<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/NCT03305588</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-160811009</org_study_id>
    <nct_id>NCT03305588</nct_id>
  </id_info>
  <brief_title>RAD 1601: EDGE Radiosurgery for Intractable Essential Tremor and Tremor-Dominant Parkinson's Disease</brief_title>
  <official_title>RAD 1601: Pilot Trial of Frameless Virtual Cone Stereotactic Radiosurgical Thalamotomy for Intractable Tremor and Advanced Functional Connectivity Parcellation of the Thalamus</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Alabama at Birmingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Alabama at Birmingham</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To determine the efficacy of frameless Virtual Cone Radiosurgical Thalamotomy for medically&#xD;
      refractory tremor resulting from either Essential Tremor or Tremor-Dominant Parkinson's&#xD;
      Disease with the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) in patients who are not&#xD;
      candidates for deep brain stimulation (DBS).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Per the National Institute of Neurological Disorders and Stroke, tremor is an involuntary,&#xD;
      rhythmic muscle contraction leading to shaking movements in one or more parts of the body. It&#xD;
      is a common movement disorder that most often affects the upper extremities but can also&#xD;
      occur in the head, vocal cords, torso, and lower extremities. Tremor may be intermittent or&#xD;
      constant. It can be present at rest, during action, or mixed between rest and action.&#xD;
&#xD;
      Tremor can occur at any age but it is most common among middle-aged and older adults; once it&#xD;
      occurs, it often progresses over time. This disorder shows no gender predilection. Although&#xD;
      tremor is not life threatening, it can be severely disabling, making it difficult or even&#xD;
      impossible to perform work and daily life tasks.&#xD;
&#xD;
      Deep parts of the brain that control movements appear to be involved in tremor development.&#xD;
      However, most types of tremor have no actual known cause. There are some forms that appear to&#xD;
      be inherited and run in families. There are more than 20 types of tremor. Tremor can occur on&#xD;
      its own (such as essential tremor (ET) or be associated with other neurological disorders,&#xD;
      such as Parkinson's disease (PD).&#xD;
&#xD;
      Tremor is a common symptom of Parkinson's disease. The classification of patients with&#xD;
      Parkinson's disease into tremor-dominant and non-tremor subtypes is well established. The&#xD;
      pathophysiology of tremor in patients with tremor-dominant Parkinson's disease (TDPD) may be&#xD;
      distinct from other their other symptoms, such as bradykinesia, rigidity, and gait and&#xD;
      balance symptoms. Importantly, tremor in PD responds less well or can even be highly&#xD;
      resistant to dopaminergic treatment than bradykinesia and rigidity. Therefore other treatment&#xD;
      strategies may need to be considered.&#xD;
&#xD;
      Essential Tremor (ET) is a common neurologic condition characterized by a tremor that can&#xD;
      occur either with posture or action. In the US, there are reported to be as many as 10&#xD;
      million people with essential tremor. A significant subset of patients experience persistent&#xD;
      disability and disruption on activities of daily living from tremor and require intervention.&#xD;
&#xD;
      Treatment approach depends on the penetrance of disability into a patient's life, but&#xD;
      typically begins with pharmacologic intervention. Patients with disabling tremor refractory&#xD;
      to primary and secondary pharmacologic interventions are evaluated for surgical treatment&#xD;
      with deep brain stimulation (DBS) or thalamotomy. However, a sizeable subset of these&#xD;
      patients are unfavorable candidates for surgery due to medical or neurological&#xD;
      co-morbidities. Additionally, a significant subset of patients simply does not wish to&#xD;
      undergo the awake craniotomy required for DBS lead placement for tremor. Stereotactic&#xD;
      radiosurgery (SRS) thalamotomy is an alternative for those patients. SRS thalamotomy targets&#xD;
      the ventral intermediate (VIM) nucleus of the thalamus based on predetermined stereotactic&#xD;
      coordinates.&#xD;
&#xD;
      Almost all prior SRS thalamotomy studies performed have used the Leksell Gamma Knife&#xD;
      treatment unit and demonstrate that about 80% of properly selected patients respond. The&#xD;
      efficacy of Gamma Knife radiosurgery for tremor has been studied prospectively and has been&#xD;
      modeled based upon prognostic factors in larger retrospective studies. These studies provide&#xD;
      benchmarks for measuring the safety and efficacy of frameless Virtual Cone radiosurgery in&#xD;
      this trial. In order for possible frameless Virtual Cone radiosurgery to be a standard of&#xD;
      care in the treatment of tremor, additional clinical data is required. This pilot trial of&#xD;
      Virtual Cone radiosurgery will assess the safety and efficacy of this treatment. A target of&#xD;
      forty patients will be treated to confirm the feasibility of the protocol procedures,&#xD;
      efficacy, and safety of the treatment. Secondary endpoints will include quality of life and&#xD;
      patient satisfaction. The investigators hypothesize that the recent improvements in LINAC&#xD;
