a small impact on the heart rate. Therefore, the left vagus nerve is selected for electrical stimulation. Commercial VNS systems have programmable pulse generators implanted under the skin that apply a low-frequency intermittent electrical pulse to the left cervical vagus nerve via a bipolar electrode. Stimulation parameters adjusted by a remote control include stimulus intensity, frequency, pulse, and a circulation coefficient, and are set based on the specifics of the case.
VNS has been widely used in the treatment of epilepsy. A significant improvement in mood in patients with epilepsy receiving VNS was first noted by Elger et al. (2000), who subsequently suggested the use of VNS as a therapy for depression. In 2005, the United States FDA approved VNS as a long-term adjuvant treatment for patients with chronic or recurrent depression who are over 18 years of age and do not respond well to at least 4 antidepressants. Studies have shown that VNS treatment for 3–12 months can significantly alleviate depressive symptoms in patients with TRD (Tisi et al., 2014). Based on the previous findings [Table 1], long-term VNS as an adjuvant therapy for TRD is expected to be safe and effective.
|Table 1: Clinical research on vagus nerve stimulation (VNS) as an adjuvant treatment for treatment-resistant disease (TRD) |
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VNS Treatment of TRD Results in Little Damage to the Patient And, Unlike Deep Brain Stimulation, Does not Require Craniotomy. In Addition, the Operator Can Use an External Programmable Controller to Adjust the Electrical Pulse Signal. at Present, Several Hospitals in China Carry Out VNS for the Treatment of Epilepsy; However, No Medical Institutions Routinely Use VNS to Treat TRD.
The Authors Intend to Conduct a Pilot Self-Controlled Trial in Collaboration With Xuanwu Hospital at Capital Medical University, China, to Evaluate the Efficacy and Safety of VNS in Patients With TRD.
| Methods/Design|| |
This Will Be a Pilot Self-Controlled Trial. VNS as an Adjuvant Therapy Will Be Performed in 10 Patients With TRD, With a Postoperative Follow-Up of 12 Months. the General Timeline of the Trial Will Be as Follows:
- Subjects Who Meet the Inclusion Criteria as Evaluated by 2 Experienced Assessors Will Be Enrolled in the Study and Undergo Systematic Psychiatric Evaluation at Beijing Anding Hospital at Capital Medical University, China. the Patients' Conditions Will Be Recorded.
- After Completing the Psychiatric Evaluation, the Patients Will Be Evaluated by the Department of Neurosurgery, Xuanwu Hospital, Capital Medical University of China, and Undergo the Relevant Preoperative Examinations.
- Preoperative Examinations Relevant to VNS Will Be Performed.
- Preoperative Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) Scans Will Be Performed.
- The Patients Will Remain in the Hospital under Observation for 3 Days Postoperatively, and the CT Will Be Repeated.
- A VNS Device Will Be Commissioned at 2 Weeks After Surgery, and Stimulation Parameters Will Be Determined.
- The Subjects Will Be Evaluated Preoperatively (Screening Period), 2 Weeks After Surgery (Commissioning Parameters), and 1, 2, 3, 6, and 12 Months of VNS Stimulation.
- The Primary Outcome Measure Will Be the Change in the Total Score on the 17-Item Hamilton Rating Scale for Depression (HAMD-17) from Baseline to 12 Months of VNS.
- The Secondary Outcome Measures Will Include the Proportions of Patients Who Achieve ≥ 50% Reduction in the HAMD-17 Total Score from Baseline to 1, 2, 3, and 6 Months After Nerve Stimulation, Complete Remission Rate, and the Quick Inventory of Depression Symptomatology-Self Report (QIDS-SR16), 7-Item Generalized Anxiety Disorder Scale (GAD-7), Global Assessment of Function (GAF), Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement (CGI-I), Hamilton Rating Scale for Anxiety (HAMA), Young Mania Rating Scale (YMRS), Patient Health Questionaire-15 (PHQ-15), Sheehan Disability Scale (SDS), Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), Perceived Deficits Questionnaire-Depression (PDQ-D), Frequency, Intensity and Burden of Side Effects Rating (FIBSER), and Columbia-Suicide Severity Rating Scale (C-SSRS) Scores.
