The RESTEP Study (ClinicalTrials.gov ID: NCT03053726) is a double blind, randomized, multicenter trial designed to evaluate the safety and effectiveness of STN-VFS treatment in participants with advanced PD. According to the trial flow chart (Figure 1), participants with advanced PD who had previously undergone DBS will be screened based on strict inclusion and exclusion criteria. A total of five follow-up surveys will be scheduled as shown in Table 1. After recruitment, pulse generators previously implanted in all participants will be upgraded from those with a single mode (CFS only) to those that are capable of dual mode stimulation (CFS or VFS). Following this upgrade, participants will be randomly and equally divided into two groups, the CFS group and the VFS group. After 3 months of stimulation in the blinded conditions, all participants will receive VFS and follow-up assessments for 6 months. The protocol design is based on the guidelines of the Consolidated Standards of Reporting Trials (CONSORT) and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT), and the study results will also be reported according to these guidelines. Informed consent will be obtained from all participants in accordance with the policies of the board.
The trial will be conducted in approximately 11 centers. These include Beijing Tiantan Hospital, the first affiliated hospital of Dalian medical university, Nanjing brain hospital, Tangdu Hospital (Fourth Military Medical University of Chinese PLA), Qilu Hospital, Peking union medical college hospital, Chinese PLA general hospital, the second people’s hospital of Shenzhen, Changhai hospital of Shanghai, Huashan hospital, Sir Run Run Shaw Hospital (Affiliated with School of Medicine, Zhejiang University). Other hospitals will be invited to join the study according to interest, feasibility, and resources. The clinical investigators from each center will be responsible for screening eligible participants.
Patient population and recruitment
We intend to enroll a total of 106 participants aged over 18 years. The prospective cohort will comprise PD patients who have received STN-DBS treatment and have implanted impulse generators that are compatible with VFS (PINS Medical).
- Patients with idiopathic Parkinson's disease
- Aged ≥ 18 years, both male and female
- Patients who have already undergone DBS and currently have an implanted STN-DBS stimulator
- A Mini-Mental State Examination (MMSE) score of ≥ 24
- A Hoehn-Yahr (H-Y) score of ≥ 2.0 when undergoing CFS in a “medication off” state
- A score of ≥ 1 on the 14-item Unified Parkinson’s Disease Rating Scale II (UPDRS-II)
- A score of ≥ 2 on the 15-item UPDRS-II
- The ability to walk ≥ 10 meters independently when receiving CFS in a “medication off” state
- Pregnant women, breastfeeding mothers, or woman who are unable to take effective measures to prevent pregnancy
- Presence of other diseases that can affect walking distance, such as joint disease in the lower body, spinal disease, neuropathy, or serious heart or lung disease
- Serious health conditions such as tumor, liver or kidney disease, etc.
- Epilepsy or other seizure disorders
- Mental disorders or dementia
- Inability to comprehend the experimental protocol or voluntarily provide informed consent
- Lack of cooperation with follow-up requirements
- Additional reasons for exclusion at the discretion of the clinical investigator
Recruitment of participants
Participants will be recruited via advertisements online and directly at the participating hospitals.
Constant Frequency Stimulation (CFS)
To deliver CFS, electrical stimulation will be set to a constant frequency by the physician programming the stimulation frequency parameters, i.e., the pulse width and amplitude. The participants with receive STN-DBS with single frequency, single pulse width, and single amplitude stimulation.
Variable Frequency Stimulation (VFS)
The VFS parameters will be selected based on previous findings regarding the relationship between stimulation frequency and movement rhythm regulation in humans. The stimulation frequency will be set to alternate between high and low frequencies.
Participants will be allowed to continue taking medications they had been on before the trial. Use of all drugs, if any, will be documented in the Case Report Form (CRF).
Randomization and blinding
Eligible participants will be randomly assigned to one of two groups (CFS group or VFS group) after completing the baseline measurements. A 1:1 assignment sequence (based on computer-generated random numbers) will be produced by The Peking University Clinical Research Institute. The computer-generated random numbers will be used to create the participant numbers and order lists, which will be placed in opaque sealed envelopes and sent to the research centers. The research clerk will keep copies of the order lists and participant numbers.
Throughout the study, with the exception of the study programmer, all participants and study staff (including investigators, trainers, and statisticians) will be blinded to the treatment allocation. Independent raters who have no therapeutic relationships with the participants and who are blind to the treatment conditions will conduct outcome assessments. The independent raters will be clinical neurologists who have received additional training on the use of the outcome assessments, had the opportunity to listen to conducted assessments, and received direct feedback regarding their assessments from supervisors. Further, the Data and Safety Monitoring Board will review a random selection of 20% of the recorded assessments. Loss of blinding may occur due to the magnitude of the therapeutic effect or any other subjective perception that indicates that VFS or CFS is delivered.
Primary clinical outcomes
The primary outcome will be Stand-Walk-Sit (SWS) task scores at 3 months compared with the baseline scores. The domain of the SWS score is the gait. The study will compare the mean scores in each group between 3 months and baseline, use the median scores from each group. The SWS test is a simple and quick functional mobility test that requires an individual to stand up, walk 5 m, turn, walk back, and sit down. The time taken to complete the test is strongly correlated with the level of functional mobility. This test will be videotaped and scored by two blinded neurologists.