      delivery, image guidance, and patient position monitoring will allow a safe frameless&#xD;
      procedure that has a high patient satisfaction and low toxicity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 5, 2017</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall tremor reduction proportion evaluated by the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS)</measure>
    <time_frame>From Baseline up to 36 months following completion of radiosurgery</time_frame>
    <description>The Fahn-Tolosa-Marin Tremor Rating Scale evaluation will assess the severity of the patient's tremor and measure the impact on their activities of daily living.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with treatment-related adverse events</measure>
    <time_frame>From Baseline up to 36 months following completion of radiosurgery</time_frame>
    <description>Based on the assessments of the patient and the responses provided by the patient in questionnaires, the investigators will assess acute and late neurologic toxicities. All adverse events/toxicities will be assessed with the utilization of CTCAE v.4.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in resting-state functional MRI (fMRI) and diffusion tensor patterns associated with Radiosurgical thalamotomy</measure>
    <time_frame>From Baseline up to 36 months following completion of radiosurgery</time_frame>
    <description>Changes will be assessed by resting-state functional MRI (fMRI) to see the impact of radiosurgery ablation on brain function or alteration of function of the ventral intermediate nucleus of the thalamus.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean of Quality of Life Scores measured by SF-36 questionnaire</measure>
    <time_frame>From Baseline up to 36 months following completion of radiosurgery</time_frame>
    <description>Quality of Life (QOL) will be measured by SF-36 questionnaire. This questionnaire consists of 36 questions (items) measuring physical and mental health in relation to 8 health concepts: physical functioning, bodily pain, role of limitations due to physical health problems, role of limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perception. All items are scored so that a high score defines a more favorable health state. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are set at 0 and 100, respectively.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean of Quality of Life Scores measured by PROMIS Upper Extremity Questionnaire</measure>
    <time_frame>From Baseline up to 36 months following completion of radiosurgery</time_frame>
    <description>PROMIS Upper Extremity questionnaire will assess effect of tremor on one's physical function of upper extremity, as well as, effects on activities of daily living.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient Satisfaction Scores</measure>
    <time_frame>3 Month Follow-Up Visit</time_frame>
    <description>3 months following the completion of radiosurgery, the patient will be asked the following two questions: 1) Would the participant have the radiosurgery procedure again? 2) Would the participant recommend it to friends and family?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Define Targeting Methods within Thalamus based on Structural and Functional Connectivity</measure>
    <time_frame>From Baseline up to 36 months following completion of radiosurgery</time_frame>
    <description>Compare how well the standard MRI conventional thalamotomy targeting technique (based on predetermined atlas coordinates) matches with advanced MRI-based (functional and structural) mapping of the thalamotomy target.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean of Quality of Life Scores measured by the Essential Tremor Rating Assessment Scale (TETRAS)</measure>
    <time_frame>From Baseline up to 36 months following completion of radiosurgery</time_frame>
    <description>TETRAS scale will assess 9 performance items of examination to create a clinical rating scale for essential tremor. Score is 0-4. Zero being no tremor.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Essential Tremor</condition>
  <condition>Parkinson Disease</condition>
  <arm_group>
    <arm_group_label>130 Gy Radiation &amp; Unframed Virtual Cone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>130 Gy Virtual Cone Radiosurgery Unframed (Face Mask)</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Unframed Virtual Cone</intervention_name>
    <description>The patient will undergo stereotactic radiosurgery. Radiosurgery is a single non-surgical radiation treatment and will be done as an outpatient procedure. High-energy radiation will be delivered to a small, precise area of the patient's brain using a linear accelerator. A face mask (unframed) will be placed over the patient's face to keep their head from moving during the procedure. During the procedure, the study doctor will confirm the exact location that needs to be treated using x-rays and optical imaging cameras. The face mask will hold the patient's head to prevent it from moving and to focus the x-rays and aim them on a small area in the thalamus of the patient's brain. For most patients, the actual time on the radiosurgery treatment machine is 30 to 60 minutes. The face mask will be removed after the treatment.</description>
    <arm_group_label>130 Gy Radiation &amp; Unframed Virtual Cone</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with medical refractory essential tremor or tremor-dominant Parkinson's&#xD;
