xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05968976</url>
    </required_header>
    <id_info>
      <org_study_id>NL80368.018.23</org_study_id>
      <nct_id>NCT05968976</nct_id>
    </id_info>
    <brief_title>Multicentre RCT of Awake Versus Asleep Tractography Based DBS for ET</brief_title>
    <acronym>TREMBLE</acronym>
    <official_title>The TREMBLE Study: Multicentre Randomized Controlled Trial of Awake Versus Asleep Tractography Based Deep Brain Stimulation for Essential Tremor</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>University Medical Center Groningen</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Medical Center Haaglanden</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>The Elisabeth-TweeSteden Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Maastricht University Medical Center</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Radboud University Medical Center</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Medisch Spectrum Twente</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Rationale: Deep brain stimulation (DBS) of the thalamus is an effective surgical treatment&#xD;
        for patients with disabling essential tremor, despite optimal pharmacological treatment. To&#xD;
        date, the standard DBS procedure is performed under local anesthesia which is very burdensome&#xD;
        for patients. It is now possible to directly visualize the target (motor) area in the&#xD;
        thalamus due to advances in modern imaging techniques. DBS surgery could be performed under&#xD;
        general anesthesia (asleep).&#xD;
  &#xD;
        Objective: The primary objective of the study is to determine whether asleep thalamic DBS&#xD;
        surgery provides an equal tremor reduction compared to awake thalamic DBS surgery, measured&#xD;
        by the clinically validated Essential Tremor Rating Assessment Scale after six months of DBS.&#xD;
  &#xD;
        Secondary outcomes are: disease related daily functioning, adverse effects, operation time,&#xD;
        quality of life, patient satisfaction with treatment outcome and patient evaluation of&#xD;
        treatment burden.&#xD;
  &#xD;
        Study design: The study will be a multicentre prospective randomized open label blinded&#xD;
        (PROBE) endpoint trial comparing thalamic DBS under general versus local anesthesia.&#xD;
  &#xD;
        Study population: A total of 110 patients with disabling essential tremor despite optimal&#xD;
        pharmacological treatment will be randomized.&#xD;
  &#xD;
        Intervention (if applicable): Patients will be randomized for asleep DBS or awake DBS.&#xD;
        According to the standard DBS procedure, two brain-electrodes are connected to an implanted&#xD;
        neurostimulator, which is placed subcutaneously in the subclavicular area&#xD;
  &#xD;
        Main study parameter/endpoints: The primary outcome measure is the change in tremor score on&#xD;
        the Essential Tremor Rating Assessment Scale after 6 months of thalamic DBS.&#xD;
  &#xD;
        The secondary outcome measures are the Amsterdam Linear Disability Score for functional&#xD;
        health status, Quality of Life in Essential Tremor Questionnaire, patient satisfaction with&#xD;
        the treatment, patient evaluation of treatment burden, operating time, hospitalization time,&#xD;
        change of tremor medication, side effects and complications.&#xD;
  &#xD;
        Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
        relatedness: Awake DBS at present is very burdensome and by many patients and health care&#xD;
        providers considered to be an overly invasive treatment for essential tremor. Through this&#xD;
        trial, we aim to investigate whether asleep DBS in essential tremor can become the new&#xD;
        treatment standard. This is expected to increase the accessibility for DBS and subsequently&#xD;
        would allow more people with essential tremor to be helped, as well as in an earlier stage of&#xD;
        their disease than currently; more patients will benefit for a longer time period from DBS.&#xD;
        Asleep DBS will have a shorter procedure length. The proposed research project involves&#xD;
        treatment options that are standard care in daily practice. The therapies will not be&#xD;
        combined with other research products. Both treatments have a low risk of serious&#xD;
        complications and a higher risk of minor side effects. Regular follow up will be used.&#xD;
        Participation in this study constitutes moderate risk according to NFU criteria for human&#xD;
        research.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        INTRODUCTION AND RATIONALE&#xD;
  &#xD;
        Essential tremor Essential tremor is the most common neurological movement disorder and often&#xD;
        begins at an early age. In 20 to 30 years, the disorder develops to an advanced stage, in&#xD;
        which patients are severely disabled by the tremor (trembling, shaking) of their hands in&#xD;
        particular (and additional shaking of the head, legs and vocal cords may occur). In most&#xD;
        severe cases, drug treatment only partially suppresses the tremor, and also loses effect over&#xD;
        time. As a result, patients can no longer use their hands properly, for example, when eating&#xD;
        and carrying out their activities of daily living. Patients become care-dependent. In&#xD;
        addition, the involuntary tremor is socially disruptive and prevents patients from showing up&#xD;
        in public places; they become socially isolated.&#xD;
  &#xD;
        Because the tremor increases gradually in severity (over decades), patients and their&#xD;
        immediate environment adapt their lives accordingly. For example, they drink with a straw,&#xD;
        eat foods that are easy to scoop up and avoid social occasions because the trembling is&#xD;
        perceived as disturbing. Often the possibility of treatment with DBS could have been&#xD;
        considered years earlier, however this possibility is unknown to both patient and caregiver,&#xD;
        or the DBS is seen as experimental.&#xD;
