Randomised, Double-Blind, Crossover Clinical Trial Comparing Bilateral Deep Brain Stimulation of the Posterior Subthalamic Area Versus the Ventral Intermediate Nucleus of the Thalamus in Essential Tremor
Phase: NA
Conditions: Essential Tremor (ET)
Sponsor: Fundación Pública Andaluza para la Investigación Biomédica Andalucía Oriental

Official Title: Randomised, Double-Blind, Crossover Clinical Trial: Deep Brain Stimulation of 
the Posterior Subthalamic Area versus the Ventral Intermediate Nucleus of the Thalamus in 
Refractory Essential Tremor 
 
Document Type: STUDY PROTOCOL 
 
Version Date: 19 February 2019 
 
 
Study Title 
Randomised, Double-Blind, Crossover Clinical Trial Comparing Bilateral Deep Brain 
Stimulation of the Posterior Subthalamic Area versus the Ventral Intermediate Nucleus of 
the Thalamus in Essential Tremor 
 
Brief Summary 
Essential tremor is one of the most common movement disorders and may become disabling 
in patients who do not respond adequately to pharmacological treatment. Deep Brain 
Stimulation (DBS) targeting the Ventral Intermediate Nucleus (VIM) of the thalamus has 
traditionally been the standard surgical approach. However, stimulation of the Posterior 
Subthalamic Area (PSA) has emerged as a promising alternative, potentially offering improved 
tremor control. 
This study aims to compare the clinical efficacy, energy expenditure, safety and quality of life 
of DBS targeting the PSA versus the VIM using a randomised, double-blind, crossover design in 
patients with medically refractory essential tremor. 
 
Detailed Description 
Deep Brain Stimulation is an established therapeutic option for patients with severe essential 
tremor who are refractory to medication. Although VIM stimulation has long been considered 
the gold standard, increasing evidence suggests that PSA stimulation may provide superior 
tremor suppression and functional outcomes. 
This study is designed as a prospective, randomised, double-blind, crossover clinical trial. 
Participants undergoing bilateral DBS implantation will receive electrodes positioned to allow 
stimulation of both targets (PSA and VIM). Following surgery, patients will undergo two 
blinded stimulation periods in which each target is activated in a randomised sequence. 
Neurological and neuropsychological assessments will be performed at baseline and during 
each stimulation phase. The crossover design allows each participant to serve as their own 
control, thereby increasing statistical power and reducing inter-individual variability. 
 
Study Design 
 
Study Type: Interventional (Clinical Trial) 
 
Allocation: Randomised 
 
Intervention Model: Crossover Assignment 

Official Title: Randomised, Double-Blind, Crossover Clinical Trial: Deep Brain Stimulation of 
the Posterior Subthalamic Area versus the Ventral Intermediate Nucleus of the Thalamus in 
Refractory Essential Tremor 
 
Document Type: STUDY PROTOCOL 
 
Version Date: 19 February 2019 
 
 
 
Masking: Double-Blind (Participant and Outcome Assessor) 
 
Primary Purpose: Treatment 
 
Estimated Enrollment 
The sample size was calculated through a hypothesis of non-inferiority, considering that the 
effect of the experimental technique (PSA-DBS) is no less than the standard technique (VIM-
DBS) in tremor control (first endpoint: total score on the Fahn-Tolosa-Marin Tremor Rating Scale, 
FTM-TRS). The calculation was based on previous results and our experience, considering the 
mean postoperative FTM-TRS scores of 15±15 in the VIM group and 10±8 in the PSA group, with 
power of 80 %, a significance level 5 % and assuming that the non-inferiority limit is 5, with the 
previous post-surgical mean scores and a standard deviation of 11.5 units for both groups. 
Taking into account a 20% increase in anticipation of possible losses and due to the nature of 
the crossover study, the recruitment target was 11 patients (22 measurements in VIM and 22 in 
PSA). In case of missing data due to loss to follow-up or withdrawal of consent, the patient will 
not contribute to the analysis. This was calculated with Ene 3.0 software. 
 
Arms and Interventions 
Experimental Arm 1: PSA Stimulation 
 
Deep Brain Stimulation targeting the Posterior Subthalamic Area 
 
Optimised stimulation parameters during blinded phase 
Experimental Arm 2: VIM Stimulation 
 
Deep Brain Stimulation targeting the Ventral Intermediate Nucleus of the thalamus 
 
Optimised stimulation parameters during blinded phase 
Intervention Description 
All participants will undergo surgical implantation of bilateral DBS electrodes along a single-
trajectory covering the VIM and PSA. Post-operatively, they were randomly (a random block 
randomization) assigned to group 1 (1º PSA – 2º VIM) or group 2 (1º VIM – 2º PSA), undergoing 
stimulation on each target for 3 months. At the end of each period, blind assessments were 
performed, always by the same evaluator (blind to target and stimulation parameters). Patient 
and physician are blinded to the stimulation site during the crossover phase. 
 
