<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/NCT04432285</url>
  </required_header>
  <id_info>
    <org_study_id>96307</org_study_id>
    <nct_id>NCT04432285</nct_id>
  </id_info>
  <brief_title>Long-term Outcome of DBS Versus Botulinum Toxin Treatment in Cervical Dystonia</brief_title>
  <official_title>Long-term Outcome in Cervical Dystonia Patients Treated With Chronic Pallidal Deep Brain Stimulation Compared to Repeated Botulinum Toxin Injections - a Cross-sectional Observational Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Oslo University Hospital</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cervical dystonia (CD) is the most common isolated dystonia in adults. Cervical dystonia&#xD;
      symptoms can in most patients be managed well by botulinum toxin (BTX) injections, and&#xD;
      supporting treatment measures. However, one-fifth to one-third of patients do not obtain&#xD;
      sufficient relief from long-term BTX therapy, resulting in reduced quality of life. Deep&#xD;
      brain stimulation (DBS) is a treatment method in which electrodes are surgically implanted&#xD;
      permanently in the brain to modulate brain networks and function. In cervical dystonia, DBS&#xD;
      of the postero-ventral part of the internal globus pallidus (GPi-DBS) has been established as&#xD;
      an effective treatment for severe cases. However, the outcome of GPi-DBS in cervical dystonia&#xD;
      has been reported mostly in some smaller series with up to 3 years follow-up. Thus, there is&#xD;
      a lack of documentation of outcome of GPi-DBS in CD beyond 3 years of treatment and in larger&#xD;
      patient materials. In this study the investigators will perform a long-term follow-up study&#xD;
      of patients who were operated with a DBS-device targeting the GPi bilaterally, and who have&#xD;
      been treated with chronic GPi-DBS for a minimum of 3 years. The investigators will measure&#xD;
      the severity of symptom burden and quality of life with validated rating scales.&#xD;
&#xD;
      The investigators will compare this DBS-treated cohort with an age- and gender matched group&#xD;
      of CD patients who are receiving the standard treatment with botulinum neurotoxin (BoNT)&#xD;
      injections and have been treated for at least 3 years as well. The investigators hypothesize&#xD;
      that the DBS-treated group will have a significantly lower burden of symptoms at long-term&#xD;
      follow-up than the BoNT treated group.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cervical dystonia (CD) is the most common isolated dystonia in adults, with a prevalence of&#xD;
      9-13/100000. CD has a mean age at onset of 40 years, and is almost twice as common in women&#xD;
      than in men. Cervical dystonia symptoms can in most patients be managed well by botulinum&#xD;
      toxin (BoNT) injections, and supporting treatment measures. However, one-fifth to one-third&#xD;
      of patients do not obtain sufficient relief from long-term BoNT therapy, resulting in reduced&#xD;
      quality of life. Deep brain stimulation in the postero-ventral part of the internal globus&#xD;
      pallidus (GPi-DBS) has been established as an effective treatment of cervical dystonia,&#xD;
      including as a part of primary generalized dystonia, segmental or focal dystonia.&#xD;
&#xD;
      Long-term outcome of pallidal DBS in cervical dystonia has only been published in some&#xD;
      smaller series. In a prospective, single-center study with blinded outcome assessments of&#xD;
      eight CD patients, an average improvement of 70% in the Severity score of the TWSTRS , and&#xD;
      91% and 92% improvement, respectively, in the Disability and Pain scores, was found at median&#xD;
      30 months follow-up (Skogseid IM et al, 2012). The two largest unblinded series showed&#xD;
      average improvements of TWSTRS Severity score of 55 % and 58 %, at mean follow-up 32 months&#xD;
      (n=10), and 2 years (n=6), respectively (Hung SW et al, 2007, Cacciola F et al, 2010).&#xD;
&#xD;
      Although these studies are promising, there is a lack of documentation of outcome of GPi-DBS&#xD;
      in CD beyond 3 years of treatment and in larger patient materials. Also, studies are lacking&#xD;
      that compare the severity of remaining CD symptoms and disease-specific quality of life&#xD;
      between a long-term treated DBS-cohort and a cohort receiving long-term BoNT treatment.&#xD;
&#xD;
      The investigators will therefore perform a cross-sectional, observational study of patients&#xD;
      who were operated at Oslo University Hospital with a Medtronic DBS-device targeting the GPi&#xD;
      bilaterally from 2004 to 2017, and who have been treated with chronic GPi-DBS for a minimum&#xD;
      of 3 years and up to 13 years. The main objective is to assess remaining CD severity and&#xD;
      CD-related Quality of Life (QoL) in this DBS-treated group and compare this with an age- and&#xD;