  &#xD;
        Thalamic DBS is an effective surgical treatment for patients with disabling essential tremor&#xD;
        who have severe limitations in their functioning despite pharmacological treatment. During&#xD;
        the surgical placement of DBS brain electrodes, patients are awake so that the effect of the&#xD;
        electrode implantation can be monitored. Awake DBS surgery is extremely burdensome and&#xD;
        therefore prevents many patients from undergoing the treatment. To increase accessibility to&#xD;
        DBS, we want to perform the surgery asleep.&#xD;
  &#xD;
        Functional stereotactic neurosurgery Currently the standard DBS procedure is performed awake.&#xD;
        Patients need to be awake during the surgery as the optimal placement of the stimulation&#xD;
        electrodes into the brain is confirmed by intra-operative clinical testing. This procedure is&#xD;
        extremely burdensome for patients: 1) cranial injections are needed for local anesthesia 2) a&#xD;
        frame is fixed to their head with four bone-pins 3) they are secured to the operating table&#xD;
        for the procedure 4) burr holes are drilled into their skull and 5) electrodes are implanted&#xD;
        during which patients are hours continuously tested for DBS effect.&#xD;
  &#xD;
        Due to advances in MRI tractography techniques (displaying connecting pathways between brain&#xD;
        regions using magnetic resonance imaging) the target area for DBS can now be clearly&#xD;
        visualized and therefore it may be possible to perform the entire procedure asleep without&#xD;
        the need for intraoperative clinical testing. Several studies, including a recent randomized&#xD;
        controlled DBS trial in Parkinson's disease at the Amsterdam UMC, have shown that asleep DBS&#xD;
        is safe. This trial also showed that Parkinson's patients experienced asleep DBS as less&#xD;
        invasive, both psychologically and physically. Logically, asleep DBS also lowers the burden&#xD;
        of surgery for essential tremor patients. This is expected to increase the accessibility for&#xD;
        DBS. This would allow more people with essential tremor to be helped, as well as in an&#xD;
        earlier stage of their disease; more patients will benefit for a longer time period from DBS.&#xD;
        To determine whether asleep DBS for essential tremor suppresses tremor as well as awake DBS,&#xD;
        a comparative study is warranted.&#xD;
  &#xD;
        General anesthesia General anesthesia is routinely used in different types of surgery. In the&#xD;
        Amsterdam UMC, all Parkinson's disease patients, patients with dystonia, obsessive-compulsive&#xD;
        disorder, anorexia or epilepsia, where peri-operative testing is not necessary, the&#xD;
        electrodes are placed asleep. The patients receiving electrode insertion under local&#xD;
        anesthesia will receive general anesthesia to implant the pulse generator subcutaneously. The&#xD;
        procedure is described in chapter 4- Treatment of subjects.&#xD;
  &#xD;
        Asleep compared to awake thalamic DBS for essential tremor&#xD;
  &#xD;
        Tremor suppression Since the 1980s, DBS for essential tremor was targeting the thalamus, a&#xD;
        deep-seated grey matter brain nucleus. Current emphasis in the field of DBS is on neural&#xD;
        networks rather than separate nuclei in the brain. Several studies showed essential tremor to&#xD;
        arise from pathological network activity in cerebellar-cortical projections. In recent years&#xD;
        the MRI techniques for visualisation of brain networks became widely available in DBS&#xD;
        software modules. The 3-Tesla MRI diffusion deterministic tractography is a powerful tool to&#xD;
        visualise structural connections between brain nuclei and different cortical areas. In recent&#xD;
        years several DBS groups reported about using tractography to visualize the&#xD;
        cerebellar-cortical projections, or dentato-rubro-thalamic-tract (DRT), in DBS for essential&#xD;
        tremor. By visualizing the DRT, a direct target for DBS electrode placement was generated. In&#xD;
        the Amsterdam UMC, we have been evaluating DRT for DBS in essential tremor from 2017. Since&#xD;
        then, we published two major studies evaluating DRT based DBS in essential tremor. First, we&#xD;
        studied the optimization of deterministic DRT tractography by applying a standardized&#xD;
        technique for constructing the tract and using a newly developed MRI sequence; the fast grey&#xD;
        matter acquisition T1 inversion recovery (FGATIR). This enabled us to construct an&#xD;
        approximation of the DRT that strongly correlated with optimal tremor control for DBS. In the&#xD;
        following prospective clinical study we implemented this DRT technique for all our DBS cases&#xD;
        in essential tremor. We showed that during intraoperative testing the pre-determined&#xD;
        trajectory based on DRT depiction showed complete tremor suppression in all cases.&#xD;
        Intraoperative testing confirmed the optimal location for tremor suppression was accurately&#xD;
        indicated by the (preoperative generated) DRT. These two studies show DRT based DBS provides&#xD;
        a direct target area for DBS in essential tremor and possibly omits the need for&#xD;
        intraoperative, awake, testing.&#xD;
  &#xD;
        Adverse effects Several studies, including a recent randomized controlled DBS trial in&#xD;
        Parkinson's disease at the Amsterdam UMC, have shown that asleep DBS is safe. This trial also&#xD;
        showed that people experience asleep DBS less invasive, both psychologically and physically.6&#xD;
        Multiple studies report on dysarthria and gait ataxia after thalamic/DRT DBS in essential&#xD;
        tremor. When dysarthria occurs during awake test stimulation, it is usually not possible to&#xD;
        differentiate between effects of intraoperative testing and edema due to electrode&#xD;
        introduction. Moreover, in a third of patients stimulation-induced dysarthria during follow&#xD;
