<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/NCT03255395</url>
  </required_header>
  <id_info>
    <org_study_id>180-16</org_study_id>
    <nct_id>NCT03255395</nct_id>
  </id_info>
  <brief_title>Focused Ultrasound Treatment of Stump Neuromas for the Relief of Chronic Post-Amputation Neuropathic Pain</brief_title>
  <official_title>Focused Ultrasound Treatment of Stump Neuromas for the Relief of Chronic Post-Amputation Neuropathic Pain</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rambam Health Care Campus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rambam Health Care Campus</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      AIM: To provide initial information on the efficacy (pain reduction) and safety of focused&#xD;
      ultrasound surgery for the ablation of stump neuromas in amputees with chronic neuropathic&#xD;
      pain.&#xD;
&#xD;
      PARTICIPANTS: The study will include 10 amputees (men/women age &gt;18 years old) with chronic&#xD;
      (&gt;3 months) phantom/residual limb pain (NPS ≥ 4).&#xD;
&#xD;
      DESIGN: Patients potentially qualifying for the study will be offered an Informed Consent to&#xD;
      sign prior to further evaluation. Those who accept will sign the informed consent, complete&#xD;
      study questionnaires and be evaluated in terms of inclusion/exclusion criteria. Specifically,&#xD;
      a complete medical history will be obtained to determine the patient's general health status,&#xD;
      current symptoms, frequency and dosage of their current analgesic intake etc. Baseline pain&#xD;
      scores will be established. If not performed within six months prior to the evaluation, a&#xD;
      contrast MRI of the stump will be performed. Patients not meeting the study criteria will be&#xD;
      exited from the study as screen failures and not be included in analyses. All qualifying&#xD;
      patients will complete a baseline MRI exam on treatment day. Any patient not meeting study&#xD;
      criteria at Imaging will be exited as screen failures.&#xD;
&#xD;
      After completion of the MRI exam, qualifying patients will proceed to the ExAblate treatment.&#xD;
      These patients will then be followed for 6-months post-ExAblate treatment; the patients will&#xD;
      complete study follow-up questionnaires at 1, 3 days, 1 and 2 weeks, and 1, 3 and 6 months&#xD;
      after treatments. Follow-up visits will take place 1 week and 1, 3 and 6 months after&#xD;
      treatment to assess their pain status, their quality of life and safety. Data regarding&#xD;
      dosage and frequency of analgesic intake for the management of post amputation NP will be&#xD;
      collected. Relevant cost data will be collected in order to enable an assessment of the total&#xD;
      cost of the procedure.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      I. BACKGROUND:&#xD;
&#xD;
      In 2005, 1.6 million people were estimated to be living with limb loss (3). Up to 70% of the&#xD;
      patients who undergo limb amputation develop chronic phantom/residual limb pain. A&#xD;
      state-of-art understanding of the pathophysiologic basis underlying post-amputation pain&#xD;
      suggests that neuroma formation by regenerative sprouting, leading to increased ectopic&#xD;
      afferent input is the predominant mechanism involved in NP. Post-amputation pain is often&#xD;
      persistent, resistant to treatment and leads to considerable disability. Therefore, new&#xD;
      &quot;anti-nueromas&quot; treatments are required.&#xD;
&#xD;
      Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive procedure that&#xD;
      combines two technologies:&#xD;
&#xD;
        -  Focused ultrasound (FUS) waves which are converted to thermal energy at precise focal&#xD;
           point, causes tissue temperature increase, resulting in irreversible thermal ablation of&#xD;
           the tissue.&#xD;
&#xD;
        -  MRI: Three-dimensional imaging of the tissue and the ultrasound beam in real time&#xD;
           enhances the safety and effectiveness of the procedure by allowing:&#xD;
&#xD;
             -  Anatomical planning of the treatment.&#xD;
&#xD;
             -  Real time thermal imaging enables of the and its surrounding tissues. The safety&#xD;