      gender matched group of CD-patients treated with BoNT-injections for a minimum of 3 years&#xD;
      (BoNT-group).&#xD;
&#xD;
      The main outcome measures are the Toronto Western Spasmodic Torticollis Rating Scale&#xD;
      (TWSTRS), with its three subscores: Severity, Disability and Pain, and the Cervical Dystonia&#xD;
      Impact Profile-58 (CDIP-58), which is a self-rated questionnaire for disease-specific quality&#xD;
      of life. The primary endpoint of the study is the difference in TWSTRS total score between&#xD;
      the two treatment groups at the time of long-term follow-up. The BoNT-group will be assessed&#xD;
      with TWSTRS both before and 4-6 weeks after the last injection, but the score 4-6 weeks after&#xD;
      injection will be used for comparison with the DBS-group. In the DBS-group the TWSTRS total&#xD;
      and subscores obtained at long-term evaluation will also be compared to the scores which were&#xD;
      obtained prior to the operation as part of the routine work-up. Secondary endpoints are&#xD;
      TWSTRS Severity, Disability and Pain score, and CDIP-58 Total scores. Exploratory variables&#xD;
      are the eight Symptom/Domain scores of the CDIP-58 and Visual Analog Scale for Global Burden&#xD;
      of Disease (VAS-GBD), at long-term follow-up. Other outcome variables are complications and&#xD;
      severe adverse events of the two treatment types, and the Anxiety and Depression scores of&#xD;
      the Hospital Anxiety and Depression Scale (HADS).&#xD;
&#xD;
      The investigators hypothesize that the DBS-treated group will have a significantly lower mean&#xD;
      TWSTRS total score at long-term follow-up than the BoNT treated group.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">August 6, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">November 30, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Total score of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS).</measure>
    <time_frame>In the DBS-group: After 3-17 years of continuous GPi-DBS. In the BoNT-group: After minimum 3 years of regular BoNT injections (minimum 12 injection cycles), and 4-6 weeks after the last injection.</time_frame>
    <description>The TWSTRS is a validated clinical scale that assesses cervical dystonia symptom severity, disability and pain (Consky et al, 1990; Consky and Lang 1994; Comella et al, 1992; Dubinsky et al, 1991). In the first part the physical signs of cervical dystonia are scored by the investigator (Severity subscale), the second part rates disability/limitation of activities (Disability subscale), and the third part rates the intensity and duration of pain related to the CD, and its impact on the patient´s ability to participate in normal activities (Pain subscale).&#xD;
The TWSTRS Total score is the sum of the TWSTRS Severity score (0-35), the TWSTRS Disability score (0-30) and the TWSTRS Pain score (0-20), with a maximum total score of 85. Higher scores indicate more severe symptoms/disability/pain.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Severity, Disability and Pain subscores of the TWSTRS</measure>
    <time_frame>In the DBS-group: After 3-17 years of continuous GPi-DBS. In the BoNT-group: After minimum 3 years of regular BoNT injections (minimum 12 injection cycles),and 4-6 weeks after the last injection.</time_frame>
    <description>The TWSTRS is a validated clinical scale that assesses cervical dystonia symptom severity, disability and pain (Consky et al, 1990; Consky and Lang 1994; Comella et al, 1992; Dubinsky et al, 1991). In the first part the physical signs of cervical dystonia are scored by the investigator (Severity subscale), the second part rates disability/limitation of activities (Disability subscale), and the third part rates the intensity and duration of pain related to the CD, and its impact on the patient´s ability to participate in normal activities (Pain subscale).&#xD;
The TWSTRS Total score is the sum of the TWSTRS Severity score (0-35), the TWSTRS Disability score (0-30) and the TWSTRS Pain score (0-20), with a maximum total score of 85. Higher scores indicate more severe symptoms/disability/pain.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total score of the Cervical Dystonia Impact Profile 58 (CDIP-58)</measure>
    <time_frame>In the DBS-group: After 3-17 years of continuous GPi-DBS. In the BoNT-group: After minimum 3 years of regular BoNT injections (minimum 12 injection cycles), and 4-6 weeks after the last injection.</time_frame>
    <description>CDIP-58 is a patient-rated questionnaire that assesses disease-specific health-related quality of life. It includes 58 items grouped into eight dimensions. Summary scores of the eight dimensions are generated by summing items and are then transformed to a 0-100 scale. High scores indicate worse health.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Cervical Dystonia</condition>
  <arm_group>