        up was not preceded by dysarthria during test stimulation, indicating that this is not a&#xD;
        reliable predictor for chronic effects. Gait ataxia cannot be tested during surgery, and&#xD;
        usually occurs gradually during follow up, both with or without pre-existing balance&#xD;
        difficulties. This shows awake intraoperative testing cannot be used to prevent these side&#xD;
        effects from occurring during follow up. Another known side effect can be induced by&#xD;
        co-stimulation of the corticospinal fibres, which are located (passing) near the thalamus. In&#xD;
        our recent essential tremor studies we have shown that tractography can also be used to&#xD;
        visualize the corticospinal fibres, ensuring sufficient distance to the DBS electrode&#xD;
        trajectory for preventing co-stimulation (which would result in involuntary muscle&#xD;
        contractions).&#xD;
  &#xD;
        In sum, due to advancing insights in essential tremor pathophysiology and MRI tractography&#xD;
        techniques, it is now possible to directly visualize part of the brain tremor network&#xD;
        involved in the occurrence of tremor, the dentato-rubro-thalamic-tract. In awake DBS, this&#xD;
        tract provided a direct target and showed high correlation with optimal tremor control, with&#xD;
        a comparable side effect profile. DBS surgery could therefore now be performed asleep. To our&#xD;
        knowledge, no randomized controlled trial has been done to compare the outcome between awake&#xD;
        and asleep tractography guided DBS in essential tremor.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">July 1, 2028</completion_date>
    <primary_completion_date type="Anticipated">July 1, 2027</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>The study will be a multicentre prospective randomized open label blinded (PROBE) endpoint trial comparing thalamic DBS under general versus local anesthesia</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Single (Outcomes Assessor)</masking>
      <masking_description>Because both patient and neurosurgeon are aware of receiving general or local anesthesia, it is not possible to blind them for treatment assignment. Patients will be instructed not to reveal the received treatment with the physician performing the 6-month assessments and neuropsychological evaluation in order to secure a blinded end-point.</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Essential Tremor Rating Assessment Scale (TETRAS)</measure>
      <time_frame>assessment will be done before DBS and after 6 months of DBS</time_frame>
      <description>The amount of decrease in motor symptoms indicated by change in the disease-specific Essential Tremor Rating Assessment Scale (TETRAS) after six months of deep brain stimulation. The TETRAS scores are between 0 and 64; higher scores indicating worse (more severe) tremor symptoms.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>The Amsterdam Linear Disability Score for functional health status</measure>
      <time_frame>assessment will be done before DBS and after 6 months of DBS</time_frame>
      <description>The Amsterdam Linear Disability Score (ALDS) is a generic itembank which measures disability, as expressed by the ability to perform activities of daily living. These scores are linearly transformed into values between 0 and 100. Lower scores indicate more disability.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Quality of Life in Essential Tremor Questionnaire</measure>
      <time_frame>assessment will be done before DBS and after 6 months of DBS</time_frame>
      <description>The Quality of Life in Essential Tremor Questionnaire (QUEST) is a 30-item scale developed specifically for patients with essential tremor to measure items impacting perceived quality of life (QOL) that generic QOL measures do not effectively capture, including activities of daily living that are affected by essential tremor. The QUEST was made to be relatively brief and easy for patients to use.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Global Impression of Change</measure>
      <time_frame>assessment will be done before DBS and after 6 months of DBS</time_frame>
      <description>The CGI provides an overall clinician-determined summary measure that takes into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. The CGI actually comprises two companion one-item measures evaluating the following: (a) severity of psychopathology from 1 to 7 and (b) change from the initiation of treatment on a similar seven-point scale.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>EQ-5D-5L</measure>
      <time_frame>assessment will be done before DBS and after 6 months of DBS</time_frame>
      <description>The EQ-5D-5L consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.&#xD;
  The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">110</enrollment>
    <condition>Essential Tremor</condition>
    <condition>Deep Brain Stimulation</condition>
    <condition>Diffusion Tensor Imaging</condition>
    <condition>Magnetic Resonance</condition>
    <condition>Central Nervous System Diseases</condition>
    <arm_group>
      <arm_group_label>55 patients with essential tremor receive awake DBS</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
    </arm_group>
    <arm_group>
      <arm_group_label>55 patients with essential tremor receive asleep DBS</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
    </arm_group>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Awake DBS</intervention_name>
      <description>55 patients receive awake DBS (current standard procedure)</description>
      <arm_group_label>55 patients with essential tremor receive awake DBS</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Asleep DBS</intervention_name>
      <description>55 patients receive asleep DBS</description>
      <arm_group_label>55 patients with essential tremor receive asleep DBS</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age &gt; 18 years;&#xD;
  &#xD;
            -  Idiopathic essential tremor&#xD;
  &#xD;
