<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/NCT03832712</url>
  </required_header>
  <id_info>
    <org_study_id>2017-238-31</org_study_id>
    <nct_id>NCT03832712</nct_id>
  </id_info>
  <brief_title>The Swedish Essential Tremor (SWEET) Trial</brief_title>
  <acronym>SWEET</acronym>
  <official_title>The Swedish Essential Tremor (SWEET) Trial - A Multicentre Randomized Controlled Trial of Deep Brain Stimulation for Essential Tremor</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Karolinska Institutet</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Umeå University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Uppsala University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Lund University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital, Linkoeping</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Göteborg University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Karolinska Institutet</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      To evaluate the effect of deep brain stimulation (DBS) vs best medical treatment in essential&#xD;
      tremor (ET) in a randomized, single-blinded controlled trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PURPOSE AND AIMS&#xD;
&#xD;
        -  Aim 1 - To evaluate the effect of deep brain stimulation (DBS) vs best medical treatment&#xD;
           in essential tremor (ET) in a randomized, single-blinded controlled trial.&#xD;
&#xD;
        -  Aim 2 - To compare the effect of DBS in the established target in the ventrolateral&#xD;
           (VL)-thalamus/ nucleus ventralis intermedius thalami (Vim) and in a new target in the&#xD;
           posterior subthalamic area (PSA)/caudal Zona incerta (cZi).&#xD;
&#xD;
        -  Aim 3 - To map the target area in the VL-thalamus and PSA concerning effects and side&#xD;
           effects of stimulation in order to identify and delineate the optimal target.&#xD;
&#xD;
        -  Aim 4 - To evaluate the long-term effects of DBS for ET in a longitudinal non-randomized&#xD;
           evaluation.&#xD;
&#xD;
      SURVEY OF THE FIELD Deep Brain Stimulation (DBS) In DBS, thin quadripolar electrode leads&#xD;
      (with four 1.5 mm long and 1.27 mm thick contacts, separated by 1.5 mm space), connected to a&#xD;
      neuropacemaker are implanted with stereotactic technique into the central parts of the brain&#xD;
      where the neuronal activity is modulated with electrical current. DBS has revolutionized the&#xD;
      treatment of Parkinson´s disease and other movement disorders, and more than 150.000 patients&#xD;
      have so far been operated. Currently, new indications and targets are emerging.&#xD;
&#xD;
      However, many of the brain targets subjected for DBS are not well defined, and one of the&#xD;
      main problem with DBS is likely to be the high number of suboptimal placed electrodes with&#xD;
      lack of effect, unacceptable side effects and costly revisions. Further, even though this is&#xD;
      an invasive and highly resource demanding therapy, most clinical indications for DBS (asides&#xD;
      from Parkinson´s disease and dystonia) are not evidence based. They are considered as&#xD;
      &quot;established treatments&quot; and often provided as clinical treatment and not within the context&#xD;
      of trials or scientific studies.&#xD;
&#xD;
      DBS for Essential Tremor ET is the most common adult movement disorder with a prevalence of&#xD;
      about 5% in the population above 65 years of age. Of patients who seek medical care up to 50%&#xD;
      do not respond adequately to drug therapy.&#xD;
&#xD;
      The thalamic nucleus ventralis intermedius (Vim) is the projection structure of the&#xD;
      cerebello-thalamic fibers mediating tremor. Hence, Vim has been an &quot;established&quot; target for&#xD;
      surgical treatment of ET during the thalamotomy era, and when DBS was introduced and replaced&#xD;
      thalamotomy, the Vim was logically the target for DBS for tremor. However, data from recent&#xD;
      years indicate that it might not be stimulation of the Vim itself, but rather, the&#xD;
      stimulation was affecting the pathologic tremor oscillations mediated by the&#xD;
      cerebello-thalamic-cortical projections, located in the PSA and the caudal zona incerta&#xD;
      (cZi). Thus, a number of studies have demonstrated that electrode contacts that reach the PSA&#xD;
      have a better effect on tremor than those located more dorsally-rostrally in the Vim. This&#xD;
      subthalamic area, which is situated immediately ventral-caudal to the Vim, is particularly&#xD;
      dense with cerebello-thalamic axons, dispersing into the Vim. Stimulation is thus likely to&#xD;
      involve more axons in the PSA than in the Vim, since these axons in the PSA constitute so to&#xD;
      speak a bottle neck of the axonal traffic mediating tremor. It is also plausible that&#xD;
      stimulation of axons rather than stimulation of nuclei actually affects by antidromic and&#xD;
      orthodromic propagation more neurons and therefore also alters tremor oscillations more&#xD;
      efficiently. A number of studies directly targeting the cZi have also recently presented&#xD;
      results comparing favorably with the results published for Vim DBS.&#xD;
&#xD;
      Level of evidence regarding DBS in ET:&#xD;
&#xD;
      Neither the Vim nor the cZi are evidence based targets, and there are no evidence-based DBS&#xD;