             disease that are not candidates for deep brain stimulation (DBS), either by&#xD;
             medical/surgical co-morbidities or by choice.&#xD;
&#xD;
          -  Patients must have an ECOG status of 0, 1, or 2.&#xD;
&#xD;
          -  Patients must be at least 18 years of age.&#xD;
&#xD;
          -  All patients must be given written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have had prior radiosurgery or therapeutic brain radiation therapy.&#xD;
&#xD;
          -  Patients with medical contra-indications to MRI imaging (e.g. pacemaker).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Markus Bredel, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Alabama at Birmingham</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama at Birmingham (UAB) Hazelrig-Salter Radiation Oncology Center</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35249</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>October 4, 2017</study_first_submitted>
  <study_first_submitted_qc>October 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 10, 2017</study_first_posted>
  <last_update_submitted>July 29, 2023</last_update_submitted>
  <last_update_submitted_qc>July 29, 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>University of Alabama at Birmingham</investigator_affiliation>
    <investigator_full_name>Markus Bredel</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>essential tremor (ET)</keyword>
  <keyword>stereotactic radiosurgery (SRS)</keyword>
  <keyword>radiosurgery (RS)</keyword>
  <keyword>deep brain stimulation (DBS)</keyword>
  <keyword>Parkinson's Disease (PD)</keyword>
  <keyword>tremor-dominant Parkinson's disease (TDPD)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Parkinson Disease</mesh_term>
    <mesh_term>Tremor</mesh_term>
    <mesh_term>Essential Tremor</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/NCT03305588
org study id: IRB-160811009
nct id: NCT03305588
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
To determine the efficacy of frameless Virtual Cone Radiosurgical Thalamotomy for medically
      refractory tremor resulting from either Essential Tremor or Tremor-Dominant Parkinson's
      Disease with the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) in patients who are not
      candidates for deep brain stimulation (DBS).
Per the National Institute of Neurological Disorders and Stroke, tremor is an involuntary,
      rhythmic muscle contraction leading to shaking movements in one or more parts of the body. It
      is a common movement disorder that most often affects the upper extremities but can also
      occur in the head, vocal cords, torso, and lower extremities. Tremor may be intermittent or
      constant. It can be present at rest, during action, or mixed between rest and action.

      Tremor can occur at any age but it is most common among middle-aged and older adults; once it
      occurs, it often progresses over time. This disorder shows no gender predilection. Although
      tremor is not life threatening, it can be severely disabling, making it difficult or even
      impossible to perform work and daily life tasks.

      Deep parts of the brain that control movements appear to be involved in tremor development.
      However, most types of tremor have no actual known cause. There are some forms that appear to
      be inherited and run in families. There are more than 20 types of tremor. Tremor can occur on
      its own (such as essential tremor (ET) or be associated with other neurological disorders,
      such as Parkinson's disease (PD).

      Tremor is a common symptom of Parkinson's disease. The classification of patients with
      Parkinson's disease into tremor-dominant and non-tremor subtypes is well established. The
      pathophysiology of tremor in patients with tremor-dominant Parkinson's disease (TDPD) may be
      distinct from other their other symptoms, such as bradykinesia, rigidity, and gait and
      balance symptoms. Importantly, tremor in PD responds less well or can even be highly
      resistant to dopaminergic treatment than bradykinesia and rigidity. Therefore other treatment
      strategies may need to be considered.

      Essential Tremor (ET) is a common neurologic condition characterized by a tremor that can
      occur either with posture or action. In the US, there are reported to be as many as 10
      million people with essential tremor. A significant subset of patients experience persistent
      disability and disruption on activities of daily living from tremor and require intervention.

      Treatment approach depends on the penetrance of disability into a patient's life, but
      typically begins with pharmacologic intervention. Patients with disabling tremor refractory
      to primary and secondary pharmacologic interventions are evaluated for surgical treatment
      with deep brain stimulation (DBS) or thalamotomy. However, a sizeable subset of these
      patients are unfavorable candidates for surgery due to medical or neurological
      co-morbidities. Additionally, a significant subset of patients simply does not wish to
      undergo the awake craniotomy required for DBS lead placement for tremor. Stereotactic
      radiosurgery (SRS) thalamotomy is an alternative for those patients. SRS thalamotomy targets
      the ventral intermediate (VIM) nucleus of the thalamus based on predetermined stereotactic
      coordinates.