Potential Patients Will Be Informed of the Upcoming Trial Through a Recruitment Poster at the Psychiatry Clinic, Beijing Anding Hospital at Capital Medical University. Patients or Their Families Interested in Participating Will Contact the Study Sponsor via Telephone or Wechat. After Preliminary Evaluation by 2 Experienced Assessors, Eligible Patients Will Undergo Psychiatric Evaluation at Beijing Anding Hospital at Capital Medical University. the Patients or Their Legal Representatives Will Provide Written Informed Consent Prior to the Commencement of the Mental Evaluation. All Patients or Their Legal Representatives Will Be Clearly Informed That Study Participation Is Voluntary and That They Have the Right to Withdraw from the Study at Any Time Without Any Consequences on the Subsequent Treatment.
All subjects will be recruited from the psychiatry clinic of Beijing Anding Hospital at Capital Medical University.
Patients will be required to meet all of the following conditions to be included in this trial:
- A diagnosis of MDD based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV; American Psychiatric Association, 1994), established in a systematic clinical evaluation by 2 attending physicians (associate chief physicians or chief physicians) independently using the Mini-International Neuropsychiatric Interview (MINI; Sheehan et al., 1998).
- Age 18–65 years
- Male or female
- An HAMD-17 (Hamilton, 1960) score > 24 at screening and baseline
- At least 4 episodes of depression, with the latest attack lasting for at least 1 year with no remission
- Taking a stable dose of antidepressants for at least 6 weeks before surgery
- A history of ineffective medication with at least two antidepressant synergist classes, including lithium, thyroid hormone, buspirone, benzodiazepines, selective gamma-aminobutyric acid (GABA) agonists, or atypical antipsychotics, for at least 4 weeks before surgery
- Undergoing no electroconvulsive therapy (ECT) 6 times or more, eventually failing
- Psychological therapy at least once per week, for at least 6 months, eventually failing
- Informed consent from the patient or a legal representative
Patients presenting with any of the following conditions will be excluded from this trial:
- Other mental diseases confirmed by 2 attending physicians through a systematic clinical evaluation based on the DSM-IV
- Past suicide attempts or a strong suicidal tendency
- Depressive episodes with psychotic symptoms (delusions, hallucinations)
- A past history of manic or hypomanic episodes
- A history of alcohol or drug abuse and dependence according to the DSM-IV within 1 year prior to screening
- Pregnant or lactating women, or those unable to take appropriate contraceptive measures during the trial
- A history of major physical disease
- A history of left vagotomy
- Patients with neurological disorders, impaired motor, sensory or cognitive functions, or those needing intermittent or long-term medication (e.g., Parkinson's disease, migraine, Huntington's disease, stroke, traumatic brain injury)
- Insulin-dependent diabetes mellitus
- Respiratory sleep apnea syndrome
- Patients undergoing, or expected to undergo, intensive electromagnetic therapy or examination during the observation period
- Confirmed coronary heart disease and a history of angina pectoris, myocardial infarction, or other cardiovascular conditions requiring any medication (except for lipid-lowering drugs)
- Having a pacemaker, defibrillator, or another implanted instrument
- Current use of anticoagulants
- Serious cardiopulmonary dysfunction
Patients will be withdrawn from the study if they fulfill any of the following criteria:
- Incomplete data affecting efficacy or safety assessment
- Complications affecting efficacy and safety adjustment, or onset of diseases affecting the outcome
The design of the trial was completed in August 2017, and the study protocol was approved by the Institutional Review Board (IRB) of Beijing Anding Hospital at Capital Medical University, China, in October 2017. The trial was registered with the Chinese Clinical Trial Registry in November 2017. Participant recruitment was started in December 2017, and data analysis will be completed by December 2021.
Patients will be continued on their regular regimens with VNS as an adjuvant therapy. The implantable VNS device, purchased from RISHENA Medical Devices Co., Ltd., Changzhou, China, consists of a generator (model No. VNS201), electrode lead (model No. VL202), and external program controller (model No. VP213A/VP213B). This device is a certified professional product rigorously tested by the Beijing Medical Device Quality Supervision and Inspection Center, China Food and Drug Administration, and approved for use in clinical trials. The parameters and modes of the device can be adjusted by the external program controller. The device can deliver electrical pulses to the vagus nerve in a predefined mode via the electrode lead.