            -  Disabling tremor despite optimal pharmacological treatment&#xD;
  &#xD;
            -  A life expectancy of at least two years&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Legally incompetent adults;&#xD;
  &#xD;
            -  Previous tremor-neurosurgery (e.g., DBS, thalamotomy);&#xD;
  &#xD;
            -  Contraindications for DBS surgery, such as a physical disorder making surgery&#xD;
               hazardous;&#xD;
  &#xD;
            -  Psychosis;&#xD;
  &#xD;
            -  Current depression;&#xD;
  &#xD;
            -  Unable to provide written informed consent.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Maarten Bot, MD, PhD</last_name>
      <phone>0031621514048</phone>
      <email>m.bot@amsterdamumc.nl</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Richard Schuurman, Md, PhD, professor</last_name>
      <phone>0031626908484</phone>
      <email>p.r.schuurman@amsterdamumc.nl</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Amsterdam UMC, location AMC</name>
        <address>
          <city>Amsterdam</city>
          <state>Noord-Holland</state>
          <zip>11015AZ</zip>
          <country>Netherlands</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Maarten Bot, MD, PhD</last_name>
        <phone>0031621514048</phone>
        <email>m.bot@amsterdamumc.nl</email>
      </contact>
      <contact_backup>
        <last_name>Richard Schuurman, MD, PhD, professor</last_name>
        <phone>0031626908484</phone>
        <email>p.r.schuurman@amsterdamumc.nl</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>Netherlands</country>
    </location_countries>
    <reference>
      <citation>1. Song P, Zhang Y, Zha M, et al. The global prevalence of essential tremor, with emphasis on age and sex: A meta-analysis. J Glob Health. Apr 10 2021;11:04028. 2. Schuurman PR, Bosch DA, Merkus MP, Speelman JD. Long-term follow-up of thalamic stimulation versus thalamotomy for tremor suppression. Movement disorders : official journal of the Movement Disorder Society. Jun 15 2008;23(8):1146-1153. 3. Bot M, van Rootselaar F, Contarino MF, et al. Deep Brain Stimulation for Essential Tremor: Aligning Thalamic and Posterior Subthalamic Targets in 1 Surgical Trajectory. Oper Neurosurg (Hagerstown). Aug 1 2018;15(2):144-152. 4. Bot M, van Rootselaari AF, Odekerken V, et al. Evaluating and Optimizing Dentato-Rubro-Thalamic-Tract Deterministic Tractography in Deep Brain Stimulation for Essential Tremor. Oper Neurosurg (Hagerstown). Sep 25 2021. 5. Bot M, Pauwels R, van den Munckhof P, et al. The Fast Gray Matter Acquisition T1 Inversion Recovery Sequence in Deep Brain Stimulation: Introducing the Rubral Wing for Dentato-Rubro-Thalamic Tract Depiction and Tremor Control. Neuromodulation. Jan 15 2022. 6. Holewijn RA, Verbaan D, van den Munckhof PM, et al. General Anesthesia vs Local Anesthesia in Microelectrode Recording-Guided Deep-Brain Stimulation for Parkinson Disease: The GALAXY Randomized Clinical Trial. JAMA Neurol. Sep 7 2021. 7. Graat I, Mocking RJT, Liebrand LC, et al. Tractography-based versus anatomical landmark-based targeting in vALIC deep brain stimulation for refractory obsessive-compulsive disorder. Mol Psychiatry. Dec 2022;27(12):5206-5212. 8. Nowacki A, Barlatey S, Al-Fatly B, et al. Probabilistic Mapping Reveals Optimal Stimulation Site in Essential Tremor. Ann Neurol. May 2022;91(5):602-612. 9. Coenen VA, Sajonz B, Prokop T, et al. The dentato-rubro-thalamic tract as the potential common deep brain stimulation target for tremor of various origin: an observational case series. Acta neurochirurgica. May 2020;162(5):1053-1066. 10. Akram H, Dayal V, Mahlknecht P, et al. Connectivity derived thalamic segmentation in deep brain stimulation for tremor. Neuroimage Clin. 2018;18:130-142. 11. Nowacki A, Schlaier J, Debove I, Pollo C. Validation of diffusion tensor imaging tractography to visualize the dentatorubrothalamic tract for surgical planning. Journal of neurosurgery. Mar 23 2018;130(1):99-108. 12. Coenen VA, Allert N, Paus S, Kronenburger M, Urbach H, Madler B. Modulation of the Cerebello-Thalamo-Cortical Network in Thalamic Deep Brain Stimulation for Tremor: A Diffusion Tensor Imaging Study. Neurosurgery. Dec 2014;75(6):657-669. 13. Kremer NI, Pauwels RWJ, Pozzi NG, et al. Deep Brain Stimulation for Tremor: Update on Long-Term Outcomes, Target Considerations and Future Directions. J Clin Med. Aug 5 2021;10(16).</citation>
    </reference>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>June 9, 2023</study_first_submitted>
    <study_first_submitted_qc>July 28, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 1, 2023</study_first_posted>
    <last_update_submitted>July 28, 2023</last_update_submitted>
    <last_update_submitted_qc>July 28, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 1, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</investigator_affiliation>
      <investigator_full_name>Maarten Bot</investigator_full_name>
      <investigator_title>Principal Investigator</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Tremor</mesh_term>
      <mesh_term>Nervous System Diseases</mesh_term>
      <mesh_term>Essential Tremor</mesh_term>
      <mesh_term>Central Nervous System Diseases</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>all IPD that underlie results in a publication</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
      <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
      <ipd_time_frame>starting 2024</ipd_time_frame>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05968976
  org study id: NL80368.018.23
  nct id: NCT05968976
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  Rationale: Deep brain stimulation (DBS) of the thalamus is an effective surgical treatment
        for patients with disabling essential tremor, despite optimal pharmacological treatment. To
        date, the standard DBS procedure is performed under local anesthesia which is very burdensome
        for patients. It is now possible to directly visualize the target (motor) area in the
        thalamus due to advances in modern imaging techniques. DBS surgery could be performed under
        general anesthesia (asleep).
  