      procedures for ET (level IV evidence only), even though this is the second most common&#xD;
      indication for DBS. However, the Vim is by tradition the established target for ET and the&#xD;
      procedure is recommended in the Swedish guidelines for treatment of tremor.&#xD;
&#xD;
      The results of Vim DBS ET have been demonstrated in a number of uncontrolled, mostly minor&#xD;
      studies. A problem is that many of these studies are likely to contain electrodes placed&#xD;
      blindly within the PSA36 and that the actual location of the active electrode contacts of the&#xD;
      DBS lead is seldom taken into consideration. Further, many reports lack a preoperative&#xD;
      baseline and the results are often reported in a heterogeneous manner, making comparison&#xD;
      between different studies difficult. Regarding cZi DBS, excluding our own studies, the&#xD;
      results of cZi DBS in 33 patients have been presented in five small and non-randomized&#xD;
      studies. Concerning the relative merits of the two targets, we have previously presented a&#xD;
      tremor reduction of 86 % following cZi, compared to only 60% in the Vim4, and demonstrated&#xD;
      that the electrode contacts with the best effect in what was called Vim were often placed in&#xD;
      the PSA. There is further a scarcity of long-term data regarding both targets.&#xD;
&#xD;
      Identifying the brain target in the individual patient In a recent study of 28 000&#xD;
      procedures, electrode revisions constituted up to one third of all DBS procedures. It is&#xD;
      likely that misplaced electrodes due to difficulties in identifying the target is one of the&#xD;
      major causes explaining a poor result in DBS for movement disorders.&#xD;
&#xD;
      There are a number of different ways in which the target can be identified. Even for brain&#xD;
      targets that can be visually identified on MRI, some centers rely mostly on statistical&#xD;
      coordinates of the targets based on anatomical atlases, but this may result in poorly placed&#xD;
      electrodes, due to significant inter-individual differences in the anatomy. However,&#xD;
      concerning the Vim, identification of that target in relation to ventricular landmarks is a&#xD;
      necessity since the Vim cannot be visualized as such in MRI.&#xD;
&#xD;
      Currently, 60 % of the centers are relying on micro-electrode recording (MER) in order to&#xD;
      identify the target in the individual patient. This is an invasive neurophysiological method&#xD;
      necessitating considerable resources. It is also associated with an increased risk of&#xD;
      hemorrhages, since it involves introducing several sharp cannulas and electrodes into the&#xD;
      target area. The third method is visual anatomical targeting, whereby the target is&#xD;
      identified on the patients´ MRI, either directly or in relation to visible very closely&#xD;
      related landmarks (Figure 2). We have over the years made significant contributions in the&#xD;
      development of this last method, both concerning the pallidum, STN and cZi. Unfortunately&#xD;
      this method demands a high level of dedication and relies to a high degree on personal&#xD;
      experience. Scientifically based guidelines delineating the target areas and identifying the&#xD;
      optimal target do not readily exist.&#xD;
&#xD;
      Common for all different methods is that it is normally required that the patient is awake&#xD;
      during surgery in order to allow for intra-operative testing of effect/side effects, even if&#xD;
      some today perform the procedure in general anesthesia concerning some of the targets. If the&#xD;
      brain targets could be identified with a high degree of certainty, and the electrode position&#xD;
      within that target can be verified during surgery, then having the patients awake during&#xD;
      surgery would no longer be necessary.&#xD;
&#xD;
      Identifying and delineating the optimal targets The literature regarding optimal target&#xD;
      point/volume for the different targets is surprisingly meagre. The most common target, the&#xD;
      subthalamic nucleus (STN), is also the most studied regarding this issue, but the effect has&#xD;
      been evaluated in relation to the location of the electrode in no more than 260 patients in a&#xD;
      total of 13 different studies. Interestingly, most of these studies have found that the best&#xD;
      effect is not achieved in the target structure itself, but in another adjacent structure, the&#xD;
      more rostral part of the Zona incerta overlying the STN. The same is true regarding the few&#xD;
      studies of thalamic surgery for tremor, where most have demonstrated that the best effect is&#xD;
      achieved from contacts outside the thalamic target, in the PSA. Concerning other&#xD;
      targets/indications the literature is even more limited.&#xD;
&#xD;
      The existing studies are further hampered by the heterogeneity of the methods. Often it is&#xD;
      not the actual location of the electrode that is reported, but the intended one. Even when&#xD;
      the actual location is reported it is most often presented according to distant landmarks,&#xD;
      even if the targeting was done visually, which is a significant problem, taking into&#xD;
      consideration the inter-individual variability. Further, even though the stimulation&#xD;
      parameters used can differ widely and hence the electrical current affect different&#xD;
