Subthalamic Nucleus (STN) and Globus Pallidus Internus (GPi) Deep Brain Stimulation (DBS) in Patients With Primary Dystonia（RELAX Study）
Phase: NA
Conditions: Dystonia
Sponsor: Beijing Pins Medical Co., Ltd

Study protocol for Subthalamic Nucleus and Globus Pallidus 
Internus Deep Brain Stimulation in Patients With Primary Dystonia: 
a multicentre randomized controlled trial（RELAX Study） 
NCT03017586 
Date: 05/26/2017 
Author: Lin Wang, Huifang Shang, Lingjing Jin, Yi Guo, Xinhua Wan 
Affiliation and organization:  
1. Department of Neurology, Peking Union Medical College Hospital, 
Chinese Academy of Medical Sciences, Peking Union Medical College 
2. Neurotoxin research center of Key Laboratory of Spine and Spinal Cord 
Injury Repair and Regeneration of Ministry of Education, Neurological 
Department of Tongji Hospital, School of Medicine, Tongji University 
3. Department of Neurology, Union Hospital, Tongji Medical College, 
Huazhong University of Science and Technology 
4. Neurology Department, Sir Run Run Shaw Hospital, School of 
Medicine, Zhejiang University 
5. Department of Neurosurgery, West China Hospital, Sichuan University 
6. Department of Neurology, Qilu Hospital, Shandong University 
7. Department of Geriatric Neurology, The Affiliated Brain Hospital of 
Nanjing Medical University 
8. Clinical Research Institute, Institute of Advanced Clinical Medicine, 
Peking University 

9. Department of Neurosurgery, Peking Union Medical College Hospital, 
Chinese Academy of Medical Sciences, Peking Union Medical College 
10. Department of Neurosurgery, Union Hospital, Tongji Medical 
College, Huazhong University of Science and Technology 
11. Department of Functional Neurosurgery, The Affiliated Brain 
Hospital of Nanjing Medical University 
12. Department of neurosurgery, Qilu Hospital, Shandong University 
13. Department of Neurology, Laboratory of Neurodegenerative 
Disorders, West China Hospital, Sichuan University 
Corresponder: Yi Guo, Xinhua Wan 
 
 

Abstract  
Background: Dystonia is a relatively rare group of movement disorders that often prove difficult 
to treat effectively. Nowadays, deep brain stimulation (DBS) has become widespread and 
established treatment for patients with dystonia. The bilateral stimulation of either the globus 
pallidus internus (GPi) or the subthalamic nucleus (STN) is effective and safe in improving clinical 
symptoms and quality of life for patients with dystonia. RELAX study is a multicenter, prospective, 
randomized study designed to evaluate the clinical effectiveness and safety of DBS in patients with 
dystonia.  
Methods/Design: Participants will be recruited in approximately 10 centers across China. All 
patients will undergo genetic testing. Eligible participants with dystonia will undergo DBS 
implantation according to the target randomization. Then, participants will be randomized to one of 
two groups: the experimental group (EG) with DBS on or the control group (CG) with DBS off. 
The primary outcome measures will focus on the changes in the Burke-Fahn-Marsden Dystonia 
Rating Scale (BFMDRS) movement scores, specifically assessed at three and six months of 
treatment. Secondary outcome measures, including specific item scores on the Short-Form General 
Health Survey (SF-36), Visual Analog Scale (VAS), walking measurements, the Beck Depression 
Inventory (BDI), Mini-Mental State Examination (MMSE), and the rate of improvement of the 
BFMDRS score, were all observed and recorded at 3 and 6 months during the treatment period. The 
aim of this trial is to investigate the efficacy and safety of DBS in patients with primary dystonia 
and gain insight regarding the therapeutic effects of different targets. Discussion: This is a large 
sample, randomized controlled trial to comprehensively evaluate the effectiveness and safety of 
DBS in patients with dystonia of different target.  
Trial registration: NCT03017586, clinicaltrials.gov, registered on January 11, 2017, 
https://www.clinicaltrials.gov/ct2/show/NCT03017586  
Keywords: Dystonia, Deep brain stimulation, Subthalamic nucleus, Globus pallidus internus 
 
 