Preoperative CT and MRI scans will be performed at baseline to confirm that the patients meet the study requirements. Under general anesthesia, a little “pouch” will be made on the left upper chest through blunt dissection, where the generator will be implanted. The electrode will be subcutaneously tunneled up to the generator. Cleaned lead wires will be connected to the generator, followed by incision suturing and bandaging. Patients will be asked to avoid excessive pressure on the implanted system, such as by sudden, excessive, or repeated bending, twisting, stretching, or jumping.
The patients will be hospitalized for 3 days postoperatively, and the CT will be reviewed. The generator will begin to send electric pulses to the vagus nerve at 2 weeks after surgery. The commencement time will be altered depending on the patient's condition, with 2 weeks as the recommended starting point.
Parameter adjustment will follow the steps below to avoid sudden changes in stimuli that may cause patient discomfort. Alteration of parameters during programming will be minimized.
Once the stimulation parameters are set, the external program controller will be retained and electronically locked by the researchers to ensure patient compliance and avoid irregular operation or operator-to-operator differences affecting efficacy adjustment of the device during the trial.
The following precautions will be taken when using the external program controller. To prevent damage to the controller, the researchers will not be allowed to immerse it in liquid or wash it with bleach, nail polish remover, mineral oil, or other cleaning solutions. Because the controller is battery-powered, it will be important to avoid using it in an inflammable or explosive environment. In patients with implanted cochlear implants, the cochlear implant will be partially closed (the external part) or kept away from the controller during controller-generator wireless communication. If necessary, the controller will be manipulated via software. Hypersensitive patients may experience unusual sensations during controller-generator communication. High-altitude conditions have no impact on implanted VNS devices. However, the patients will be made aware that excessive body flexion and extension may affect the implanted device.
The surgical implantation site and a schematic of the VNS device are shown in [Figure 1].
|Figure 1: Vagus nerve stimulation device implant location and its working diagram.|
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Primary outcome measure
The primary outcome measure will be the change in the HAMD-17 score from baseline to 12 months of nerve stimulation. The HAMD-17 scale, originally developed by Hamilton (1960), contains 17 items including signs of depression, guilt, suicide, difficulty falling asleep, poor sleep, early awakening, work and interests, lag, agitation, psychic anxiety, somatic anxiety, gastrointestinal symptoms, general symptoms, sex symptoms, suspicion, weight loss, and self-awareness. A higher score indicates greater depression severity.
Secondary outcome measures
- Changes in the HAMD-17 total score from baseline to 2 weeks after surgery, and to 1, 2, 3, and 6 months of nerve stimulation
- The proportion of patients with HAMD-17 total scores reduced by at least 50% from baseline to 2 weeks after surgery, and to 1, 2, 3, 6, and 12 months of nerve stimulation
- Complete remission rate defined as the proportion of patients with HAMD-17 total scores ≤ 7 at 12 months of nerve stimulation.
- Changes in the QIDS-SR16 score from baseline to 2 weeks after surgery, and to 1, 2, 3, and 6 months of nerve stimulation. The QIDS-SR is a new measure of depression developed by Dr A. John Rush at the University of Texas Southwestern Medical Center, USA. It is derived from the 30-item Inventory of Depressive Symptomatology (IDS), and has 16 questions on different topics, including falling asleep, sleep during the night, waking up too early, sleeping too much, feeling sad, decreased appetite, increased appetite, decreased weight (within the last 2 weeks), increased weight (within the last 2 weeks), concentration/decision making, view of oneself, thoughts of death or suicide, general interest, energy level, feeling slowed down, and feeling restless. A higher score indicates a greater severity of depression (Brown et al., 2008).