      neighboring structures, this is virtually never taken into account.&#xD;
&#xD;
      DBS for ET - Conclusions and aim DBS for ET is thus not an evidence based therapy and the&#xD;
      same is true regarding both target areas used for ET. The relative merits of the different&#xD;
      targets used have not been clearly demonstrated and the individual targets are not well&#xD;
      delineated. There is thus a need to address these issues.&#xD;
&#xD;
      Overview - What are we going to study? The effect of DBS for ET will be evaluated in a&#xD;
      multicentre study recruiting 100 patients randomized to immediate surgery (group A) or best&#xD;
      medical treatment only (as decided by the movement disorder neurologist, with few exceptions&#xD;
      likely to be identical to their current medication) with delayed surgery at 6 months if still&#xD;
      needed /indicated (group B). Primary outcome is tremor reduction as measured with Essential&#xD;
      tremor rating scale11 (ETRS), with focus on items 5/6 (hand tremor) &amp; 11-14 (hand function),&#xD;
      at baseline before surgery and at 6 months. Secondary outcome includes the essential tremor&#xD;
      rating assessment scale (TETRAS), quality of life measured with QUEST and electrical energy&#xD;
      consumption18. After 6 months group B is operated -as indicated-, and group A and B are&#xD;
      thereafter evaluated as one single group for long-term effects and analyses of electrode&#xD;
      location. The electrodes will in all patients be inserted with a trajectory developed for&#xD;
      this study allowing stimulation both in the established and traditionally used target Vim as&#xD;
      well as in the new target cZi. Each contact will be evaluated individually concerning&#xD;
      location, effects and side effects, in relation to stimulation parameters. This is done in&#xD;
      order to, a) compare the two targets, but more importantly, b) to create a map of the whole&#xD;
      area with identification/delineation of the optimal target point/volume. The time necessary&#xD;
      to gather 100 patients is estimated to 2.5 - 3 years.&#xD;
&#xD;
      Study design:&#xD;
&#xD;
        -  Step 1 is designed as a randomized controlled trial in order to compare the effect of&#xD;
           DBS (Group A) and medical treatment (Group B) on ET (Aim 1).&#xD;
&#xD;
        -  In step 2 - 4 the patients in group A are operated and group A and B joined into one&#xD;
           single group.&#xD;
&#xD;
             -  Step 2 - all electrode contacts are individually analysed regarding chronic and&#xD;
                acute stimulation effects in relation to their location in either the Vim or the&#xD;
                cZi in order to decide which target is more effective (Aim 2).&#xD;
&#xD;
             -  Step 3 - Effects and side effects, with consideration to field of stimulation, are&#xD;
                analyzed in relation to neighboring structures in order to map the whole area and&#xD;
                delineate the optimal target points (Aim 3).&#xD;
&#xD;
             -  Step 4 - The long-term effect is evaluated in a non-randomized longitudinal study&#xD;
                at 1, 3, 5, 10 years (Aim 4).&#xD;
&#xD;
      Sample size and power:&#xD;
&#xD;
      In step 1, with a confidence interval of 95%, and an expected improvement of 85 % in the&#xD;
      surgical group and none (or at least &lt; 25%) in the medical group, regarding contralateral&#xD;
      items 5/6 &amp; 11-14, a power of 100 % is achieved. In step 2, with an expected improvement of&#xD;
      85% in one target and 60% in the other, a power of 98% is achieved. The high number of&#xD;
      patients is, however, necessary for step 3, mapping of the area, in order to give a good&#xD;
      cover of the periphery (Length of contact carrying electrode surface 7.5 mm, expected mean&#xD;
      non-random intended deviation from target point (as defined in the study) 1 mm, expected mean&#xD;
      random deviation from intended target point 1.5 mm). Based on the previous experience, less&#xD;
      than 5% of patients is expected to be lost during the follow up, which will have an&#xD;
      insignificant effect on the power.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 30, 2018</start_date>
  <completion_date type="Anticipated">January 30, 2027</completion_date>
  <primary_completion_date type="Anticipated">January 30, 2026</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>Crossover Assignment</intervention_model>
    <intervention_model_description>Study design:&#xD;
Step 1 is designed as a randomized controlled trial in order to compare the effect of DBS (Group A) and medical treatment (Group B) on ET (Aim 1).&#xD;
In step 2 - 4 the patients in group A are operated and group A and B joined into one single group.&#xD;
Step 2 - all electrode contacts are individually analysed regarding chronic and acute stimulation effects in relation to their location in either the Vim or the cZi in order to decide which target is more effective (Aim 2).&#xD;
Step 3 - Effects and side effects, with consideration to field of stimulation, are analyzed in relation to neighboring structures in order to map the whole area and delineate the optimal target points (Aim 3).&#xD;
