Study setting

The study will be conducted in two university hospitals, Zhujiang Hospital and Nanfang Hospital affiliated to Southern Medical University (Guangzhou, China) and in Sichuan Provincial Bayi Rehabilitation Hospital, a general hospital in Chengdu, China. The patients will be assessed for enrolment, and eligible patients will be hospitalised for treatment in the departments of neurology in the three hospitals.

Trial design

This randomised double-blind placebo-controlled multicentre superiority trial is designed to recruit two parallel groups, and randomisation will be performed by block randomisation in a 1:1 allocation ratio. The study design is shown in the flow chart in figure 1.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Flow chart of the trial design.

Participant enrolment and eligibility criteria

The participants will be recruited by advertisement on the internet and using posters in hospitals. Potential eligible patients will be screened for enrolment according to the inclusion and exclusion criteria listed in table 1.

Ethical considerations

This study has been approved by the Ethics Committee of Zhujiang Hospital of Southern Medical University. The methods, purpose and potential risks of this study will be fully explained to the participants and their family members. Each patient will be asked to sign three informed consents before participating in the study.

Sample size calculation

The sample size was calculated based on the data of Valiengo et al,16 who reported a response rate of 0.041 in patients receiving sham rTMS treatment and a rate of 0.375 in patients having active rTMS treatment. Considering the low efficiency of sham rTMS treatment, we calculated the sample size using the following formula:

The result showed that a sample size of 26 in each group was sufficient by assuming a two-tailed significance level of 5% with a statistical power of 90%. We estimate that the dropout rate will be less than 25%, and considering the need for randomisation, we assume that at least 33 participants are required in each group.

Randomisation and blinding

For randomisation of the patients, random numbers will be generated using SAS9.4 software by statisticians based on a randomised block design with a block length of s. The magnetic stimulation coils for active and sham treatments have identical appearances and will be numbered by a statistician. The random numbers will be printed and sent to each trial centre in sealed envelopes. Upon enrolment of an eligible patient, the investigator opens the envelope to reveal the number of the magnetic stimulation coil to be used, without knowing whether the patient receives active or sham treatment. In this double-blind trial, both the participants and investigators are blinded to the nature of treatment (active or sham).

Interventions

The participants enrolled in this trial will receive either active or sham rTMS treatment in addition to routine supportive treatments including antiplatelet agents, blood pressure control, neurotrophic therapy, physical therapy and cognitive rehabilitation prescribed based on the condition of the individual participant. The enrolled patients will not receive any other antidepressants, anxiolytics or hypnotic treatments that may have an impact on depression treatment during the study. All the participants will receive psychiatric and neuropsychological tests and MRI examination at the time of enrolment and at the end of treatment. rTMS will be performed using a Mag Pro R30 device (Mag Venture Company, Frum, Denmark) via 121 mm circular coils (MCF-125). The participants will receive active or sham treatment 5 days per week for four consecutive weeks. The motor threshold (MT) is defined as the lowest stimulation intensity capable of inducing at least 50 μV peak-to-peak amplitude of motor evoked potentials in at least half of 10 trials. The detailed parameters of the protocols of active rTMS treatment are listed in table 2.

MRI

On enrolment and at the end of the trial, the patient will receive a MRI examination using a 3.0T PHILIPS Magnetic Trio Tim scanner. For the standard investigation, MRI will be performed using the following scan parameters for different sequences: for T1-weighted sequence, time of echo (TE) 20 ms, time of repetition (TR) 2000 ms, number of signal averaged (NSA) 1, number of slices 32, slice thickness 3 mm; for T2-weighted sequence, TE 80 ms, TR 3000 ms, NSA 2, 32 slices, slice thickness 3 mm; for FLAIR sequence, TE 80 ms, TR 3000 ms, NSA 2, 32 slices, slice thickness 3 mm; for diffusion tensor imaging (DTI) using single short echo planar imaging (SE-EPI), TE 68 ms, TR 2300 ms, NSA 1, 32 slices, slice thickness 3 mm, b₀=0, b₁=1000, matrix=512*512. Once the original data have been obtained, an experienced imaging physician will select the caudate nucleus, lentiform nucleus, dorsal medial nucleus of the thalamus  and the nucleus of the thalamus as the regions of interest (ROIs) at the imaging layer of the basal ganglia. The three-dimensional fibre bundle imaging technique will be used to display the fibrous pathway of the dorsal basal ganglia system and the fibrous pathway of the ventral basal ganglia system. The DTI parameters will be obtained, including the fractional anisotropy (FA), apparent diffusion coefficient (ADC) and neural fibre number (NFN). The MRI scanners at the three centres will be tested for homogeneity before the trial, while ROI selection and DTI data acquisition will be performed by an experienced radiologist using PHILIP 2.1 software.