Background 
Dystonia is the third most common movement disorder, characterized by sustained or intermittent 
involuntary muscle contractions causing twisting and repetitive movements or abnormal postures 
[1]. Primary dystonia is the most common form of dystonia, comprises a group of idiopathic, 
incurable movement disorders that vary with respect to age at onset, body distribution, and genetic 
association, to be 16.4 per 100,000 individuals [2]. Primary dystonia is a severe motor disease, 
causing physical and social incapacity in patients, devastating with significant morbidity and 
mortality [3]. Botulinum toxin is recommended as first-line treatment for dystonia, but its efficacy 
is variable and may wane over time. Besides, botulinum toxin is useful in focal dystonia but is 
difficult to use in generalized dystonia. The pharmacological treatment of dystonia is more 
challenging, bearing poor results [4]. The deep brain stimulation (DBS), available since the late 
1980s, has become more widespread and now has established efficacy in a range of medically 
refractory movement disorders, such as Parkinson's disease (PD) and essential tremor (ET) [5]. DBS 
for treatment of dystonia was approved by the US Food and Drug Administration under a 
Humanitarian Device Exemption in 2003 [2]. DBS is now applied worldwide and the benefit-to-
risk ratio of the therapy for dystonia is under scrutiny [6]. Typically, the globus pallidus internus 
(GPi) is the primary and the most studied target in dystonia. Recently, subthalamic nucleus (STN) 
stimulation has also shown a good response rate [4]. Studies have demonstrated that either the GPi 
or the STN is effective and safe in improving clinical symptoms and quality of life for patients with 
dystonia [7]. To our knowledge, however, only few studies has directly compared the clinical effects 
of GPi and STN stimulations in patients with dystonia, and best target for DBS in dystonia is still 
unknown [7]. Thus, randomized controlled trial (RCT) evidence is needed to confirm the efficacy 
and safety of DBS in dystonia patients, gain insight regarding the therapeutic effects of different 
targets (STN and GPi). To this end, we designed present multicenter, prospective, randomized and 
controlled study in patients with primary dystonia. 
Aims 
The purpose of this study is to evaluate the safety and effectiveness of deep brain stimulation 
(DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) for primary dystonia. 
Design and Methods 
Trial design 
The RELAX study (ClinicalTrials.gov ID: NCT03017586) is a double blind, randomized, 
multicenter trial designed to evaluate the clinical effectiveness and safety of DBS using new device 
(G104, E202, L301/L302, PINS, Inc., Beijing, BJ, China) on patients with primary dystonia. Based 
on strict inclusion and exclusion criteria, patients with dystonia will undergo rigorous screening for 
the study. A total of five follow-up surveys have been arranged for the research. After recruitment, 
in the follow-up V2, participants will undertake the implantation of lead and IPG according to the 
target randomization. After the implantation, participants will be randomized (1:1) to one of two 
groups: the experimental group (EG) or the control group (CG). The IPG of participants in EG will 
be turned ON, the IPG of participants in CG will be turned OFF for 3 months. After 3 months of 
stimulation in the blinded conditions, unblinding, the IPG of participants will turn ON and receive 
follow-up assessments for another 3 months. The clinical measurements for the two groups include 
the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), the Short-Form General Health 
Survey (SF-36), the Beck Depression Inventory (BDI) et all. All outcomes will be calculated by 
blinded statisticians appointed by clinical research institute of Peking University following the end 

