Trial design
This study is a randomized, multicenter, double blind clinical trial with two treatment groups (tVNS and sham tVNS). Please see flow chart (Figure 1) for more details regarding the clinical procedures. The clinical endpoints are assessed by blinded independent observers. The central randomization system is used to assign patients to the tVNS or sham tVNS treatment groups. All procedures are performed by the Clinical Evaluation Center at the China Academy of Chinese Medical Sciences (CACMS) in Beijing. The Ethics committee of Institute of Acupuncture and Moxibustion, CACMS approved the experiment procedure.
Setting
Investigators are conducting the trial in four hospitals in Beijing, China. These four hospitals are: Guang An Men Hospital, China Academy of Chinese Medical Sciences; Huguosi TCM Hospital, Beijing University of TCM; Acupuncture Hospital, China Academy of Chinese Medical Sciences.
Blinding
As a double-blinded trial, both study physicians/investigators and patients are blinded to treatment group (tVNS versus sham tVNS). To ensure that both investigators and patients remain blinded, two carbon-impregnated silicone electrodes are fixed to one ear clamp (Figure 2). Only one of the electrodes; however, is connected to the electrical lead (wire) imbedded in the clamp in order to keep the operation of the study double blind. In the tVNS group, the upper electrode was wired to the transcutaneous electrical nerve stimulator (TENS) while in the sham tVNS group the lower electrode is inactively wired to the TENS.
Both the physician’s and the patient’s blindness to the mode of treatment are assessed after completion of all post-treatment measurements by asking each individual to guess the treatment modality they received given three options, “real tVNS”, “sham tVNS” or “uncertain”.
Patients
Study population
Patients with mild or moderate MDD are recruited for the trial. ICD-10 Classification of Mental and Behavioral Disorders are used for diagnosis of MDD. Patients who voluntarily provide informed consent and meet inclusion/exclusion criteria are enrolled in this study. Inclusion and exclusion criteria include:
Inclusion criteria
-
1.
Patient meets ICD-10 diagnosis standard: mild (2 typical + 2 other core symptoms), moderate (2 typical+3 other core symptoms).
-
2.
Patient is 16–70 years of age
-
3.
Patient stopped taking anti-depressive medication or other psychiatric medications 2 weeks before the intervention started.
-
4.
Patient is educated beyond junior high school, in order to understand the scales.
-
5.
Patient has exhibited symptoms for at least 2 months, and no longer than 2 years.
Exclusion criteria
-
1.
Patients with current addiction to drugs
-
2.
Patients with severe depression or suicidal thoughts
-
3.
Patients with severe medical disorders
-
4.
Patients with poor compliance
Recruitment procedures
The investigators recruit patients with mild or moderate depressive symptoms using advertising and by sending flyers to the four hospitals involved in the study. After passing a pre-screening, potentially eligible patients provide informed consent in the presence of a study physician.
Intervention and comparison
tVNS treatment
Location
The points for tVNS are located in the auricular concha area where there is rich vagus nerve branch distribution (Figure 2).
Intervention procedure
Patients take a seated position or they lay on their side. After the stimulation points are disinfected according to standard practice, ear clips are attached to the ear area (auricular concha) that will be stimulated. Stimulation parameters include: 1) density wave adjusted to 20Hz, with less than 1ms wave width; and 2) 1mA current turned on. The intensity is adjusted based on the tolerance of the patient. Each treatment lasts for 30 minutes and is carried on twice a day, 5 days per week for the duration of the treatment period (12 weeks).
Sham tVNS treatment
Location
The stimulation points for sham tVNS are located at the superior scapha (outer ear margin midpoint), where there is no vagus nerve distribution (Figure 2).
Intervention procedure
All procedures performed in the sham tVNS treatment group are identical to the procedures for the verum tVNS group.
Choice of endpoints
All endpoints are measured at week 0 and week 10. The endpoints include the 24-item Hamilton Depression Rating Scale (HAM-D-24), the 17-item Hamilton Depression Rating Scale (HAM-D-17), Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), electrocardiogram rate, breathing rate, and skin conduction response. Similar to previous studies [12, 13], the primary outcome is the categorical classification of treatment response. We are interested in comparing the difference in treatment response rate between the two groups as measured by HAM-D-24, where treatment response is defined as a 50% or greater reduction in HAM-D-24 scores following a 10-week treatment.
In addition, previous studies [14–17] suggest that expectations for symptom relief can significantly influence the response to medications, acupuncture, and placebo. Thus, before the first treatment, patients are asked to rate on a scale how much they expect the treatment will relieve their symptoms, from “complete relief” to “do not work at all”.
Sample size calculation and statistical analysis
Sample size
We present here our power analysis for the primary outcome only. Since this is a novel therapy, we used the data from a previous non-controlled pilot study on treatment-resistant MDD in senior patients [18] to calculate the power. The primary outcome measure is the categorical classification of response; we define the treatment response as a 50% or greater reduction in HAM-D-24 scores following treatments. From a previous proof of concept study [18], the response rate in the tVNS group is 39%; assuming a 20% dropout rate, with 60 patient in each group, we will have 80% power to detect a difference of 25% or greater in response rate between the tVNS and the sham tVNS group based on a chi square test at a 0.05 significance level.
Statistical analysis
In this study, the primary outcome measure is the categorical classification of treatment response. We define the treatment response as a 50% or greater reduction in HAM-D-24 scores following treatments. Response rates across the two groups will be compared with the chi square (x
2) test.
Additionally, we will also use the HAM-D-24 score as continuous variable and apply a regression model to compare the different between two treatment groups. More specifically, in the model, the dependent variable is post-treatment HAM-D-24 score, the independent variable is treatment mode (tVNS versus sham tVNS), and covariances will include pre-treatment HAM score, age and gender. Similar analyses will also be performed in other clinical and physiological outcome measurements.
Data safety monitoring
Independent data safety monitoring board members will meet every 6 months or as needed. Participants who show persistent worsening symptoms during the course of a clinical trial or develop unstable psychiatric symptoms (e.g., suicidality, homicidality, psychosis) will be withdrawn from the study and will be referred for appropriate treatment immediately.
According to the following classifications, a safety monitoring board will review and rate adverse events to determine whether to suspend the test condition.
-
Level 1: Security, without any adverse reactions.
-
Level 2: Safe, and have mild adverse reaction, do not need any treatment can continue to treatment.
-
Level 3: There are security issues; there is a moderate adverse reaction, after treatment may continue to treatment.
-
Level 4: Because of adverse reactions, terminate this research.
All adverse events will be reported to the Human Research Committee promptly in accordance with guidelines.