Step 4 - The long-term effect is evaluated in a non-randomized longitudinal study at 1, 3, 5, 10 years (Aim 4).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Tremor is measured with the Essential tremor rating scale (ETRS) with focus on items 5/6 (hand tremor) &amp; 11-14 (hand function). ETRS is performed before surgery at baseline and at 6 months on/off med/stim. The evaluation is done blinded to the patients in the surgical group. The evaluation is documented on video (with the patient wearing a head cap) and segmented for blinded evaluation of two expert evaluators</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Essential Tremor Rating Scale (ETRS)</measure>
    <time_frame>Change from Baseline ETRS at 6 months</time_frame>
    <description>Fahn S, Tolosa E, Marin C (1993) Clinical rating scale for tremor. In: Jankovic J, Tolosa E (eds) Parkinson´s disease and movement disorders. Urban and Schwarzenberg Munich, pp 271-280&#xD;
Scale: Total sum 0-144 points. Contralateral Tremor (item 5/6) &amp; Handfunction (item 11-14) 0-28 points.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Quality of life in ET (QUEST)</measure>
    <time_frame>Change from Baseline at 6 months</time_frame>
    <description>Questionnaire Quality of Life in Essential Tremor Minimum score 0 (no self rated symptoms of ET) maximum 128 (maximum self rated symptoms of ET)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>electric energy consumption</measure>
    <time_frame>Change from Baseline at 6 months</time_frame>
    <description>Pulse effective voltage (PEV) i s calculated för each operated patient</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Essential Tremor</condition>
  <arm_group>
    <arm_group_label>Surgical</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants randomized to surgery</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Medical</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants randomized to best medical treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Deep Brain Stimulation</intervention_name>
    <description>Surgical implantation of intracranial leads for deep brain stimulation, extension cables and implantable pulse generator</description>
    <arm_group_label>Surgical</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Best Medical Treatment</intervention_name>
    <description>Unselective β-blockers such as Propanolol</description>
    <arm_group_label>Medical</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of ET, as decided by the movement disorder specialist; Substantial&#xD;
             incapacity; Duration of symptoms &gt; 5 years; Age 18 - 75; unsatisfying effect from&#xD;
             β-blockers, or be unable to tolerate the medical therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Cognitive impairment; Co-morbidity or non-compliance likely to jeopardize the result&#xD;
             or to confuse the evaluation; Normal surgical exclusion criteria.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Patric Blomstedt, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Umeå Universitet</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Anders Fytagoridis, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Karolinska Institutet</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Anne-Louice Eriksson</last_name>
    <phone>+468907850000</phone>
    <email>annelouice.eriksson@vll.se</email>
  </overall_contact>
  <location>
    <facility>
      <name>Sahlgrenska University Hospital</name>
      <address>
        <city>Göteborg</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Thomas Skoglund, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Linköping University Hospital</name>
      <address>
        <city>Linköping</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Peter Zsigmond, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Lund University Hospital</name>
      <address>
        <city>Lund</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hjalmar Bjartmarz, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Karolinska University Hospital</name>
      <address>
        <city>Stockholm</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anders Fytagoridis, PhD</last_name>
    </contact>
    <investigator>
      <last_name>Göran Lind, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Umeå University Hospital</name>
      <address>
        <city>Umeå</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Patric Blomstedt, PhD</last_name>
    </contact>
    <investigator>
      <last_name>Marwan Hariz, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Akademiska Sjukhuset</name>
      <address>
        <city>Uppsala</city>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Elena Jiltsova, MD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>January 11, 2019</study_first_submitted>
  <study_first_submitted_qc>February 4, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 6, 2019</study_first_posted>
  <last_update_submitted>May 24, 2022</last_update_submitted>
  <last_update_submitted_qc>May 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Karolinska Institutet</investigator_affiliation>
    <investigator_full_name>Anders Fytagoridis</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Deep Brain Stimulation</keyword>
  <keyword>Randomized Controlled Trial</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tremor</mesh_term>
    <mesh_term>Essential Tremor</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>December 20, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/12/NCT03832712/Prot_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


