<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/NCT02249572</url>
  </required_header>
  <id_info>
    <org_study_id>2014/314</org_study_id>
    <nct_id>NCT02249572</nct_id>
  </id_info>
  <brief_title>Vestibular Schwannoma - Radiosurgery or Expectation: V-REX.</brief_title>
  <acronym>V-REX</acronym>
  <official_title>Vestibular Schwannoma - Radiosurgery or Expectation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Haukeland University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Haukeland University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to compare the outcome of patients with vestibular schwannomas&#xD;
      in two groups of randomised to either radiosurgery or expectation.&#xD;
&#xD;
      The optimal treatment for a small vestibular schwannoma is a matter of controversy and there&#xD;
      are no class 1 studies investigating this. Even the natural tumor growth rate remains&#xD;
      controversial and is reported to be from near 100% of cases showing growth to 40-60% in&#xD;
      various reports. The clinical results of various treatment strategies are documented, but&#xD;
      comparative studies are very few. Immediate radiosurgery or wait-and scan with subsequent&#xD;
      treatment upon growth are two strategies that have both been used in many different centers.&#xD;
      There are only two studies comparing these treatment modalities .These studies indicate&#xD;
      significant effect of GKRS in reducing tumor growth, with less differences in hearing and&#xD;
      complaint outcomes. None of the studies are blinded or randomised, allowing for bias.&#xD;
&#xD;
      The present study aims at comparing the two modalities above. To achieve this, we intend to&#xD;
      randomise patients with newly diagnosed VS to either of Wait-and Scan or immediate&#xD;
      radiosurgery.&#xD;
&#xD;
      The primary study endpoint is the relative tumor size measured as the ratio between tumor&#xD;
      volume at four years compared with volume at inclusion. Secondary endpoints include symptom&#xD;
      and sign development measured by clinical examination and by patient's responses to&#xD;
      standardised validated questionnaires. In addition, the health economics involved with both&#xD;
      strategies will be evaluated and compared, as well as the patient's working status.&#xD;
&#xD;
      Patients will be asked to participate if their VS is diagnosed within the last six months,&#xD;
      their age is between 18 and 70, and pending there are no exclusion criteria (see below). A&#xD;
      power analysis indicates that about 50 patients per group is sufficient.&#xD;
&#xD;
      In case of failure to recruit patients, we will change the design to a study based on&#xD;
      patient's own choice of treatment.&#xD;
&#xD;
      The study will be announced according to international guidelines. A steering committee will&#xD;
      monitor the study and an intermediate analysis will be performed when the study group has&#xD;
      been followed for two years. If the effect aim is already observed, the study should&#xD;
      nonetheless continue, as it is too early to evaluate the results after such a short time&#xD;
      course.&#xD;
&#xD;
      It will also be discussed to do a follow-up of all patients ten years after inclusion.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design and purpose:&#xD;
&#xD;
      Design: Randomised study blinded to observer on primary endpoint (tumor volume).&#xD;
      Intention-to-treat, ie patients who cross over from conservative to GKRS group during the&#xD;
      study period are assigned to their original group. Patients who refrain from radiosurgery&#xD;
      despite randomisation are assigned to radiosurgery group.&#xD;
&#xD;
      Purpose: compare the treatment of small and medium-sized VS treated with a standardised dose&#xD;
      of 12 Gy to the tumor periphery with expectative treatment.&#xD;
&#xD;
      Primary endpoint:&#xD;
&#xD;
      Growth measured as volume ratio V4years/Vbaseline and 1/volume doubling time, evaluated by T1&#xD;
      contrast MRI volumetry at one, two, three and four years.&#xD;
&#xD;
      Secondary endpoints:&#xD;
&#xD;
      Hearing acuity according to Gardner Robertson scale at four years (safety endpoint).&#xD;
&#xD;
      Conversion to other treatment during study period Adverse effects&#xD;
&#xD;
      Subjective complaints assessed by questionnaires:&#xD;
&#xD;
      Penn Vestibular Schwannoma QOL Scale EQ-50 Scale&#xD;
&#xD;
      Investigations:&#xD;
&#xD;
      Prior to inclusion: MRI less than 6 months showing VS.&#xD;
&#xD;
      After inclusion and at 1,2 3,4 years, all at study site:&#xD;
&#xD;
      MRI of inner ear (acoustic neuroma protocol) Balance platform Nystagmometry Audiometry&#xD;
&#xD;
      Effect registration:&#xD;
&#xD;
      Main variable:&#xD;
&#xD;
      Tumor volume, measured on a T1 contrast MRI scan with 2mm slice interval/thickness. For&#xD;
      study, the measurement is to be done by a blinded observer.&#xD;
&#xD;
      Economy. Costs associated with study are financed by research donations from Helse-Vest and&#xD;
      The National Center for Vestibular Schwannomas.&#xD;
&#xD;
      Radiology: Image based tumor volumes As the primary endpoint is relative tumor size, an&#xD;
      accurate measure of tumor volume and changes thereof, is mandatory. This will be obtained&#xD;
      using a state-of-the-art magnetic resonance imaging (MRI) system suited for acquiring high&#xD;
      resolution (1mm3), three dimensional (3D) anatomical images. A 1.5T imaging system which&#xD;