Secondary clinical outcomes
As secondary outcomes, we will use the Freezing of Gait Questionnaire (FOGQ), Gait and Falls Questionnaire (GAFQ), and Parkinson's Disease Quality of Life questionnaire (PDQ-39), as well as total UPDRS and UPDRS III scores to assess PD symptom severity at 3 and 6 months compared with the baseline. These questionnaires assess physiological symptoms and emotional function in PD patients. Participants in both trial groups will be asked to complete these questionnaires at baseline and post-treatment, and the trial group will also be asked to complete the measures 3-months and 6-months post-treatment. The study will compare the mean change scores from baseline at each time point, use the median scores from each group.
An adverse event (AE) could include an abnormal laboratory finding, symptom, or disease temporally associated with the administration of an investigational product, regardless of whether it is related to that investigational product. In the present study, an unexpected AE is anything that is not identified in nature, severity, or frequency in the Investigator’s Brochure. During routine assessments, the investigator will questions the participants about the occurrence of AEs and record the information in the source documents and patient case report form (CRF).
Serious Adverse Events (SAEs)
- A life-threatening adverse experience
- Inpatient hospitalization or prolongation of existing hospitalization
- A persistent or significant disability/incapacity
- A congenital anomaly/birth defect
Other important medical events may also be considered SAEs when, based on appropriate medical judgment, they jeopardize the participant or require intervention to prevent one of the outcomes listed.
When AEs occur throughout the clinical trial, investigators may take necessary measures according to the condition of the participant. Based on the severity of the AE, the investigators may choose hospitalization, outpatient treatment, home visits, communication, or other follow-up methods.
Data and Safety Monitoring Board (DSMB)
The DSMB will review the safety, ethics, and outcomes of the study. It is independent from the sponsor and has no competing interests. DSMB members will monitor blinded assessment data for SAEs or potential harmful effects. A charter that will outline member responsibilities, procedures, and confidentiality will govern the DSMB. The DSMB will also review unblinded data at regular intervals during the follow-up period and will monitor neurological and functional differences between the two groups, as well as dropout and event rates.
Data quality and management
The participants will be randomly selected and any reasons for exclusion will be recorded in their medical records and reviewed by the trial monitor.
Data collection and monitoring
- CRFs must be completed according to the schedule.
- All SAEs that occur during the observation period must be reported to the medical expert overseeing the investigation, i.e., the medical director of Beijing PINS Medical Co., Ltd.
- The investigators are responsible for all information collected about participants enrolled in this study. The investigators and sponsor will conduct regular telephone or home follow-up of patients.
- The monitoring system will assure the quality of the assessments.
- The data will be entered into a validated database.
- The Data Management Group will be responsible for data processing, in accordance with procedural documentation. The database will be locked once quality assurance procedures have been completed.
Withdrawal and terminate from the study
In case of endangerment of personal safety, lack of compliance, or withdrawal of informed consent, a patient will instantly be excluded from the study. Further, participants will be withdrawn from the study in the following conditions: (1) The patient’s parents require withdrawal; (2) The patient develops heart failure, respiratory failure, or another serious disease. The DSMB might terminate the study in the following conditions: (1) SAEs occurred during the trial, the investigator determined that the trial should be terminated; (2) The Ethics Committee require.
Handling of Missing Data
All variables included in the CRF are mandatory. The method last visit carried forward will be used to handle the missing data.
This trial will be audited by the Research Ethics Committee and the China Food and Drug Administration. The audits will be performed when the first participant enrollment, half and all of the enrolled cases are completed.
The sample size was calculated based on the primary outcome measure according to the results of our pilot study. Power was set at 80% and calculated based on two-sided 95% confidence intervals. In our pilot data, we detected a post-treatment difference in PD symptoms of at least 20% between the VFS and CFS groups of SWS scores. We assume that the placebo effect can account for about 10% of such differences. The sample size in each group was determined using a formula derived by Whitley et al. We assume that 10% of the trial participants will be lost to attrition. Thus, 53 participants need to be allocated to each treatment group to establish a difference among the treatments at a level of 5% with a power value of 90%.
All evaluations of effectiveness and safety will be conducted according to the intention-to-treat (ITT) principle. The final data will be analyzed using IBM SPSS 13.0 or higher (SPSS, Inc., Chicago, IL, USA) and SAS 9.4 or higher (SAS Institute Inc., Cary, NC, USA) software. A p-value < 0.05 will be considered statistically significant. Data will be analyzed with t-tests and χ2 tests for continuous variables and categorical variables, respectively.
When participating in research there is always a risk regarding the confidentiality of information. All information gathered in the present study will be stored in a secure database. All participants will provide written informed consent prior to being assessed for eligibility for inclusion in any part of the study. Every precaution will be taken to respect the privacy of participants in the conduct of the study. Information will be stored on a password-protected server with access that is limited to members of the study team. In the course of monitoring data quality and adherence to the study protocol, the monitors will refer to medical records at the participating hospitals. All individual and site information will be de-identified when reporting the data and results to protect the confidentiality of the participants.