Outcome Measures 

Official Title: Randomised, Double-Blind, Crossover Clinical Trial: Deep Brain Stimulation of 
the Posterior Subthalamic Area versus the Ventral Intermediate Nucleus of the Thalamus in 
Refractory Essential Tremor 
 
Document Type: STUDY PROTOCOL 
 
Version Date: 19 February 2019 
 
 
Primary Outcome 
 
Change in tremor severity measured by a validated tremor rating scale (Fahn-Tolosa-
Marin Tremor Rating Scale) 
 
Time Frame: at the end of each stimulation phase 
 
Secondary Outcomes 
 
Stimulation efficiency measured by stimulation amplitudes and total electrical energy 
delivered (TEED) 
 
Quality of life assessed using generic and specific scales 
 
Stimulation-related side effects 
 
Neuropsychological performance assessed using a multi-domain assessment 
 
Eligibility Criteria 
Inclusion Criteria 
 
Confirmed diagnosis of bilateral ET or ET-plus according to the Movement Disorders 
Society criteria.  
 
Refractoriness to medication: at least two attempts at medical treatment with at least 
two groups of different medication (fundamentally propranolol and primidone), which 
were ineffective (insufficient tremor control or adverse effects).  
 
Subjects of both sexes, older than 18 years old.  
 
Sufficient competence to collaborate and comply with the study protocols.  
 
Ability to provide informed consent 
 
Exclusion Criteria 
 
Clinically relevant cognitive decline which may interfere with the study.  
 
Clinically relevant active psychiatric disorder.  
 
Contraindication for general surgery or bilateral DBS.  
 
Unsuitable electrode location according to neuroimaging.  
 
Participation in other interventional study.  
 
Cerebral atrophy (width of the third ventricle >10 mm) or other anatomical anomalies 
that would interfere with optimal stereotactic localization.
 
Study Procedures 

Official Title: Randomised, Double-Blind, Crossover Clinical Trial: Deep Brain Stimulation of 
the Posterior Subthalamic Area versus the Ventral Intermediate Nucleus of the Thalamus in 
Refractory Essential Tremor 
 
Document Type: STUDY PROTOCOL 
 
Version Date: 19 February 2019 
 
 
1. Screening and recruitment 
2. Baseline neurological and neuropsychological assessment 
3. Surgical implantation of bilateral DBS electrodes 
4. Randomisation of the stimulation sequence 
5. Initial programming phase (unblinded optimisation) 
6. Blinded assessments at the end of each crossover phase 
7. End of crossover phase 
8. Open-label phase (during 6 months after crossover phase) 
9. Final evaluation and data analysis 
 
Statistical Analysis 
A within-subject comparison will be performed using appropriate statistical tests for crossover 
designs (e.g. paired analyses). Both primary and secondary outcomes will be analysed, 
adjusting for potential carryover effects. 
 
Safety Monitoring 
Adverse events related to surgery and stimulation will be recorded and classified according to 
severity and relationship to the intervention. 
 
Study Duration 
Approximately 5 years, including recruitment, intervention, and follow-up. 
 
Study Location 
University Hospital Virgen de las Nieves, Granada, Spain 
 
Investigators 
 
Principal Investigator:  

Official Title: Randomised, Double-Blind, Crossover Clinical Trial: Deep Brain Stimulation of 
the Posterior Subthalamic Area versus the Ventral Intermediate Nucleus of the Thalamus in 
Refractory Essential Tremor 
 
Document Type: STUDY PROTOCOL 
 
Version Date: 19 February 2019 
 
 
1. Majed Jouma Katati. Neurosurgeon (University Hospital Virgen de las Nieves/ 
University of Granada, Granada, Spain) 
2. Francisco Escamilla Sevilla. Neurologist (University Hospital Virgen de las 
Nieves/ Instituto de Investigación Biosanitaria ibs. GRANADA. Granada, Spain) 
 
Co-Investigator:  
1. Lucia Triguero Cueva. Neurologist (University Hospital Virgen de las Nieves/ 
Instituto de Investigación Biosanitaria ibs. GRANADA. Granada, Spain) 
2. Carlos Javier Madrid Navarro. Neurologist (University Hospital Virgen de las 
Nieves/ University of Granada/Instituto de Investigación Biosanitaria ibs. 
GRANADA. Granada, Spain) 
3. María José Pérez Navarro. Neurologist (University Hospital Virgen de las 
Nieves, Granada, Spain) 
4. Adolfo Mínguez-Castellanos. Neurologist (University Hospital Virgen de las 
Nieves/ Instituto de Investigación Biosanitaria ibs. GRANADA. Granada, Spain) 
5. Benjamín Iáñez Velasco. Neurosurgeon (University Hospital Virgen de las 
Nieves, Granada, Spain) 
6. Bartolomé Marín-Romero. Neuropsychologist (University Hospital Virgen de 
las Nieves, Granada, Spain) 
7. José Pablo Martínez Barbero. Neuroradiologist (University Hospital Virgen de 
las Nieves, Granada, Spain). 
 