- Changes in the GAD-7 score from baseline to 2 weeks after surgery, and to 1, 2, 3, 6, and 12 months of nerve stimulation. The GAD-7 scale comprises seven questions: feeling nervous, feeling anxious or on edge; being unable to stop or control worrying; worrying too much about different things; having trouble relaxing; being so restless than it is hard to sit still; becoming easily annoyed or irritable; and feeling afraid as if something awful might happen. A higher score indicates a more serious anxiety (Spitzer et al., 2006).
- Changes in the GAF score from baseline to 2 weeks after surgery, and to 1, 2, 3, 6, and 12 months of nerve stimulation. The GAF is a numerical scale subjectively rating current treatment and care needs. A higher score indicates better patient function.
- Changes in the CGI-S score from the baseline to 12 months of nerve stimulation. The CGI-S score is a common measure of depressive symptoms often used in clinical practice as a valid aid to a comprehensive psychiatric scale. A higher score indicates a more serious mental disorder (Forkmann et al., 2011).
- Changes in the CGI-I score from baseline to 1, 2, 3, 6, and 12 months of nerve stimulation. A lower score indicates a better outcome (Forkmann et al., 2011).
- The HAMA score will be tested preoperatively, 2 weeks after surgery, and 1, 2, 3, 6, and 12 months of nerve stimulation. This 14-item scale was developed by Hamilton (1959) and is one of the common psychological questionnaires currently in clinical practice. A higher score indicates more severe anxiety.
- The YMRS score will be tested preoperatively, 2 weeks after surgery, and 1, 2, 3, 6, and 12 months of nerve stimulation. This scale, developed by Young et al. (1978), is a measure of the severity of manic episodes. A higher score indicates more serious mania.
- The PHQ-15 score will be tested preoperatively, 2 weeks after surgery, and 1, 2, 3, 6, and 12 months of nerve stimulation. This scale is a diagnostic tool for depression and also a measure of the severity of depression. A higher score indicates more serious depression (Lyoo et al., 2014).
- The SDS score will be tested preoperatively, 2 weeks after surgery, and 1, 2, 3, 6, and 12 months of nerve stimulation. This scale is a tool to measure disability in work/school activities, family relationships, and social functioning resulting from depression. A higher score indicates more severe disability (Sheehan et al., 2016).
- The Q-LES-Q-SF score will be tested preoperatively, 2 weeks after surgery, and 1, 2, 3, 6, and 12 months of nerve stimulation. A higher score indicates a better quality of life and higher social function (Stevanovic, 2011).
- To assess the patient's cognitive function, the PDQ-D score will be tested preoperatively, 2 weeks after surgery, and 1, 2, 3, 6, and 12 months of nerve stimulation. A higher score indicates worse cognitive function (Kim et al., 2016).
- The FIBSER score will be tested preoperatively, 2 weeks after surgery, and 1, 2, 3, 6, and 12 months of nerve stimulation. A higher score indicates higher frequency and intensity of side effects as well as a heavier financial burden (Wisniewski et al., 2006).
- The C-SSRS score will be tested preoperatively, 2 weeks after surgery, and 1, 2, 3, 6, and 12 months of nerve stimulation. A higher score indicates a higher risk of suicide (Interian et al., 2017).
During the trial, any adverse event will be recorded in detail and followed until the symptoms disappear. The total incidence of adverse events will be calculated. An adverse event will be defined as any unfavorable medical event during the trial, regardless of whether it is directly associated with the medical device. An adverse event can therefore be any unfavorable and unexpected sign (including abnormalities in laboratory findings), symptom, or disease temporally coinciding with, but not necessarily related to, the use of the medical device. Generally, the relationship between an adverse event and the medical device will be categorized as definitely related, probably related, possibly related, possibly unrelated, and definitely unrelated. The adverse events related to the clinical use of the device will be analyzed. In the case of an adverse event, the researchers will be liable to review all relevant records (e.g., course history, laboratory data, and diagnostic reports) and record the event-related information in a case report form (CRF). Researchers will evaluate the patient's symptoms, disease signs, and other clinical data. The diagnosis will be recorded as an adverse event or a serious adverse event rather than signs/symptoms. The patients will be given targeted treatment for adverse events and followed up until the symptoms disappear or are stable.