    <arm_group_label>Deep Brain Stimulation (GPi-DBS)</arm_group_label>
    <description>Patients with cervical dystonia (CD) who were operated at Oslo University Hospital between June 2004 and December 2017 with a DBS-device targeting the GPi bilaterally, and who have been treated with chronic GPi-DBS for a minimum of 3 years.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Botulinum toxin treatment</arm_group_label>
    <description>CD patients who for a minimum of 3 years have received treatment with botulinum neurotoxin (BoNT) injections at regular intervals (minimum 12 injection cycles) and still are receiving them (Age- and gender matched to the GPi-DBS group)</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>DBS-device, implanted in GPi bilaterally</intervention_name>
    <description>Chronic/continuous bilateral GPi-DBS</description>
    <arm_group_label>Deep Brain Stimulation (GPi-DBS)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Botulinum toxin</intervention_name>
    <description>Repeated intramuscular injections at regular intervals of around 3 months</description>
    <arm_group_label>Botulinum toxin treatment</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Adult patients who have cervical dystonia, focal or segmental, and who have been receiving&#xD;
        either GPi-DBS, or Botulinum toxin injections, for a minimum of 3 years, and who still&#xD;
        receives such treatment. All patients to be included give their written informed consent to&#xD;
        participate.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  DBS-group: Patients with isolated cervical dystonia (focal or part of segmental&#xD;
             dystonia) who have been operated at Oslo University between June 2004 and June 2017&#xD;
             and treated with bilateral GPi-DBS for a minimum of 3 years, and who give their&#xD;
             informed consent to participate in this follow-up study.&#xD;
&#xD;
          -  BoNT-group: Patients who are receiving regular BoNT-injections at Oslo University&#xD;
             Hospital for isolated cervical dystonia (focal or part of segmental dystonia), who are&#xD;
             gender-and age-matched to the operated patients, and who give their informed consent&#xD;
             to participate in this follow-up study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Dementia/inability to respond to the CDIP-58.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Inger Marie Skogseid, MDPhD</last_name>
    <role>Study Director</role>
    <affiliation>Oslo University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Oslo University Hospital</name>
      <address>
        <city>Oslo</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>June 11, 2020</study_first_submitted>
  <study_first_submitted_qc>June 12, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>April 26, 2022</last_update_submitted>
  <last_update_submitted_qc>April 26, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Oslo University Hospital</investigator_affiliation>
    <investigator_full_name>Inger Marie Skogseid</investigator_full_name>
    <investigator_title>Consultant neurologist, Project leader</investigator_title>
  </responsible_party>
  <keyword>Deep Brain Stimulation</keyword>
  <keyword>Botulinum Toxin treatment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dystonia</mesh_term>
    <mesh_term>Dystonic Disorders</mesh_term>
    <mesh_term>Torticollis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Botulinum Toxins</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04432285
org study id: 96307
nct id: NCT04432285
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Cervical dystonia (CD) is the most common isolated dystonia in adults. Cervical dystonia
      symptoms can in most patients be managed well by botulinum toxin (BTX) injections, and
      supporting treatment measures. However, one-fifth to one-third of patients do not obtain
      sufficient relief from long-term BTX therapy, resulting in reduced quality of life. Deep
      brain stimulation (DBS) is a treatment method in which electrodes are surgically implanted
      permanently in the brain to modulate brain networks and function. In cervical dystonia, DBS
      of the postero-ventral part of the internal globus pallidus (GPi-DBS) has been established as
      an effective treatment for severe cases. However, the outcome of GPi-DBS in cervical dystonia
      has been reported mostly in some smaller series with up to 3 years follow-up. Thus, there is
      a lack of documentation of outcome of GPi-DBS in CD beyond 3 years of treatment and in larger
      patient materials. In this study the investigators will perform a long-term follow-up study
      of patients who were operated with a DBS-device targeting the GPi bilaterally, and who have
      been treated with chronic GPi-DBS for a minimum of 3 years. The investigators will measure
      the severity of symptom burden and quality of life with validated rating scales.