of the trial. 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. 
Study setting 
The trial will be conducted at approximately 10 investigative centers domestically. Other hospitals 
will be invited to join the study according to interest, feasibility, and resources. No single center 
could exceed 30% of all enrolled patients. The clinical investigators from each center will be 
responsible for screening eligible participants. The protocol has been approved by the Clinical Trial 
Ethics Committee of Peking Union Medical College Hospital and registered on ClinicalTrials.gov 
protocol system (Clinical Trials Identifier: NCT03017586).  
Patient population and recruitment 
The study population comprises 70 patients suffering from primary dystonia. A patient must meet 
all of the inclusion criteria and none of the exclusion criteria to be eligible for the study. A 
neurologist specialized in movement disorders will assess the patients’ eligibility for study 
participation. 
Inclusion and exclusion criteria 
In detail, the key inclusion criteria are: 
1. Refractory primary (systemic, segmental) dystonia diagnosed by a movement disorders 
neurologist 
2. Severe functional impairment despite optimal medical management, including failed 
botulinum toxin therapy 
3. Ability to follow up with post-operative study visits 
4. Patients and their relatives have reasonable surgery expectations 
5. Volunteer to participate in clinical trials, and signed consent form 
6. Age 6-60 years 
Exclusion criteria are: 
1. Pregnancy or plan a pregnancy 
2. Good treatment with Non-invasive therapy 
3. Dopamine reactive dystonia ，Genetic degeneration ，Paroxysmal dystonia ，Secondary 
dystonia， Psychogenic dystonia 
4. Brain MRI showing extensive brain atrophy or small vessel ischemic disease 
5. Cognitive impairment(MMSE<24) 
6. Severe depression or other serious mental illness 
7. History of traumatic brain injury, tumor, or severe cerebrovascular disease 
8. Severe brain atrophy (diagnosed by CT or MRI) 
9. Hyperthermia therapy in implant parts 
10. Abnormal in blood inspection, blood clotting disorders, liver and kidney dysfunction, or 
other clinical judgment cannot tolerate surgery 
11. High blood pressure, serious heart diseases, or respiratory diseases 
12. Diabetes 
13. Long-term treatment of immunosuppressive or hormones 

14. Implant pacemakers, defibrillators, cochlear and other nerve stimulators 
15. Other diseases need frequent MRI examinations 
16. Participated in any other clinical trials within 3 months 
17. Reluctant or unable to implant surgery 
18. Reluctant or unable to cooperate with follow-up 
19. Other exclusion Criteria by researchers 
 
Recruitment of participants 
Participants will be recruited by placing advertisements and posters in clinics and directly at the 
participating centers. The recruitment information mainly includes eligibility criteria and contact 
details. A well-trained investigator in each participating center will be responsible for screening all 
potentially eligible patients based on the eligibility criteria and obtaining the informed consent. 
Randomization and blinding 
There are two step of randomization allocation in this study. Firstly, eligible participants will be 
randomly assigned to one of two targets (STN or GPi) after completing the baseline measurements. 
The 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. After implantation of the device, 
participants will be randomly assigned to one of two groups (EG group or CG group). The 
participants randomized to the EG undergoing the DBS stimulation, participants in the CG will be 
OFF the DBS stimulation for 3 months follow-up. The assignment sequence (based on computer- 
generated random numbers) will be produced by The Peking University Clinical Research Institute. 
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. Loss of blinding may occur due to the magnitude of the therapeutic 
effect or any other subjective perception. 
Outcomes measures 
Primary clinical outcomes 
The primary outcome measures will focus on the changes in movement scores on the Burke-Fahn-
Marsden Dystonia Rating Scale (BFMDRS), which will be specifically assessed after three and six 
months of treatment.  
Secondary clinical outcomes 
Secondary outcome measures, including specific item scores on the Short-Form General Health 
Survey (SF-36), Visual Analog Scale (VAS), walking measurements, the Beck Depression Inventory 
(BDI), Mini-Mental State Examination (MMSE), and the rate of improvement of the BFMDRS 
score, were all observed and recorded at 3 and 6 months during the treatment period. 
Safety outcomes 
The occurrence rate of adverse events (AEs)/serious adverse events (SAEs) are documented at the 
scheduled and unscheduled clinical visits will be used to evaluate the safety of DBS. The 