Dissemination Plan 
Results will be disseminated through: 
 
Peer-reviewed scientific journals 
 
National and international conferences 
 
Ethics and Informed Consent 
Ethical Approval 
This study will be conducted in accordance with the ethical principles set out in the 
Declaration of Helsinki, as well as applicable national and European regulations, including 
Regulation (EU) 536/2014 on clinical trials and relevant data protection legislation. 
The study protocol, informed consent form, and all relevant study documentation have been 
submitted for approval to a duly authorised Research Ethics Committee prior to study 
initiation. 

Official Title: Randomised, Double-Blind, Crossover Clinical Trial: Deep Brain Stimulation of 
the Posterior Subthalamic Area versus the Ventral Intermediate Nucleus of the Thalamus in 
Refractory Essential Tremor 
 
Document Type: STUDY PROTOCOL 
 
Version Date: 19 February 2019 
 
 
The trial will not commence until written approval has been obtained from the Ethics 
Committee and, where applicable, from the competent regulatory authority. 
Any protocol amendments will be submitted for ethical review and approval before 
implementation, except where necessary to eliminate immediate hazards to participants. 
 
Regulatory Compliance 
The study will be conducted in compliance with: 
 
Good Clinical Practice (GCP) guidelines (ICH-GCP E6(R2)) 
 
Applicable local regulatory requirements 
 
Institutional policies of the participating centre 
All study personnel will be appropriately trained in GCP and study-specific procedures. 
 
Informed Consent Process 
Written informed consent will be obtained from all participants prior to the performance of 
any study-specific procedures. 
Participants will receive both oral and written information regarding: 
 
The purpose and nature of the study 
 
Study procedures and duration 
 
Potential risks and benefits 
 
Alternative treatment options 
 
Data handling and confidentiality 
 
Their rights as research participants 
Adequate time will be provided for participants to consider participation and to ask questions. 
Consent will be obtained by a qualified member of the research team. 
Participants will be informed that their participation is entirely voluntary and that they may 
withdraw from the study at any time without providing a reason and without any impact on 
their standard medical care. 
 
Risks and Benefits 

Official Title: Randomised, Double-Blind, Crossover Clinical Trial: Deep Brain Stimulation of 
the Posterior Subthalamic Area versus the Ventral Intermediate Nucleus of the Thalamus in 
Refractory Essential Tremor 
 
Document Type: STUDY PROTOCOL 
 
Version Date: 19 February 2019 
 
 
The potential risks associated with participation include those inherent to Deep Brain 
Stimulation surgery and stimulation-related adverse effects, such as: 
 
Surgical complications (e.g. haemorrhage, infection) 
 
Neurological or neuropsychiatric side effects 
 
Device-related complications 
Potential benefits include improved tremor control and functional capacity, although these 
cannot be guaranteed. 
A careful risk–benefit assessment has been conducted, and the study is considered ethically 
justified. 
 
Confidentiality and Data Protection 
All participant data will be handled in accordance with the General Data Protection Regulation 
(GDPR) (EU) 2016/679 and applicable national data protection laws. 
Participants will be assigned a unique study identification number, and all data will be 
pseudonymised. Identifiable information will be kept separate from research data and stored 
securely. 
Access to identifiable data will be restricted to authorised study personnel. Data may be 
inspected by regulatory authorities or ethics committees for monitoring purposes, in 
compliance with confidentiality requirements. 
 
Data Handling and Record Keeping 
All study data will be recorded in a secure and validated data collection system. Records will be 
retained for the period required by applicable regulations. 
 
Participant Withdrawal 
Participants may withdraw from the study at any time without prejudice.  
Data collected prior to withdrawal may be retained and used for analysis unless the participant 
explicitly requests otherwise, in accordance with applicable regulations. 
 
Publication Policy 

Official Title: Randomised, Double-Blind, Crossover Clinical Trial: Deep Brain Stimulation of 
the Posterior Subthalamic Area versus the Ventral Intermediate Nucleus of the Thalamus in 
Refractory Essential Tremor 
 
Document Type: STUDY PROTOCOL 
 
Version Date: 19 February 2019 
 
 
Study results will be published in peer-reviewed journals and presented at scientific 
conferences. Participant confidentiality will be preserved in all publications.