                and effectiveness of MRgFUS has been shown in a prospective, randomized (3:1),&#xD;
                two-arm, sham-controlled, multicenter, international clinical study with a&#xD;
                sham-crossover option in patients with metastatic bone pain, who were not suitable&#xD;
                candidates for radiation therapy. A much higher proportion of MRgFUS patients than&#xD;
                controls were responders (65.2% vs 18.9%).&#xD;
&#xD;
      II. AIMS:&#xD;
&#xD;
      To provide initial information on the efficacy (pain reduction) and safety of focused&#xD;
      ultrasound surgery for the ablation of stump neuromas in amputees with chronic neuropathic&#xD;
      pain.&#xD;
&#xD;
      III. PARTICIPANTS:&#xD;
&#xD;
      The study will include 10 amputees with chronic phantom/residual limb pain.&#xD;
&#xD;
      Inclusion Criteria&#xD;
&#xD;
        1. Men and women amputees, aged 18 and older&#xD;
&#xD;
        2. Patients who are able and willing to give consent and able to attend all study visits&#xD;
&#xD;
        3. Patients who are suffering from post-amputation phantom/residual limb pain for at least&#xD;
           3 months&#xD;
&#xD;
        4. Patient with average pain intensity on a 0-10 numerical pain scale (NPS) ≥ 4 during a 3&#xD;
           days period prior to enrollment irrespective of medication use&#xD;
&#xD;
        5. Patient whose targeted (treated) lesion is deeper than 10-mm from the skin&#xD;
&#xD;
        6. Targeted (treated) neuroma is clearly visible by non-contrast MRI, and ExAblate MRgFUS&#xD;
           device accessible Exclusion Criteria&#xD;
&#xD;
      1. Patients with any acute or unstable medical condition that is expected to hinder them from&#xD;
      completing this study 2. Patients with standard contraindications for MR imaging. 3. Known&#xD;
      intolerance or allergies to the MRI contrast agent (e.g. Gadolinium or Magnevist) including&#xD;
      advanced kidney disease 4. Individuals who are not able or willing to tolerate the required&#xD;
      prolonged stationary position during treatment 5. Are participating or have participated in&#xD;
      another clinical trial in the last 30 days 6. Patients with persistent undistinguishable pain&#xD;
      (pain source unidentifiable) 7. Patients whose neuroma is &lt; 10-mm from the skin, blood&#xD;
      vessels or bone 8. Patients with more than three neuromas in the affected limb 9. Targeted&#xD;
      (treated) neuroma is NOT visible by non-contrast MRI 10. Targeted neuroma is not accessible&#xD;
      to ExAblate due to scar tissue or any other reason&#xD;
&#xD;
      IV. STUDY DESIGN Patients potentially qualifying for the study will be offered an Informed&#xD;
      Consent to sign prior to further evaluation. Those who accept will sign the informed consent,&#xD;
      complete study questionnaires and be evaluated in terms of inclusion/exclusion criteria.&#xD;
      Specifically, a complete medical history will be obtained to determine the patient's general&#xD;
      health status, current symptoms, frequency and dosage of their current analgesic intake etc.&#xD;
      Baseline pain scores will be established. If not performed within six months prior to the&#xD;
      evaluation, a contrast MRI of the stump will be performed. Patients not meeting the study&#xD;
      criteria will be exited from the study as screen failures and not be included in analyses.&#xD;
      All qualifying patients will complete a baseline MRI exam on treatment day. Any patient not&#xD;
      meeting study criteria at Imaging will be exited as screen failures.&#xD;
&#xD;
      Qualifying patients will proceed to the ExAblate treatment. These patients will then be&#xD;
      followed for 6-months post-ExAblate treatment; patients will complete study follow-up&#xD;
      questionnaires at 1, 3 days, 1 and 2 weeks, and 1, 3 and 6 months after treatments. Follow-up&#xD;
      visits will take place 1 week and 1, 3 and 6 months after treatment to assess their pain&#xD;
      status, their quality of life and safety. Data regarding dosage and frequency of analgesic&#xD;
      intake for the management of post amputation NP will be collected.&#xD;
&#xD;
      Outcome measures Primary endpoint: Change from baseline in the average daily pain intensity,&#xD;