investigators are responsible for the management of participants’ AEs and SAEs. During 
assessments, the investigator will question the participants about the occurrence of AEs and record 
the information in the source documents and patient case report form (CRF). The clinician will turn 
off the DBS therapy and evaluate the vital signs of the participant if the SAE occurs, then the suited 
therapy would be given for the participant. The investigators may choose hospitalization, outpatient 
treatment, home visits, communication, or other follow-up methods. All incidents are reported to 
the regulatory authority. All safety-relevant events are promptly reported tothe ethics committee and 
the safety monitor within 24 hours. 
Sample size and power calculations 
The study concerns the improvement of dystonia between EG and CG in terms of BFMDRS score 
in the 3 months follow-up. According to the results of study, which design is basically the same as 
this trial. With a power setting of 80% and calculations based on two-sided 95% confidence intervals, 
the study required 17 pairs for GPi and 14 pairs for STN. We assume that 10% of the trial participants 
will be lost to attrition. Thus, a total of 70 participants need to be allocated to each treatment group.  
Statistical analysis 
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.  
Quality assurance/monitoring 
Monitoring is performed by the Data and Safety Monitoring Board (DSMB). DSMB will review 
the safety, ethics, and outcomes of the study. It is independent from the sponsor and has no 
competing interests.  
Data management 
Data collection will be restricted to the those meet the eligibility criteria. Participants who withdraw 
from the study for any reason will be recorded in their medical records and reviewed by the trial 
monitor.  
Withdrawal and terminate from the study 
In case of unexpected harm to the patient, insufficient compliance, or withdrawal of informed 
consent, a patient will promptly be excluded from further study treatment. The reasons for 
withdrawal must be documented in the CRF.  
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.  
Data auditing 
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. 
Discussion 
Dystonia is a movement disorder characterized by abnormal movements or postures. There are many 
different clinical manifestations and underlying causes. This potentially debilitating disease can 
cause various problems, leading to impaired health-related quality of life [8]. Deep brain stimulation 
(DBS) is a well-established surgical treatment for patients with dystonia refractory to medical 

treatment including botulinum toxin injections [8-10]. Although DBS is a well-established treatment 
for dystonia, there is significant heterogeneity in treatment effect and few data are available to 
identify ideal surgical candidates [11]. It is widely understood that the GPi and STN have been two 
used targets in DBS surgery with robustly reduce the BFMDRS score. However, the optimal choice 
is still debate [12-14]. Additionally, its reported that the different subtypes of dystonia also 
contribute to the variation of DBS outcome [15-16].  
This multicenter double-blind randomized clinical trial will enable us to evaluate the effect and 
potential side effects of DBS stimulation in patients with dystonia. We hope to exploring the relative 
effectiveness of different targets (GPi vs STN) after follow-up periods. This study has several 
strengths. First, group-assignment in the double-blinded phase was randomized. Second, we 
performed a power calculation for this study. Most important of all, this outcome might influence 
the target selection and patients who are candidates for DBS to treat dystonia. 
 
Trial status 
The trial is ongoing and is actively enrolling. Target enrollment for this study is 70 participants. 
Protocol version 
The protocol version 1.1, PINS-DBS-1601, 05/26/2017.  
Abbreviations 
AEs, adverse events; BFMDRS, Burke-Fahn-Marsden Dystonia Rating Scale; BDI, Beck 
Depression Inventory; CONSORT, Consolidating Standards of Reporting Trials; CG, control group; 
CRF, case report form; DBS, deep brain stimulation; DSMB, Data and Safety Monitoring Board; 
EG, experimental group; ET, essential tremor; GPi, globus pallidus internus; ITT, intention-to-treat; 
MMSE, Mini Mental Status Examination; PD, Parkinson’s disease; RCT, randomized controlled 
trial; STN, subthalamic nucleus; SF-36, Short-Form General Health Survey; SPIRIT, Standard 
Protocol Items: Recommendations for Interventional Trials; SAEs, serious adverse events; VAS, 
Visual-analogue scale.  
Acknowledgements 
We would like to thank the entire team of researchers, including the nurses and staff at all 10 
hospitals, for their determination, professional skills, enthusiasm, and effort. 
Funding 
This study was supported by Beijing biomedical industry leapfrog development project (G20), No. 
Z181100002218011. 
Availability of data and material 
Data from this randomized controlled study are unavailable at the time of publication. Individual 
participant data is available upon request. 
Author contributions 
Conception and design: Yi Guo, Lin Wang, Lingjing Jin; Study coordination: Huifang Shang, 
Xinhua Wan; Acquisition of legal authorization and data: Yi Guo and Xinhua Wan; Drafting and 
writing of the manuscript: Lin Wang, Huifang Shang, Lingjing Jin; Revision the approval of the 
final version of the manuscript:Yi Guo and Xinhua Wan; All authors reviewed and approved the 
final version of the manuscript. 
Ethics, consent, and participants 
The study will be conducted according to the Good Clinical Practice Guidelines and the principles 
of the Declaration of Helsinki. Written informed consent will be obtained from each participant. 