Researchers will make preliminary judgments on whether an adverse event is device-related.
The details of the measures taken to manage adverse events will be recorded in the original documents and CRFs. Proper therapeutic measures will be taken if a severe adverse event occurs, to protect the rights and interests of the subjects. If necessary, the IRB will have the right to terminate the trial immediately. At the end of the trial, the subjects, sponsors, and IRB will be informed of the adverse events and their causes and explanations. In addition, the adverse events will be reported to the state and provincial food and drug administrations that have approved the medical device and to other medical institutions using the medical device in clinical trials.
The flow chart of the trial is shown in [Figure 2], and the schedule of outcome measurement assessments is shown in [Table 2].
|Figure 2: Flow chart of the trial.|
Note: MINI: Mini-International Neuropsychiatric Interview; HAMD-17: 17-item Hamilton Rating Scale for Depression; QIDS-SR16: Quick Inventory of Depression Symptomatology-Self Report; GAD-7: the 7-item Generalized Anxiety Disorder Scale; GAF: Global Assessment of Function; CGI-S: Clinical Global Impression-severity; CGI-I: Clinical Global Impression-improvement; HAMA: Hamilton Rating Scale for Anxiety; YMRS: Young Mania Rating Scale; PHQ-15: Patient Health Questionaire-15; SDS: Sheehan Disability Scale; Q-LES-Q-SF: Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form; PDQ-D: Perceived Deficits Questionnaire-Depression; FIBSER: Frequency, Intensity and Burden of Side Effects Rating; C-SSRS: Columbia-Suicide Severity Rating Scale; VNS: vagus nerve stimulation; TRD: treatment-resistant depression.
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For this pilot self-controlled study, a minimal required sample size was not calculated. Ten consecutive patients will be included. Therefore, this trial will only describe the demographic data, medical histories, and trial statuses of the subjects. The stability of the medical device and occurrence of adverse events will be tabulated.
Data collection and management
The researchers will complete a CRF for each subject who provides written informed consent. The research representative or a deputy designated by the research representative will authorize the principal investigator or researchers to access the electronic CRF system. The data will be entered directly into the electronic CRF system. The principal investigator or other researchers will confirm that the CRF is accurate and complete, and register the data in the electronic CRF system. The principal investigator will be solely responsible for the accuracy and reliability of all data entered into the CRF. The completed CRF will be property of the research center. The principal investigator and other researchers will have no right to disclose the information in the CRF to supervising organizations without written approval by Research Center Director. Only inspectors will have access to the data.
During the trial, regular audits by inspectors responsible for quality control will be performed to ensure that the trial is conducted in strict accordance with the study protocol, as well as that the information is recorded correctly.
The researchers will carefully implement the standard operating rules of clinical trials before, during, and after the trial. During the trial, inspectors responsible for quality control, assigned by the principal investigator, will audit the trial records for the correctness and completeness of the CRF data
The researchers must receive professional training and follow uniform data recording methods and evaluation standards.
Patients included in this trial will receive a transportation allowance and have their appointment and follow-up examination fees waived. The researchers will provide insurance coverage for all subjects, cover the costs of treatment, and provide financial compensation for subjects suffering damage or death associated with the trial.
Ethics and data dissemination
This trial will follow the relevant laws and regulations of the Declaration of Helsinki, as well as the relevant ethical medical principles in China.
The sponsor has the responsibility to provide the research institutions with relevant information on the medical products used in the trial. The research institution will study the information and formulate a reasonable study protocol that includes the informed consent form approved by the IRB of Beijing Anding Hospital at Capital Medical University (approval No. 201775fs-2; Additional file 1 [Additional file 1]). The trial was not initiated until approval from the IRB was received.