      measured for 3 consecutive days, on the Numerical Pain Scale (NPS), an 11-point numeric&#xD;
      rating scale.&#xD;
&#xD;
      Secondary endpoints:&#xD;
&#xD;
        -  Change from baseline in the maximum daily pain intensity, measured for 3 consecutive&#xD;
           days, on the NPS.&#xD;
&#xD;
        -  Change from the baseline in the minimum daily pain intensity, measured for 3 consecutive&#xD;
           days, on the NPS.&#xD;
&#xD;
        -  Change from the baseline in the consumption of analgesic medications used for the post&#xD;
           amputation NP (i.e., increase, unchanged, decreased).&#xD;
&#xD;
        -  Change from baseline in Short-Form McGill Pain Questionnaire (SF-MPQ) score&#xD;
&#xD;
        -  Change from the baseline in the Pittsburgh sleep quality index (PSQI).&#xD;
&#xD;
        -  Change from the baseline in the European Quality of Life Five-Dimensional (EQ-5D)&#xD;
           questionnaire.&#xD;
&#xD;
        -  Change from the baseline in the Brief Pain Inventory (BPI).&#xD;
&#xD;
        -  Clinician's Global Impression of Change from the baseline.&#xD;
&#xD;
        -  Patient's Global Impression of Change from the baseline.&#xD;
&#xD;
        -  Change from the baseline in MRI findings in the treated neuroma(s).&#xD;
&#xD;
      Treatment Procedure&#xD;
&#xD;
        -  Baseline MRI examinations (without contrast) will be performed to identify the neuroma&#xD;
           size, location and extent and device accessibility as well as to evaluate the patient's&#xD;
           ability to cooperate during the ExAblate procedure. If at this point it is determined&#xD;
           that the patient does not meet all Inclusion and Exclusion criteria and cannot be&#xD;
           treated, the patient will be exited from the study. These patients will be considered&#xD;
           screening failures, and will not be included in any of the safety or efficacy endpoint&#xD;
           analyses.&#xD;
&#xD;
        -  If the patient meets all study criteria, the patient will have the ExAblate treatment&#xD;
           during this same MRI examination session.&#xD;
&#xD;
        -  An IV line will be positioned for the delivery of medications and will be maintained&#xD;
           throughout the procedure. Monitoring of heart rate and pO2 will be maintained throughout&#xD;
           the procedure using standard MR-compatible monitoring devices. The patients' skin will&#xD;
           be closely examined for hair in the treatment path. If necessary, the hair will be&#xD;
           removed around the treatment area and the skin will be cleaned, for example with&#xD;
           alcohol, from any oil based skin product. Degassed water and possibly an acoustic gel&#xD;
           pad will be placed atop of the transducers' window to generate acoustic coupling.&#xD;
&#xD;
        -  Patients will be positioned on the ExAblate therapy bed in a selected position according&#xD;
           to the planned treatment area. The patient's area of treatment may be placed in a&#xD;
           special-purpose imaging coil and positioned in the magnet in the treatment position.&#xD;
&#xD;
        -  An MRI scan will be performed with T2 and T1 weighted sequences in all three&#xD;
           orientations to localize and measure the target neuroma(s) to be treated.&#xD;
&#xD;
        -  Any prior scar will be identified on the image and the ultrasound treatment plan will be&#xD;
           planned to avoid sonicating through the scar whenever possible.&#xD;
&#xD;
        -  If the neuroma(s) to be treated is identifiable on the MR images, accessible by the&#xD;
           device for treatment, and the patient meets all inclusion and exclusion criteria,&#xD;
           treatment planning will begin.&#xD;
&#xD;
        -  The physician will trace the neuroma(s) in the targeted area.&#xD;
&#xD;
        -  The physician will draw the treatment volume using MR images from one or more scan&#xD;
           orientations using the following guidelines:&#xD;
&#xD;
        -  Up to three well defined neuromas can be treated.&#xD;
&#xD;
        -  A central point on the neuroma (depending on patient anatomy) will be sonicated with a&#xD;
           low thermal dose, to verify targeting accuracy in the patient. Target placement and&#xD;