      meets the required field homogeneity will be used for imaging. The image contrast will be T1&#xD;
      weighted with gadolinium based contrast agent, yet a T2 weighted image volume will also be&#xD;
      included (preferably also acquired in 3D). An identical imaging protocol will be acquired at&#xD;
      each time point (prior to randomization, on site follow up, 4-year annual follow up), and&#xD;
      image slices will be positioned according to anatomical landmarks in each patients to&#xD;
      minimize variability across time. All 3D acquisitions will be performed with sagittal slicing&#xD;
      to minimize artifacts, but will also be reformatted into coronal and axial views (1mm slice&#xD;
      thickness, no gap between slices) on the scanner system.&#xD;
&#xD;
      The subsequent imaging processing, i.e. the estimation of tumor volume and longitudinal&#xD;
      changes thereof, will be performed using available software at time of analysis.&#xD;
&#xD;
      Study schedule&#xD;
&#xD;
      Clinical examination, MRI, Questionnaires, Audiometry, Vestibular tests are done at baseline&#xD;
      and then annually for 4 years. Patients randomised for radiosurgery are treated within 3&#xD;
      months after baseline.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2014</start_date>
  <completion_date type="Actual">October 1, 2021</completion_date>
  <primary_completion_date type="Actual">October 1, 2017</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>Block randomization of 100 individuals to radiosurgery or expectative treatment of vestibular schwannoma.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Investigator, Outcomes Assessor)</masking>
    <masking_description>Study investigator masked to whether patient has had radiosurgery og no active treatment. Scars due to radiosurgery frame hidden With surgical cap at all study consultations in all pts. Radiologist measuring tumor size masked as to treatment</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Relative Tumor volume</measure>
    <time_frame>4 years</time_frame>
    <description>Growth measured as volume ratio V4years/Vbaseline and 1/volume doubling time</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hearing acuity</measure>
    <time_frame>4 years</time_frame>
    <description>Hearing acuity according to Gardner Robertson scale at four years</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Conversion to other treatment during study period</measure>
    <time_frame>4 years</time_frame>
    <description>If patient is in need of other treatment for tumor (radiosurgery, microsurgery, other) within the time frame of the study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Subjective complaints</measure>
    <time_frame>4 years</time_frame>
    <description>Penn Vestibular Schwannoma QOL Scale (PANQOL) EQ-50 Scale</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Neurovestibular testing</measure>
    <time_frame>4 years</time_frame>
    <description>Outcomes of caloric test and Balance Platform test (Equitest, SOT)</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">100</enrollment>
  <condition>Vestibular Schwannoma</condition>
  <arm_group>
    <arm_group_label>gamma knife radiosurgery</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single fraction gamma knife radiosurgery given at 12 Gy to tumor periphery for vestibular schwannoma</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Expectation</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No active treatment given for vestibular schwannoma</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>gamma knife radiosurgery</intervention_name>
    <description>Leksell Perfection model gamma knife.</description>
    <arm_group_label>gamma knife radiosurgery</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Vestibular schwannoma diagnosed by MRI of less than 6 months.&#xD;
&#xD;
          -  Diameter 4-20mm. Willing to participate. Age 18 -70 years.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Dementia&#xD;
&#xD;
          -  Active malignant disease&#xD;
&#xD;
          -  Type II neurofibromatosis in patient or first grade relative.&#xD;
&#xD;
          -  Other severe co-morbidity&#xD;
&#xD;
          -  Type 2 neurofibromatosis in patient or first-grade relative&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Morten Lund-Johansen, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Haukeland University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Haukeland Unviersity Hospital</name>
      <address>
        <city>Bergen</city>
        <zip>5021</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>September 23, 2014</study_first_submitted>
  <study_first_submitted_qc>September 23, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 25, 2014</study_first_posted>
  <last_update_submitted>October 19, 2022</last_update_submitted>
  <last_update_submitted_qc>October 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Vestibular schwannoma</keyword>
  <keyword>Radiosurgery</keyword>
  <keyword>Neurosurgery</keyword>
  <keyword>Randomized</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neurilemmoma</mesh_term>
    <mesh_term>Neuroma, Acoustic</mesh_term>
  </condition_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/NCT02249572
org study id: 2014/314
nct id: NCT02249572
lead sponsor: 
has dmc: Yes
The purpose of this study is to compare the outcome of patients with vestibular schwannomas
      in two groups of randomised to either radiosurgery or expectation.