        Objective: The primary objective of the study is to determine whether asleep thalamic DBS
        surgery provides an equal tremor reduction compared to awake thalamic DBS surgery, measured
        by the clinically validated Essential Tremor Rating Assessment Scale after six months of DBS.
  
        Secondary outcomes are: disease related daily functioning, adverse effects, operation time,
        quality of life, patient satisfaction with treatment outcome and patient evaluation of
        treatment burden.
  
        Study design: The study will be a multicentre prospective randomized open label blinded
        (PROBE) endpoint trial comparing thalamic DBS under general versus local anesthesia.
  
        Study population: A total of 110 patients with disabling essential tremor despite optimal
        pharmacological treatment will be randomized.
  
        Intervention (if applicable): Patients will be randomized for asleep DBS or awake DBS.
        According to the standard DBS procedure, two brain-electrodes are connected to an implanted
        neurostimulator, which is placed subcutaneously in the subclavicular area
  
        Main study parameter/endpoints: The primary outcome measure is the change in tremor score on
        the Essential Tremor Rating Assessment Scale after 6 months of thalamic DBS.
  
        The secondary outcome measures are the Amsterdam Linear Disability Score for functional
        health status, Quality of Life in Essential Tremor Questionnaire, patient satisfaction with
        the treatment, patient evaluation of treatment burden, operating time, hospitalization time,
        change of tremor medication, side effects and complications.
  