      Almost all prior SRS thalamotomy studies performed have used the Leksell Gamma Knife
      treatment unit and demonstrate that about 80% of properly selected patients respond. The
      efficacy of Gamma Knife radiosurgery for tremor has been studied prospectively and has been
      modeled based upon prognostic factors in larger retrospective studies. These studies provide
      benchmarks for measuring the safety and efficacy of frameless Virtual Cone radiosurgery in
      this trial. In order for possible frameless Virtual Cone radiosurgery to be a standard of
      care in the treatment of tremor, additional clinical data is required. This pilot trial of
      Virtual Cone radiosurgery will assess the safety and efficacy of this treatment. A target of
      forty patients will be treated to confirm the feasibility of the protocol procedures,
      efficacy, and safety of the treatment. Secondary endpoints will include quality of life and
      patient satisfaction. The investigators hypothesize that the recent improvements in LINAC
      delivery, image guidance, and patient position monitoring will allow a safe frameless
      procedure that has a high patient satisfaction and low toxicity.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall tremor reduction proportion evaluated by the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS)
time frame: From Baseline up to 36 months following completion of radiosurgery
description: The Fahn-Tolosa-Marin Tremor Rating Scale evaluation will assess the severity of the patient's tremor and measure the impact on their activities of daily living.
measure: Number of Participants with treatment-related adverse events
time frame: From Baseline up to 36 months following completion of radiosurgery
description: Based on the assessments of the patient and the responses provided by the patient in questionnaires, the investigators will assess acute and late neurologic toxicities. All adverse events/toxicities will be assessed with the utilization of CTCAE v.4.0.
measure: Changes in resting-state functional MRI (fMRI) and diffusion tensor patterns associated with Radiosurgical thalamotomy
time frame: From Baseline up to 36 months following completion of radiosurgery
description: Changes will be assessed by resting-state functional MRI (fMRI) to see the impact of radiosurgery ablation on brain function or alteration of function of the ventral intermediate nucleus of the thalamus.
measure: Mean of Quality of Life Scores measured by SF-36 questionnaire
time frame: From Baseline up to 36 months following completion of radiosurgery
description: Quality of Life (QOL) will be measured by SF-36 questionnaire. This questionnaire consists of 36 questions (items) measuring physical and mental health in relation to 8 health concepts: physical functioning, bodily pain, role of limitations due to physical health problems, role of limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perception. All items are scored so that a high score defines a more favorable health state. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are set at 0 and 100, respectively.
measure: Mean of Quality of Life Scores measured by PROMIS Upper Extremity Questionnaire
time frame: From Baseline up to 36 months following completion of radiosurgery
description: PROMIS Upper Extremity questionnaire will assess effect of tremor on one's physical function of upper extremity, as well as, effects on activities of daily living.
measure: Patient Satisfaction Scores
time frame: 3 Month Follow-Up Visit
description: 3 months following the completion of radiosurgery, the patient will be asked the following two questions: 1) Would the participant have the radiosurgery procedure again? 2) Would the participant recommend it to friends and family?
measure: Define Targeting Methods within Thalamus based on Structural and Functional Connectivity
time frame: From Baseline up to 36 months following completion of radiosurgery
description: Compare how well the standard MRI conventional thalamotomy targeting technique (based on predetermined atlas coordinates) matches with advanced MRI-based (functional and structural) mapping of the thalamotomy target.
measure: Mean of Quality of Life Scores measured by the Essential Tremor Rating Assessment Scale (TETRAS)
time frame: From Baseline up to 36 months following completion of radiosurgery
description: TETRAS scale will assess 9 performance items of examination to create a clinical rating scale for essential tremor. Score is 0-4. Zero being no tremor.
arm group label: 130 Gy Radiation & Unframed Virtual Cone
arm group type: Experimental
description: 130 Gy Virtual Cone Radiosurgery Unframed (Face Mask)
intervention type: Device
intervention name: Unframed Virtual Cone
description: The patient will undergo stereotactic radiosurgery. Radiosurgery is a single non-surgical radiation treatment and will be done as an outpatient procedure. High-energy radiation will be delivered to a small, precise area of the patient's brain using a linear accelerator. A face mask (unframed) will be placed over the patient's face to keep their head from moving during the procedure. During the procedure, the study doctor will confirm the exact location that needs to be treated using x-rays and optical imaging cameras. The face mask will hold the patient's head to prevent it from moving and to focus the x-rays and aim them on a small area in the thalamus of the patient's brain. For most patients, the actual time on the radiosurgery treatment machine is 30 to 60 minutes. The face mask will be removed after the treatment.
arm group label: 130 Gy Radiation & Unframed Virtual Cone
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Markus Bredel, MD, PhD
role: Principal Investigator
affiliation: University of Alabama at Birmingham
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Alabama at Birmingham
investigator full name: Markus Bredel
investigator title: Principal Investigator
mesh term: Parkinson Disease
mesh term: Tremor
mesh term: Essential Tremor