The entire trial process will be supervised by the IRB of Beijing Anding Hospital at Capital Medical University. All subjects will voluntarily participate in the trial and provide written informed content prior to its commencement. The content of the informed consent and the procedure to obtain such consent will be in accordance with the requirements of Good Clinical Practice (GCP). Written informed consent from each subject will be stored as a research archive. This manuscript was prepared and modified according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Additional file 2 [Additional file 2]). The results of this trial will be disseminated through presentations at scientific meetings or by publications in peer-reviewed journals. Anonymized trial data will be published at www.figshare.com.
| Discussion|| |
The efficacy and safety of VNS for the treatment of TRD have been demonstrated in a large number of clinical trials in multiple countries. In 2005, the U.S. FDA approved VNS as a long-term adjuvant treatment for patients with chronic or recurrent depression who are over 18 years of age and do not respond well to at least 4 antidepressants. However, no clinical trials of VNS for TRD are currently underway in China.
Beijing Xuanwu Hospital affiliated with Capital Medical University has performed VNS surgery in 120 cases of epilepsy, thus gaining rich experience in VNS surgery. The research team will receive professional training prior to the commencement of the trial. The trial will be performed in strict accordance with the study protocol and relevant laws and regulations. Enrollment of the patients will be also in strict accordance with the inclusion/exclusion criteria. All the subjects will be followed up for 12 months after nerve stimulation. A comprehensive assessment of the efficacy, quality of life and social function, cognitive function, and safety will be performed in TRD patients undergoing VNS adjuvant therapy. In China, VNS for epileptic treatment has been carried out in several hospitals, but it has not been routinely used as a therapy for TRD. For the benefit of patients with TRD in China, we attempt to perform a pioneering study in cooperation with the Xuanwu Hospital of Capital Medical University to explore the initial efficacy and safety of VNS in TRD patients.
This is the first clinical trial of VNS for TRD by the research team. In addition, only 10 patients will be enrolled. Large randomized controlled trials will be required to confirm the results of this study. 
The trial will provide a clinical basis for the VNS treatment of TRD and explore new approaches to the treatment of TRD in China.
| Trial Status|| |
Patient recruitment is ongoing at the time of submission.
We sincerely thank the Xuanwu Hospital of Capital Medical University, China for its technical support.
GW will be responsible for research guidance. JJZ and Zhou Yang conceived and designed the trial, and will be responsible for subsequent trial operations. XHZ will be responsible for surgical treatment. All authors approved the final version of this manuscript for publication.
Conflicts of interest
Implantable VNS system will be used as an assistant therapy. The authors declare that no competing financial interests exist.
The study was supported by the National Key Research & Development Program of China, No. 2016YFC1307200; the National Natural Science Foundation of China, 81527901; the Special Fund for Clinical Development by Beijing Municipal Administration of Hospitals, China, No. ZYLX201607; the Special Fund for Climbing Plan by Beijing Municipal Administration of Hospitals, China, No. DFL20151801. The conception, design, execution, and analysis of experiments, as well as the preparation of and decision to publish this manuscript, were made independent of any funding organization.
The protocol has been approved by the Ethics Committee of the Beijing Anding Hospital of Capital Medical University in China (approval No. 201775FS-2). All the patients and their families will voluntarily participate in the trial, and provide written informed consent with the premise of fully understanding the treatment plan. Clinicians and the research institute involved in the trial will follow the relevant laws and regulations of the Declaration of Helsinki and relevant hospital's ethical principles. The results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. This trial was registered in the Chinese Clinical Trial Registry with registration No. ChiCTR-ONC-174013430 (version 2.0) on November 17, 2017.
Declaration of patient consent
The authors certify that they will obtain patient consent forms. In the form, patients will give their consent for their images and other clinical information to be reported in the journal. The patients will understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Data sharing statement
Individual participant data that underlie the results reported in this article after deidentification (text, tables, figures, and appendices) will be shared. Study protocol, informed consent form and clinical study report will be promulgated within 6 months after the completion of the trial. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.
Checked twice by iThenticate.
Externally peer reviewed.
Additional file 1: Ethical approval by the Beijing Anding Hospital.
Additional file 2: SPIRIT checklist.
Funding: The study was supported by the National Key Research & Development Program of China, No. 2016YFC1307200; the National Natural Science Foundation of China, No. 81527901; the Special Fund for Clinical Development by Beijing Municipal Administration of Hospitals, China, No. ZYLX201607; and the Special Fund for Climbing Plan by Beijing Municipal Administration of Hospitals, China, No. DFL20151801.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]