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/NCT03832712
org study id: 2017-238-31
nct id: NCT03832712
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
To evaluate the effect of deep brain stimulation (DBS) vs best medical treatment in essential
      tremor (ET) in a randomized, single-blinded controlled trial.
PURPOSE AND AIMS

        -  Aim 1 - To evaluate the effect of deep brain stimulation (DBS) vs best medical treatment
           in essential tremor (ET) in a randomized, single-blinded controlled trial.

        -  Aim 2 - To compare the effect of DBS in the established target in the ventrolateral
           (VL)-thalamus/ nucleus ventralis intermedius thalami (Vim) and in a new target in the
           posterior subthalamic area (PSA)/caudal Zona incerta (cZi).

        -  Aim 3 - To map the target area in the VL-thalamus and PSA concerning effects and side
           effects of stimulation in order to identify and delineate the optimal target.

        -  Aim 4 - To evaluate the long-term effects of DBS for ET in a longitudinal non-randomized
           evaluation.

      SURVEY OF THE FIELD Deep Brain Stimulation (DBS) In DBS, thin quadripolar electrode leads
      (with four 1.5 mm long and 1.27 mm thick contacts, separated by 1.5 mm space), connected to a
      neuropacemaker are implanted with stereotactic technique into the central parts of the brain
      where the neuronal activity is modulated with electrical current. DBS has revolutionized the
      treatment of Parkinson´s disease and other movement disorders, and more than 150.000 patients
      have so far been operated. Currently, new indications and targets are emerging.