The study protocol was approved by the Medical Ethics Committee Board of every center. To make 
any amendments to the protocol (Protocol Number: PINS-DBS-1601; Date: 05/26/2017), approval 
will be sought from the Institutional Review Board of Peking Union Medical College hospital. 
Informed consent must be provided in standard writing, the investigators elaborate the content to 
the participants. Informed consent will be provided by all participants, including their consent 
regarding the publication of the results to the investigators. Confidentiality will be ensured during 
all handling of the data. This study has been approved by Ethics Committee of Peking Union 
Medical College Hospital.  
Consent for publication 
Not applicable.  
Competing interests 
The authors declared that they have no competing interests 
 
 

Reference  
1. Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Benabid AL, Cornu P, et al: Bilateral 
DeepBrain Stimulation of the Globus Pallidus in Primary Generalized Dystonia. N Engl J Med 2005, 
352(5):459-467.  
2. Dietz N, Neimat J: Neuromodulation Deep Brain Stimulation for Treatment of Dystonia. 
Neurosurg Clin N Am 2019, 30(2):161-168.  
3. Borgohain R, Mridula RK, Tandra S: Deep brain stimulation in dystonia: The current status. 
Neurol India 2017, 65(6):1234-1235.  
4. Cecchi F: Is deep brain stimulation (DBS) a safe and effective treatment for adults with dystonia? 
- A Cochrane Review summary with commentary. NeuroRehabilitation 2019, 18.  
5. Harding KE, Robertson NP: Deep brain stimulation for dystonia. J Neurol 2016, 263(5):1045- 
1046.  
6. Volkmann J, Wolters A, Kupsch A, Müller J, Kühn AA, Schneider GH, et al: Pallidal deep brain 
stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a 
randomised trial. Lancet Neurol 2012, 11(12):1029-1038.  
7. Lin S, Wu Y, Li H, Zhang C, Wang T, Pan Y, et al: Deep brain stimulation of the globus pallidus 
internus versus the subthalamic nucleus in isolated dystonia. J Neurosurg 2019, 8:11-12.  
8. Tsuboi T, Wong JK, Okun MS, Ramirez-Zamora A: Quality of life outcomes after deep brain 
stimulation in dystonia: A systematic review. Parkinsonism Relat Disord 2019, 18. pii: S1353- 
8020(19):30492-30494.  
9. Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, Lagrange C, Yelnik J, et al: Bilateral, pallidal, 
deep-brain stimulation in primary generalised dystonia: a prospective 3 year followup study. Lancet 
Neurol 2007, 6(3):223–229.  
10. Kupsch A, Benecke R, Müller J, Trottenberg T, Schneider GH, Poewe W, et al: Pallidal deep-
brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006, 355(19):1978-
90.  
11. Badhiwala JH, Karmur B, Elkaim LM, Alotaibi NM, Morgan BR, Lipsman N, et al: Clinical 
phenotypes associated with outcomes following deep brain stimulation for childhood dystonia. J 
Neurosurg Pediatr 2019, 12:1-9.  
12. Wu YS, Ni LH, Fan RM, Yao MY: Meta-Regression Analysis of the Long-Term Effects of 
Pallidal and Subthalamic Deep Brain Stimulation for the Treatment of Isolated Dystonia. World 
Neurosurg 2019, 129:e409-e416.  
13. Meoni S, Fraix V, Castrioto A, Benabid AL, Seigneuret E, Vercueil L, et al: Pallidal deep brain 
stimulation for dystonia: a long term study. J Neurol Neurosurg Psychiatry 2017, 88(11):960- 967.  
14. Deng Z, Pan Y, Zhang C, Zhang J, Qiu X, Zhan S, et al: Subthalamic deep brain stimulation in 
patients with primary dystonia: a ten-year follow-up study. Parkinsonism Relat Disord. 2018, 
55:103-110.  
15. Alterman RL, Filippidis AS: Genetic Subtypes and Deep Brain Stimulation in Dystonia. Mov 
Disord Clin Pract 2018, 5(4):357-360.  
16. Jinnah HA, Alterman R, Klein C, Krauss JK, Moro E, Vidailhet M, et al: Deep Brain Stimulation 
for Dystonia: A Novel Perspective on the Value of Genetic Testing. J Neural Transm (Vienna) 2017, 
124(4):417-430.