        Nature and extent of the burden and risks associated with participation, benefit and group
        relatedness: Awake DBS at present is very burdensome and by many patients and health care
        providers considered to be an overly invasive treatment for essential tremor. Through this
        trial, we aim to investigate whether asleep DBS in essential tremor can become the new
        treatment standard. This is expected to increase the accessibility for DBS and subsequently
        would allow more people with essential tremor to be helped, as well as in an earlier stage of
        their disease than currently; more patients will benefit for a longer time period from DBS.
        Asleep DBS will have a shorter procedure length. The proposed research project involves
        treatment options that are standard care in daily practice. The therapies will not be
        combined with other research products. Both treatments have a low risk of serious
        complications and a higher risk of minor side effects. Regular follow up will be used.
        Participation in this study constitutes moderate risk according to NFU criteria for human
        research.
  INTRODUCTION AND RATIONALE
  
        Essential tremor Essential tremor is the most common neurological movement disorder and often
        begins at an early age. In 20 to 30 years, the disorder develops to an advanced stage, in
        which patients are severely disabled by the tremor (trembling, shaking) of their hands in
        particular (and additional shaking of the head, legs and vocal cords may occur). In most
        severe cases, drug treatment only partially suppresses the tremor, and also loses effect over
        time. As a result, patients can no longer use their hands properly, for example, when eating
        and carrying out their activities of daily living. Patients become care-dependent. In
        addition, the involuntary tremor is socially disruptive and prevents patients from showing up
        in public places; they become socially isolated.
  
        Because the tremor increases gradually in severity (over decades), patients and their
        immediate environment adapt their lives accordingly. For example, they drink with a straw,
        eat foods that are easy to scoop up and avoid social occasions because the trembling is
        perceived as disturbing. Often the possibility of treatment with DBS could have been
        considered years earlier, however this possibility is unknown to both patient and caregiver,
        or the DBS is seen as experimental.
  
        Thalamic DBS is an effective surgical treatment for patients with disabling essential tremor
        who have severe limitations in their functioning despite pharmacological treatment. During
        the surgical placement of DBS brain electrodes, patients are awake so that the effect of the
        electrode implantation can be monitored. Awake DBS surgery is extremely burdensome and
        therefore prevents many patients from undergoing the treatment. To increase accessibility to
        DBS, we want to perform the surgery asleep.
  
        Functional stereotactic neurosurgery Currently the standard DBS procedure is performed awake.
        Patients need to be awake during the surgery as the optimal placement of the stimulation
        electrodes into the brain is confirmed by intra-operative clinical testing. This procedure is
        extremely burdensome for patients: 1) cranial injections are needed for local anesthesia 2) a
        frame is fixed to their head with four bone-pins 3) they are secured to the operating table
        for the procedure 4) burr holes are drilled into their skull and 5) electrodes are implanted
        during which patients are hours continuously tested for DBS effect.
  
        Due to advances in MRI tractography techniques (displaying connecting pathways between brain
        regions using magnetic resonance imaging) the target area for DBS can now be clearly
        visualized and therefore it may be possible to perform the entire procedure asleep without
        the need for intraoperative clinical testing. Several studies, including a recent randomized
        controlled DBS trial in Parkinson's disease at the Amsterdam UMC, have shown that asleep DBS
        is safe. This trial also showed that Parkinson's patients experienced asleep DBS as less
        invasive, both psychologically and physically. Logically, asleep DBS also lowers the burden
        of surgery for essential tremor patients. This is expected to increase the accessibility for
        DBS. This would allow more people with essential tremor to be helped, as well as in an
        earlier stage of their disease; more patients will benefit for a longer time period from DBS.
        To determine whether asleep DBS for essential tremor suppresses tremor as well as awake DBS,
        a comparative study is warranted.
  
        General anesthesia General anesthesia is routinely used in different types of surgery. In the
        Amsterdam UMC, all Parkinson's disease patients, patients with dystonia, obsessive-compulsive
        disorder, anorexia or epilepsia, where peri-operative testing is not necessary, the
        electrodes are placed asleep. The patients receiving electrode insertion under local
        anesthesia will receive general anesthesia to implant the pulse generator subcutaneously. The
        procedure is described in chapter 4- Treatment of subjects.
  
        Asleep compared to awake thalamic DBS for essential tremor
  
        Tremor suppression Since the 1980s, DBS for essential tremor was targeting the thalamus, a
        deep-seated grey matter brain nucleus. Current emphasis in the field of DBS is on neural
        networks rather than separate nuclei in the brain. Several studies showed essential tremor to
        arise from pathological network activity in cerebellar-cortical projections. In recent years
        the MRI techniques for visualisation of brain networks became widely available in DBS
        software modules. The 3-Tesla MRI diffusion deterministic tractography is a powerful tool to
        visualise structural connections between brain nuclei and different cortical areas. In recent
        years several DBS groups reported about using tractography to visualize the
        cerebellar-cortical projections, or dentato-rubro-thalamic-tract (DRT), in DBS for essential
        tremor. By visualizing the DRT, a direct target for DBS electrode placement was generated. In
        the Amsterdam UMC, we have been evaluating DRT for DBS in essential tremor from 2017. Since
        then, we published two major studies evaluating DRT based DBS in essential tremor. First, we
        studied the optimization of deterministic DRT tractography by applying a standardized
        technique for constructing the tract and using a newly developed MRI sequence; the fast grey
        matter acquisition T1 inversion recovery (FGATIR). This enabled us to construct an
        approximation of the DRT that strongly correlated with optimal tremor control for DBS. In the
        following prospective clinical study we implemented this DRT technique for all our DBS cases
        in essential tremor. We showed that during intraoperative testing the pre-determined
        trajectory based on DRT depiction showed complete tremor suppression in all cases.
        Intraoperative testing confirmed the optimal location for tremor suppression was accurately
        indicated by the (preoperative generated) DRT. These two studies show DRT based DBS provides
        a direct target area for DBS in essential tremor and possibly omits the need for
        intraoperative, awake, testing.
  