      However, many of the brain targets subjected for DBS are not well defined, and one of the
      main problem with DBS is likely to be the high number of suboptimal placed electrodes with
      lack of effect, unacceptable side effects and costly revisions. Further, even though this is
      an invasive and highly resource demanding therapy, most clinical indications for DBS (asides
      from Parkinson´s disease and dystonia) are not evidence based. They are considered as
      "established treatments" and often provided as clinical treatment and not within the context
      of trials or scientific studies.

      DBS for Essential Tremor ET is the most common adult movement disorder with a prevalence of
      about 5% in the population above 65 years of age. Of patients who seek medical care up to 50%
      do not respond adequately to drug therapy.

      The thalamic nucleus ventralis intermedius (Vim) is the projection structure of the
      cerebello-thalamic fibers mediating tremor. Hence, Vim has been an "established" target for
      surgical treatment of ET during the thalamotomy era, and when DBS was introduced and replaced
      thalamotomy, the Vim was logically the target for DBS for tremor. However, data from recent
      years indicate that it might not be stimulation of the Vim itself, but rather, the
      stimulation was affecting the pathologic tremor oscillations mediated by the
      cerebello-thalamic-cortical projections, located in the PSA and the caudal zona incerta
      (cZi). Thus, a number of studies have demonstrated that electrode contacts that reach the PSA
      have a better effect on tremor than those located more dorsally-rostrally in the Vim. This
      subthalamic area, which is situated immediately ventral-caudal to the Vim, is particularly
      dense with cerebello-thalamic axons, dispersing into the Vim. Stimulation is thus likely to
      involve more axons in the PSA than in the Vim, since these axons in the PSA constitute so to
      speak a bottle neck of the axonal traffic mediating tremor. It is also plausible that
      stimulation of axons rather than stimulation of nuclei actually affects by antidromic and
      orthodromic propagation more neurons and therefore also alters tremor oscillations more
      efficiently. A number of studies directly targeting the cZi have also recently presented
      results comparing favorably with the results published for Vim DBS.

      Level of evidence regarding DBS in ET:

      Neither the Vim nor the cZi are evidence based targets, and there are no evidence-based DBS
      procedures for ET (level IV evidence only), even though this is the second most common
      indication for DBS. However, the Vim is by tradition the established target for ET and the
      procedure is recommended in the Swedish guidelines for treatment of tremor.

      The results of Vim DBS ET have been demonstrated in a number of uncontrolled, mostly minor
      studies. A problem is that many of these studies are likely to contain electrodes placed
      blindly within the PSA36 and that the actual location of the active electrode contacts of the
      DBS lead is seldom taken into consideration. Further, many reports lack a preoperative
      baseline and the results are often reported in a heterogeneous manner, making comparison
      between different studies difficult. Regarding cZi DBS, excluding our own studies, the
      results of cZi DBS in 33 patients have been presented in five small and non-randomized
      studies. Concerning the relative merits of the two targets, we have previously presented a
      tremor reduction of 86 % following cZi, compared to only 60% in the Vim4, and demonstrated
      that the electrode contacts with the best effect in what was called Vim were often placed in
      the PSA. There is further a scarcity of long-term data regarding both targets.

      Identifying the brain target in the individual patient In a recent study of 28 000
      procedures, electrode revisions constituted up to one third of all DBS procedures. It is
      likely that misplaced electrodes due to difficulties in identifying the target is one of the
      major causes explaining a poor result in DBS for movement disorders.

      There are a number of different ways in which the target can be identified. Even for brain
      targets that can be visually identified on MRI, some centers rely mostly on statistical
      coordinates of the targets based on anatomical atlases, but this may result in poorly placed
      electrodes, due to significant inter-individual differences in the anatomy. However,
      concerning the Vim, identification of that target in relation to ventricular landmarks is a
      necessity since the Vim cannot be visualized as such in MRI.