      The investigators will compare this DBS-treated cohort with an age- and gender matched group
      of CD patients who are receiving the standard treatment with botulinum neurotoxin (BoNT)
      injections and have been treated for at least 3 years as well. The investigators hypothesize
      that the DBS-treated group will have a significantly lower burden of symptoms at long-term
      follow-up than the BoNT treated group.
Cervical dystonia (CD) is the most common isolated dystonia in adults, with a prevalence of
      9-13/100000. CD has a mean age at onset of 40 years, and is almost twice as common in women
      than in men. Cervical dystonia symptoms can in most patients be managed well by botulinum
      toxin (BoNT) injections, and supporting treatment measures. However, one-fifth to one-third
      of patients do not obtain sufficient relief from long-term BoNT therapy, resulting in reduced
      quality of life. Deep brain stimulation in the postero-ventral part of the internal globus
      pallidus (GPi-DBS) has been established as an effective treatment of cervical dystonia,
      including as a part of primary generalized dystonia, segmental or focal dystonia.

      Long-term outcome of pallidal DBS in cervical dystonia has only been published in some
      smaller series. In a prospective, single-center study with blinded outcome assessments of
      eight CD patients, an average improvement of 70% in the Severity score of the TWSTRS , and
      91% and 92% improvement, respectively, in the Disability and Pain scores, was found at median
      30 months follow-up (Skogseid IM et al, 2012). The two largest unblinded series showed
      average improvements of TWSTRS Severity score of 55 % and 58 %, at mean follow-up 32 months
      (n=10), and 2 years (n=6), respectively (Hung SW et al, 2007, Cacciola F et al, 2010).

      Although these studies are promising, there is a lack of documentation of outcome of GPi-DBS
      in CD beyond 3 years of treatment and in larger patient materials. Also, studies are lacking
      that compare the severity of remaining CD symptoms and disease-specific quality of life
      between a long-term treated DBS-cohort and a cohort receiving long-term BoNT treatment.

      The investigators will therefore perform a cross-sectional, observational study of patients
      who were operated at Oslo University Hospital with a Medtronic DBS-device targeting the GPi
      bilaterally from 2004 to 2017, and who have been treated with chronic GPi-DBS for a minimum
      of 3 years and up to 13 years. The main objective is to assess remaining CD severity and
      CD-related Quality of Life (QoL) in this DBS-treated group and compare this with an age- and
      gender matched group of CD-patients treated with BoNT-injections for a minimum of 3 years
      (BoNT-group).

      The main outcome measures are the Toronto Western Spasmodic Torticollis Rating Scale
      (TWSTRS), with its three subscores: Severity, Disability and Pain, and the Cervical Dystonia
      Impact Profile-58 (CDIP-58), which is a self-rated questionnaire for disease-specific quality
      of life. The primary endpoint of the study is the difference in TWSTRS total score between
      the two treatment groups at the time of long-term follow-up. The BoNT-group will be assessed
      with TWSTRS both before and 4-6 weeks after the last injection, but the score 4-6 weeks after
      injection will be used for comparison with the DBS-group. In the DBS-group the TWSTRS total
      and subscores obtained at long-term evaluation will also be compared to the scores which were
      obtained prior to the operation as part of the routine work-up. Secondary endpoints are
      TWSTRS Severity, Disability and Pain score, and CDIP-58 Total scores. Exploratory variables
      are the eight Symptom/Domain scores of the CDIP-58 and Visual Analog Scale for Global Burden
      of Disease (VAS-GBD), at long-term follow-up. Other outcome variables are complications and
      severe adverse events of the two treatment types, and the Anxiety and Depression scores of
      the Hospital Anxiety and Depression Scale (HADS).