        Adverse effects Several studies, including a recent randomized controlled DBS trial in
        Parkinson's disease at the Amsterdam UMC, have shown that asleep DBS is safe. This trial also
        showed that people experience asleep DBS less invasive, both psychologically and physically.6
        Multiple studies report on dysarthria and gait ataxia after thalamic/DRT DBS in essential
        tremor. When dysarthria occurs during awake test stimulation, it is usually not possible to
        differentiate between effects of intraoperative testing and edema due to electrode
        introduction. Moreover, in a third of patients stimulation-induced dysarthria during follow
        up was not preceded by dysarthria during test stimulation, indicating that this is not a
        reliable predictor for chronic effects. Gait ataxia cannot be tested during surgery, and
        usually occurs gradually during follow up, both with or without pre-existing balance
        difficulties. This shows awake intraoperative testing cannot be used to prevent these side
        effects from occurring during follow up. Another known side effect can be induced by
        co-stimulation of the corticospinal fibres, which are located (passing) near the thalamus. In
        our recent essential tremor studies we have shown that tractography can also be used to
        visualize the corticospinal fibres, ensuring sufficient distance to the DBS electrode
        trajectory for preventing co-stimulation (which would result in involuntary muscle
        contractions).
  
        In sum, due to advancing insights in essential tremor pathophysiology and MRI tractography
        techniques, it is now possible to directly visualize part of the brain tremor network
        involved in the occurrence of tremor, the dentato-rubro-thalamic-tract. In awake DBS, this
        tract provided a direct target and showed high correlation with optimal tremor control, with
        a comparable side effect profile. DBS surgery could therefore now be performed asleep. To our
        knowledge, no randomized controlled trial has been done to compare the outcome between awake
        and asleep tractography guided DBS in essential tremor.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: The study will be a multicentre prospective randomized open label blinded (PROBE) endpoint trial comparing thalamic DBS under general versus local anesthesia
  primary purpose: Treatment
  masking: Single (Outcomes Assessor)
  masking description: Because both patient and neurosurgeon are aware of receiving general or local anesthesia, it is not possible to blind them for treatment assignment. Patients will be instructed not to reveal the received treatment with the physician performing the 6-month assessments and neuropsychological evaluation in order to secure a blinded end-point.
  measure: Essential Tremor Rating Assessment Scale (TETRAS)
  time frame: assessment will be done before DBS and after 6 months of DBS
  description: The amount of decrease in motor symptoms indicated by change in the disease-specific Essential Tremor Rating Assessment Scale (TETRAS) after six months of deep brain stimulation. The TETRAS scores are between 0 and 64; higher scores indicating worse (more severe) tremor symptoms.
  measure: The Amsterdam Linear Disability Score for functional health status
  time frame: assessment will be done before DBS and after 6 months of DBS
  description: The Amsterdam Linear Disability Score (ALDS) is a generic itembank which measures disability, as expressed by the ability to perform activities of daily living. These scores are linearly transformed into values between 0 and 100. Lower scores indicate more disability.
  measure: Quality of Life in Essential Tremor Questionnaire
  time frame: assessment will be done before DBS and after 6 months of DBS
  description: The Quality of Life in Essential Tremor Questionnaire (QUEST) is a 30-item scale developed specifically for patients with essential tremor to measure items impacting perceived quality of life (QOL) that generic QOL measures do not effectively capture, including activities of daily living that are affected by essential tremor. The QUEST was made to be relatively brief and easy for patients to use.
  measure: Global Impression of Change
  time frame: assessment will be done before DBS and after 6 months of DBS
  description: The CGI provides an overall clinician-determined summary measure that takes into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. The CGI actually comprises two companion one-item measures evaluating the following: (a) severity of psychopathology from 1 to 7 and (b) change from the initiation of treatment on a similar seven-point scale.