      The optimal treatment for a small vestibular schwannoma is a matter of controversy and there
      are no class 1 studies investigating this. Even the natural tumor growth rate remains
      controversial and is reported to be from near 100% of cases showing growth to 40-60% in
      various reports. The clinical results of various treatment strategies are documented, but
      comparative studies are very few. Immediate radiosurgery or wait-and scan with subsequent
      treatment upon growth are two strategies that have both been used in many different centers.
      There are only two studies comparing these treatment modalities .These studies indicate
      significant effect of GKRS in reducing tumor growth, with less differences in hearing and
      complaint outcomes. None of the studies are blinded or randomised, allowing for bias.

      The present study aims at comparing the two modalities above. To achieve this, we intend to
      randomise patients with newly diagnosed VS to either of Wait-and Scan or immediate
      radiosurgery.

      The primary study endpoint is the relative tumor size measured as the ratio between tumor
      volume at four years compared with volume at inclusion. Secondary endpoints include symptom
      and sign development measured by clinical examination and by patient's responses to
      standardised validated questionnaires. In addition, the health economics involved with both
      strategies will be evaluated and compared, as well as the patient's working status.

      Patients will be asked to participate if their VS is diagnosed within the last six months,
      their age is between 18 and 70, and pending there are no exclusion criteria (see below). A
      power analysis indicates that about 50 patients per group is sufficient.

      In case of failure to recruit patients, we will change the design to a study based on
      patient's own choice of treatment.

      The study will be announced according to international guidelines. A steering committee will
      monitor the study and an intermediate analysis will be performed when the study group has
      been followed for two years. If the effect aim is already observed, the study should
      nonetheless continue, as it is too early to evaluate the results after such a short time
      course.

      It will also be discussed to do a follow-up of all patients ten years after inclusion.
Study design and purpose:

      Design: Randomised study blinded to observer on primary endpoint (tumor volume).
      Intention-to-treat, ie patients who cross over from conservative to GKRS group during the
      study period are assigned to their original group. Patients who refrain from radiosurgery
      despite randomisation are assigned to radiosurgery group.

      Purpose: compare the treatment of small and medium-sized VS treated with a standardised dose
      of 12 Gy to the tumor periphery with expectative treatment.