      The investigators hypothesize that the DBS-treated group will have a significantly lower mean
      TWSTRS total score at long-term follow-up than the BoNT treated group.
observational model: Cohort
time perspective: Cross-Sectional
measure: Total score of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS).
time frame: In the DBS-group: After 3-17 years of continuous GPi-DBS. In the BoNT-group: After minimum 3 years of regular BoNT injections (minimum 12 injection cycles), and 4-6 weeks after the last injection.
description: The TWSTRS is a validated clinical scale that assesses cervical dystonia symptom severity, disability and pain (Consky et al, 1990; Consky and Lang 1994; Comella et al, 1992; Dubinsky et al, 1991). In the first part the physical signs of cervical dystonia are scored by the investigator (Severity subscale), the second part rates disability/limitation of activities (Disability subscale), and the third part rates the intensity and duration of pain related to the CD, and its impact on the patient´s ability to participate in normal activities (Pain subscale).
The TWSTRS Total score is the sum of the TWSTRS Severity score (0-35), the TWSTRS Disability score (0-30) and the TWSTRS Pain score (0-20), with a maximum total score of 85. Higher scores indicate more severe symptoms/disability/pain.
measure: Severity, Disability and Pain subscores of the TWSTRS
time frame: In the DBS-group: After 3-17 years of continuous GPi-DBS. In the BoNT-group: After minimum 3 years of regular BoNT injections (minimum 12 injection cycles),and 4-6 weeks after the last injection.
description: The TWSTRS is a validated clinical scale that assesses cervical dystonia symptom severity, disability and pain (Consky et al, 1990; Consky and Lang 1994; Comella et al, 1992; Dubinsky et al, 1991). In the first part the physical signs of cervical dystonia are scored by the investigator (Severity subscale), the second part rates disability/limitation of activities (Disability subscale), and the third part rates the intensity and duration of pain related to the CD, and its impact on the patient´s ability to participate in normal activities (Pain subscale).
The TWSTRS Total score is the sum of the TWSTRS Severity score (0-35), the TWSTRS Disability score (0-30) and the TWSTRS Pain score (0-20), with a maximum total score of 85. Higher scores indicate more severe symptoms/disability/pain.
measure: Total score of the Cervical Dystonia Impact Profile 58 (CDIP-58)
time frame: In the DBS-group: After 3-17 years of continuous GPi-DBS. In the BoNT-group: After minimum 3 years of regular BoNT injections (minimum 12 injection cycles), and 4-6 weeks after the last injection.
description: CDIP-58 is a patient-rated questionnaire that assesses disease-specific health-related quality of life. It includes 58 items grouped into eight dimensions. Summary scores of the eight dimensions are generated by summing items and are then transformed to a 0-100 scale. High scores indicate worse health.
arm group label: Deep Brain Stimulation (GPi-DBS)
description: Patients with cervical dystonia (CD) who were operated at Oslo University Hospital between June 2004 and December 2017 with a DBS-device targeting the GPi bilaterally, and who have been treated with chronic GPi-DBS for a minimum of 3 years.
arm group label: Botulinum toxin treatment
description: CD patients who for a minimum of 3 years have received treatment with botulinum neurotoxin (BoNT) injections at regular intervals (minimum 12 injection cycles) and still are receiving them (Age- and gender matched to the GPi-DBS group)
intervention type: Device
intervention name: DBS-device, implanted in GPi bilaterally
description: Chronic/continuous bilateral GPi-DBS
arm group label: Deep Brain Stimulation (GPi-DBS)
intervention type: Drug
intervention name: Botulinum toxin
description: Repeated intramuscular injections at regular intervals of around 3 months
arm group label: Botulinum toxin treatment
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Inger Marie Skogseid, MDPhD
role: Study Director
affiliation: Oslo University Hospital
facility: 
country: Norway
responsible party type: Principal Investigator
investigator affiliation: Oslo University Hospital
investigator full name: Inger Marie Skogseid
investigator title: Consultant neurologist, Project leader
mesh term: Dystonia
mesh term: Dystonic Disorders
mesh term: Torticollis
mesh term: Botulinum Toxins