  measure: EQ-5D-5L
  time frame: assessment will be done before DBS and after 6 months of DBS
  description: The EQ-5D-5L consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.
  The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.
  arm group label: 55 patients with essential tremor receive awake DBS
  arm group type: Active Comparator
  arm group label: 55 patients with essential tremor receive asleep DBS
  arm group type: Experimental
  intervention type: Procedure
  intervention name: Awake DBS
  description: 55 patients receive awake DBS (current standard procedure)
  arm group label: 55 patients with essential tremor receive awake DBS
  intervention type: Procedure
  intervention name: Asleep DBS
  description: 55 patients receive asleep DBS
  arm group label: 55 patients with essential tremor receive asleep DBS
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Maarten Bot, MD, PhD
  phone: 0031621514048
  email: m.bot@amsterdamumc.nl
  last name: Richard Schuurman, Md, PhD, professor
  phone: 0031626908484
  email: p.r.schuurman@amsterdamumc.nl
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: Netherlands
  citation: 1. Song P, Zhang Y, Zha M, et al. The global prevalence of essential tremor, with emphasis on age and sex: A meta-analysis. J Glob Health. Apr 10 2021;11:04028. 2. Schuurman PR, Bosch DA, Merkus MP, Speelman JD. Long-term follow-up of thalamic stimulation versus thalamotomy for tremor suppression. Movement disorders : official journal of the Movement Disorder Society. Jun 15 2008;23(8):1146-1153. 3. Bot M, van Rootselaar F, Contarino MF, et al. Deep Brain Stimulation for Essential Tremor: Aligning Thalamic and Posterior Subthalamic Targets in 1 Surgical Trajectory. Oper Neurosurg (Hagerstown). Aug 1 2018;15(2):144-152. 4. Bot M, van Rootselaari AF, Odekerken V, et al. Evaluating and Optimizing Dentato-Rubro-Thalamic-Tract Deterministic Tractography in Deep Brain Stimulation for Essential Tremor. Oper Neurosurg (Hagerstown). Sep 25 2021. 5. Bot M, Pauwels R, van den Munckhof P, et al. The Fast Gray Matter Acquisition T1 Inversion Recovery Sequence in Deep Brain Stimulation: Introducing the Rubral Wing for Dentato-Rubro-Thalamic Tract Depiction and Tremor Control. Neuromodulation. Jan 15 2022. 6. Holewijn RA, Verbaan D, van den Munckhof PM, et al. General Anesthesia vs Local Anesthesia in Microelectrode Recording-Guided Deep-Brain Stimulation for Parkinson Disease: The GALAXY Randomized Clinical Trial. JAMA Neurol. Sep 7 2021. 7. Graat I, Mocking RJT, Liebrand LC, et al. Tractography-based versus anatomical landmark-based targeting in vALIC deep brain stimulation for refractory obsessive-compulsive disorder. Mol Psychiatry. Dec 2022;27(12):5206-5212. 8. Nowacki A, Barlatey S, Al-Fatly B, et al. Probabilistic Mapping Reveals Optimal Stimulation Site in Essential Tremor. Ann Neurol. May 2022;91(5):602-612. 9. Coenen VA, Sajonz B, Prokop T, et al. The dentato-rubro-thalamic tract as the potential common deep brain stimulation target for tremor of various origin: an observational case series. Acta neurochirurgica. May 2020;162(5):1053-1066. 10. Akram H, Dayal V, Mahlknecht P, et al. Connectivity derived thalamic segmentation in deep brain stimulation for tremor. Neuroimage Clin. 2018;18:130-142. 11. Nowacki A, Schlaier J, Debove I, Pollo C. Validation of diffusion tensor imaging tractography to visualize the dentatorubrothalamic tract for surgical planning. Journal of neurosurgery. Mar 23 2018;130(1):99-108. 12. Coenen VA, Allert N, Paus S, Kronenburger M, Urbach H, Madler B. Modulation of the Cerebello-Thalamo-Cortical Network in Thalamic Deep Brain Stimulation for Tremor: A Diffusion Tensor Imaging Study. Neurosurgery. Dec 2014;75(6):657-669. 13. Kremer NI, Pauwels RWJ, Pozzi NG, et al. Deep Brain Stimulation for Tremor: Update on Long-Term Outcomes, Target Considerations and Future Directions. J Clin Med. Aug 5 2021;10(16).
  responsible party type: Principal Investigator
  investigator affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
  investigator full name: Maarten Bot
  investigator title: Principal Investigator
  mesh term: Tremor
  mesh term: Nervous System Diseases
  mesh term: Essential Tremor
  mesh term: Central Nervous System Diseases
  sharing ipd: Yes
  ipd description: all IPD that underlie results in a publication
  ipd info type: Study Protocol
  ipd info type: Statistical Analysis Plan (SAP)
  ipd info type: Clinical Study Report (CSR)
  ipd time frame: starting 2024