      Currently, 60 % of the centers are relying on micro-electrode recording (MER) in order to
      identify the target in the individual patient. This is an invasive neurophysiological method
      necessitating considerable resources. It is also associated with an increased risk of
      hemorrhages, since it involves introducing several sharp cannulas and electrodes into the
      target area. The third method is visual anatomical targeting, whereby the target is
      identified on the patients´ MRI, either directly or in relation to visible very closely
      related landmarks (Figure 2). We have over the years made significant contributions in the
      development of this last method, both concerning the pallidum, STN and cZi. Unfortunately
      this method demands a high level of dedication and relies to a high degree on personal
      experience. Scientifically based guidelines delineating the target areas and identifying the
      optimal target do not readily exist.

      Common for all different methods is that it is normally required that the patient is awake
      during surgery in order to allow for intra-operative testing of effect/side effects, even if
      some today perform the procedure in general anesthesia concerning some of the targets. If the
      brain targets could be identified with a high degree of certainty, and the electrode position
      within that target can be verified during surgery, then having the patients awake during
      surgery would no longer be necessary.

      Identifying and delineating the optimal targets The literature regarding optimal target
      point/volume for the different targets is surprisingly meagre. The most common target, the
      subthalamic nucleus (STN), is also the most studied regarding this issue, but the effect has
      been evaluated in relation to the location of the electrode in no more than 260 patients in a
      total of 13 different studies. Interestingly, most of these studies have found that the best
      effect is not achieved in the target structure itself, but in another adjacent structure, the
      more rostral part of the Zona incerta overlying the STN. The same is true regarding the few
      studies of thalamic surgery for tremor, where most have demonstrated that the best effect is
      achieved from contacts outside the thalamic target, in the PSA. Concerning other
      targets/indications the literature is even more limited.

      The existing studies are further hampered by the heterogeneity of the methods. Often it is
      not the actual location of the electrode that is reported, but the intended one. Even when
      the actual location is reported it is most often presented according to distant landmarks,
      even if the targeting was done visually, which is a significant problem, taking into
      consideration the inter-individual variability. Further, even though the stimulation
      parameters used can differ widely and hence the electrical current affect different
      neighboring structures, this is virtually never taken into account.

      DBS for ET - Conclusions and aim DBS for ET is thus not an evidence based therapy and the
      same is true regarding both target areas used for ET. The relative merits of the different
      targets used have not been clearly demonstrated and the individual targets are not well
      delineated. There is thus a need to address these issues.

      Overview - What are we going to study? The effect of DBS for ET will be evaluated in a
      multicentre study recruiting 100 patients randomized to immediate surgery (group A) or best
      medical treatment only (as decided by the movement disorder neurologist, with few exceptions
      likely to be identical to their current medication) with delayed surgery at 6 months if still
      needed /indicated (group B). Primary outcome is tremor reduction as measured with Essential
      tremor rating scale11 (ETRS), with focus on items 5/6 (hand tremor) & 11-14 (hand function),
      at baseline before surgery and at 6 months. Secondary outcome includes the essential tremor
      rating assessment scale (TETRAS), quality of life measured with QUEST and electrical energy
      consumption18. After 6 months group B is operated -as indicated-, and group A and B are
      thereafter evaluated as one single group for long-term effects and analyses of electrode
      location. The electrodes will in all patients be inserted with a trajectory developed for
      this study allowing stimulation both in the established and traditionally used target Vim as
      well as in the new target cZi. Each contact will be evaluated individually concerning
      location, effects and side effects, in relation to stimulation parameters. This is done in
      order to, a) compare the two targets, but more importantly, b) to create a map of the whole
      area with identification/delineation of the optimal target point/volume. The time necessary
      to gather 100 patients is estimated to 2.5 - 3 years.

      Study design:

        -  Step 1 is designed as a randomized controlled trial in order to compare the effect of
           DBS (Group A) and medical treatment (Group B) on ET (Aim 1).

        -  In step 2 - 4 the patients in group A are operated and group A and B joined into one
           single group.

             -  Step 2 - all electrode contacts are individually analysed regarding chronic and
                acute stimulation effects in relation to their location in either the Vim or the
                cZi in order to decide which target is more effective (Aim 2).