      Primary endpoint:

      Growth measured as volume ratio V4years/Vbaseline and 1/volume doubling time, evaluated by T1
      contrast MRI volumetry at one, two, three and four years.

      Secondary endpoints:

      Hearing acuity according to Gardner Robertson scale at four years (safety endpoint).

      Conversion to other treatment during study period Adverse effects

      Subjective complaints assessed by questionnaires:

      Penn Vestibular Schwannoma QOL Scale EQ-50 Scale

      Investigations:

      Prior to inclusion: MRI less than 6 months showing VS.

      After inclusion and at 1,2 3,4 years, all at study site:

      MRI of inner ear (acoustic neuroma protocol) Balance platform Nystagmometry Audiometry

      Effect registration:

      Main variable:

      Tumor volume, measured on a T1 contrast MRI scan with 2mm slice interval/thickness. For
      study, the measurement is to be done by a blinded observer.

      Economy. Costs associated with study are financed by research donations from Helse-Vest and
      The National Center for Vestibular Schwannomas.

      Radiology: Image based tumor volumes As the primary endpoint is relative tumor size, an
      accurate measure of tumor volume and changes thereof, is mandatory. This will be obtained
      using a state-of-the-art magnetic resonance imaging (MRI) system suited for acquiring high
      resolution (1mm3), three dimensional (3D) anatomical images. A 1.5T imaging system which
      meets the required field homogeneity will be used for imaging. The image contrast will be T1
      weighted with gadolinium based contrast agent, yet a T2 weighted image volume will also be
      included (preferably also acquired in 3D). An identical imaging protocol will be acquired at
      each time point (prior to randomization, on site follow up, 4-year annual follow up), and
      image slices will be positioned according to anatomical landmarks in each patients to
      minimize variability across time. All 3D acquisitions will be performed with sagittal slicing
      to minimize artifacts, but will also be reformatted into coronal and axial views (1mm slice
      thickness, no gap between slices) on the scanner system.

      The subsequent imaging processing, i.e. the estimation of tumor volume and longitudinal
      changes thereof, will be performed using available software at time of analysis.

      Study schedule

      Clinical examination, MRI, Questionnaires, Audiometry, Vestibular tests are done at baseline
      and then annually for 4 years. Patients randomised for radiosurgery are treated within 3
      months after baseline.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Block randomization of 100 individuals to radiosurgery or expectative treatment of vestibular schwannoma.
primary purpose: Treatment
masking: Double (Investigator, Outcomes Assessor)
masking description: Study investigator masked to whether patient has had radiosurgery og no active treatment. Scars due to radiosurgery frame hidden With surgical cap at all study consultations in all pts. Radiologist measuring tumor size masked as to treatment
measure: Relative Tumor volume
time frame: 4 years
description: Growth measured as volume ratio V4years/Vbaseline and 1/volume doubling time
measure: Hearing acuity
time frame: 4 years
description: Hearing acuity according to Gardner Robertson scale at four years
measure: Conversion to other treatment during study period
time frame: 4 years
description: If patient is in need of other treatment for tumor (radiosurgery, microsurgery, other) within the time frame of the study
measure: Subjective complaints
time frame: 4 years
description: Penn Vestibular Schwannoma QOL Scale (PANQOL) EQ-50 Scale
measure: Neurovestibular testing
time frame: 4 years
description: Outcomes of caloric test and Balance Platform test (Equitest, SOT)
arm group label: gamma knife radiosurgery
arm group type: Experimental
description: Single fraction gamma knife radiosurgery given at 12 Gy to tumor periphery for vestibular schwannoma
arm group label: Expectation
arm group type: No Intervention
description: No active treatment given for vestibular schwannoma
intervention type: Radiation
intervention name: gamma knife radiosurgery
description: Leksell Perfection model gamma knife.
arm group label: gamma knife radiosurgery
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Morten Lund-Johansen, MD PhD
role: Principal Investigator
affiliation: Haukeland University Hospital
facility: 
country: Norway
responsible party type: Sponsor
mesh term: Neurilemmoma
mesh term: Neuroma, Acoustic