Outcome assessment

Primary efficacy parameters

The primary efficacy parameter is the change in 24-item Hamilton Depression Rating Scale (HAMD-24) scores from the baseline at the end of the treatment. We plan to measure the response rate and remission rate as the primary efficacy parameters, determined by changes in the HAMD-24 scores from baseline at the end of the treatment. Response to treatment is defined as a reduction of at least 50% in the HAMD-24 total score, with a final HAMD-24 score below 9. Remission is defined as a reduction in the HAMD-24 total score of at least 50% from baseline. As a valid and reliable scale for assessing the severity of depression, the HAMD scale has been widely used in studies of PSD and shows a good sensitivity in assessing treatment responses. The HAMD-24 scale consists of subscales that examine interest, anxiety, hopelessness, sleep status and self-abasement, and a higher score suggests a poorer condition of mental disorder.17 The HAMD-24 scale will be scored three times at 0, 2 and 4 weeks after the commencement of the treatment.

Secondary outcome measures

Assessment of adverse events

All adverse events (AEs) will be reported and recorded on the case report form (CRF) by investigators. The investigators will record the date of occurrence, duration and severity of the AEs, along with the treatments and consequences. Cases of serious AEs will be immediately reported to the project leader and the ethics committee, and the latter will evaluate whether the patient should receive further treatment. We will discontinue the allocated interventions if the disease shows significant worsening. Those participants who suffer harm from this trial will be provided with compensation.

Quality control and data management

The trial protocol has been revised several times by experts in neurology, rehabilitation, medical imaging, statistics and psychology. All the investigators have participated in the training sessions to ensure that they fully understand the trial protocols and the standard procedures before the study. Inspectors will be nominated to regularly visit each research centre to monitor the implementation of the protocols and assess the compliance of the participants and investigators. The CRF data will be double-entered by statisticians to ensure the accuracy of the data. Statisticians in our team will be responsible for data management and analysis. To improve the participants’ adherence to this study, we will select the participants rigorously and cover the costs of neuropsychological assessment and MRI. At the end of treatment the patients will be informed about the follow-up and a telephone call will be made in the fourth week after the end-point to remind them about follow-up.

Statistical analysis

The quantitative data including the demographic indicators, laboratory test results, MRI results and neuropsychological test results will be expressed as numbers, means with SD or median with range or quartile range as appropriate. These data will be compared using the independent sample t-test or rank-sum test depending on whether the data are normally distributed. Qualitative data, including the response and emission rates and incidence of AEs, will be expressed as frequency or frequency rate and compared using a χ² test between the two groups. The missing data will be described in terms of exit data, exit reason, treatment arm, frequencies and percentage of missing data in each group and the data imbalances will be evaluated by a χ² test or Fisher’s exact test. All the data will be double-entered into Epidata software and analysed using SAS software by statisticians blinded to the participants’ allocation. A P value <0.05 will be considered to indicate a statistically significant difference.

Monitoring

All personal information collected from the potential and enrolled participants will be stored in the medical record management system maintained by the Information Security Department of each hospital to ensure confidentiality. Investigators will record the research information on the CRFs and identify the CRFs with only initials and participation number rather than the participants’ real identity. The research information has been detailed above, including neuropsychological tests, MRI results and baseline parameters. All the CRFs will be kept securely in a locked area. The data managers, study statisticians and investigators will have access to the final trial dataset. The data managers and study statisticians will only access the data for data management and statistical analysis and will not be involved in the clinical treatment and psychological assessment. An annual audit by the Delegation of the Research Department of Southern Medical University is provided.