             -  Step 3 - Effects and side effects, with consideration to field of stimulation, are
                analyzed in relation to neighboring structures in order to map the whole area and
                delineate the optimal target points (Aim 3).

             -  Step 4 - The long-term effect is evaluated in a non-randomized longitudinal study
                at 1, 3, 5, 10 years (Aim 4).

      Sample size and power:

      In step 1, with a confidence interval of 95%, and an expected improvement of 85 % in the
      surgical group and none (or at least < 25%) in the medical group, regarding contralateral
      items 5/6 & 11-14, a power of 100 % is achieved. In step 2, with an expected improvement of
      85% in one target and 60% in the other, a power of 98% is achieved. The high number of
      patients is, however, necessary for step 3, mapping of the area, in order to give a good
      cover of the periphery (Length of contact carrying electrode surface 7.5 mm, expected mean
      non-random intended deviation from target point (as defined in the study) 1 mm, expected mean
      random deviation from intended target point 1.5 mm). Based on the previous experience, less
      than 5% of patients is expected to be lost during the follow up, which will have an
      insignificant effect on the power.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Study design:
Step 1 is designed as a randomized controlled trial in order to compare the effect of DBS (Group A) and medical treatment (Group B) on ET (Aim 1).
In step 2 - 4 the patients in group A are operated and group A and B joined into one single group.
Step 2 - all electrode contacts are individually analysed regarding chronic and acute stimulation effects in relation to their location in either the Vim or the cZi in order to decide which target is more effective (Aim 2).
Step 3 - Effects and side effects, with consideration to field of stimulation, are analyzed in relation to neighboring structures in order to map the whole area and delineate the optimal target points (Aim 3).
Step 4 - The long-term effect is evaluated in a non-randomized longitudinal study at 1, 3, 5, 10 years (Aim 4).
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: Tremor is measured with the Essential tremor rating scale (ETRS) with focus on items 5/6 (hand tremor) & 11-14 (hand function). ETRS is performed before surgery at baseline and at 6 months on/off med/stim. The evaluation is done blinded to the patients in the surgical group. The evaluation is documented on video (with the patient wearing a head cap) and segmented for blinded evaluation of two expert evaluators
measure: Essential Tremor Rating Scale (ETRS)
time frame: Change from Baseline ETRS at 6 months
description: Fahn S, Tolosa E, Marin C (1993) Clinical rating scale for tremor. In: Jankovic J, Tolosa E (eds) Parkinson´s disease and movement disorders. Urban and Schwarzenberg Munich, pp 271-280
Scale: Total sum 0-144 points. Contralateral Tremor (item 5/6) & Handfunction (item 11-14) 0-28 points.
measure: Quality of life in ET (QUEST)
time frame: Change from Baseline at 6 months
description: Questionnaire Quality of Life in Essential Tremor Minimum score 0 (no self rated symptoms of ET) maximum 128 (maximum self rated symptoms of ET)
measure: electric energy consumption
time frame: Change from Baseline at 6 months
description: Pulse effective voltage (PEV) i s calculated för each operated patient
arm group label: Surgical
arm group type: Active Comparator
description: Participants randomized to surgery
arm group label: Medical
arm group type: Active Comparator
description: Participants randomized to best medical treatment
intervention type: Procedure
intervention name: Deep Brain Stimulation
description: Surgical implantation of intracranial leads for deep brain stimulation, extension cables and implantable pulse generator
arm group label: Surgical
intervention type: Drug
intervention name: Best Medical Treatment
description: Unselective β-blockers such as Propanolol
arm group label: Medical
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Patric Blomstedt, PhD
role: Study Chair
affiliation: Umeå Universitet
last name: Anders Fytagoridis, PhD
role: Principal Investigator
affiliation: Karolinska Institutet
last name: Anne-Louice Eriksson
phone: +468907850000
email: annelouice.eriksson@vll.se
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
country: Sweden
responsible party type: Principal Investigator
investigator affiliation: Karolinska Institutet
investigator full name: Anders Fytagoridis
investigator title: MD, PhD
mesh term: Tremor
mesh term: Essential Tremor
provided document: 