           transducer positioning will be adjusted as necessary.&#xD;
&#xD;
        -  If at this point it is determined that the patient cannot be treated, he or she will be&#xD;
           withdrawn from the magnet and the IV line and pulse oximeter will be removed. The&#xD;
           patient will be taken to the recovery area for observation and release. Follow-up will&#xD;
           consist of a phone call at 1-week post treatment. These patients will be considered&#xD;
           screen failures and will not be included in the efficacy analysis.&#xD;
&#xD;
        -  Prior to the delivery of any treatment sonications the patient will receive analgesia&#xD;
           and sedation or other measures to reduce pain and limit patient motion, and help&#xD;
           alleviate anxiety and claustrophobia. Monitoring of heart rate and pO2 saturation will&#xD;
           be maintained throughout the procedure.&#xD;
&#xD;
        -  Treatment will begin. Sonications will be performed on successive points [sonication&#xD;
           duration between 15 - 60 sec]. The effect of each sonication will be measured by MR&#xD;
           using phase map imaging, reflecting the temperature-dependent change in the proton&#xD;
           resonance frequency. Acoustic power will be adjusted throughout the treatment, to&#xD;
           achieve temperature between 65 and 85 degrees from MR thermal images at the targeted&#xD;
           neuroma.&#xD;
&#xD;
        -  Sonications will continue until the prescribed targeted area has been treated. The goal&#xD;
           is that the total time from 1st to last sonication will be limited to 180-minutes, or to&#xD;
           patient tolerance.&#xD;
&#xD;
        -  If no more than 3 planned sonications can be performed using therapeutic energies, then&#xD;
           these patients will be considered as screen failures, and will not be included in the&#xD;
           intent-to-treat analysis. However, they will be added to the Safety analyses. Criteria&#xD;
           to terminate treatment include patient intolerance to the treatment, targeting&#xD;
           difficulties due to patient motion or a decision of the treating physician.&#xD;
&#xD;
        -  Immediately post-treatment, a series of MR scans will be performed. The scanning will&#xD;
           include T2 weighted sequences and T1 weighted contrast enhanced sequences to evaluate&#xD;
           general anatomy and to assess treatment effect.&#xD;
&#xD;
        -  The patient will be taken off the therapeutic table and escorted to a recovery area for&#xD;
           observation period pending release from hospital.&#xD;
&#xD;
        -  All MR exams taken during the study will be archived for later analyses.&#xD;
&#xD;
        -  If during the treatment session, the physician did not complete the planned treatment,&#xD;
           and determines that it would be to the benefit of the patient to continue treatment at a&#xD;
           second session, a second treatment session may be completed within two (2) weeks of the&#xD;
           first treatment. However, up to three painful neuromas can be treated under this&#xD;
           protocol and the purpose of the second treatment is to complete the original treatment&#xD;
           plan. This protocol does not allow for a second treatment due to continued pain at the&#xD;
           treated site or the treatment of additional painful lesions. The preparation procedures&#xD;
           for the second treatment will be the same as the first. No more than two treatments&#xD;
           should be performed within a two (2) week period.&#xD;
&#xD;
      Follow-up Telephone follow-up visits will be completed at 1 and 3 days, and 2 weeks post&#xD;
      treatment. Clinic visits will be completed at 1 week and 1, 3 and 6 months post-ExAblate&#xD;
      treatment. Patients will be evaluated for general health, efficacy measurements as well as&#xD;
      for device/procedure related AEs that may have occurred during the follow-up period.&#xD;
      Additional data regarding dosage and frequency of analgesic intake for the management of NP&#xD;
      will also be collected. For phone visits, study personnel will contact the patient, inquire&#xD;
      about AEs and question the patient according to the pain questionnaire, pain medication&#xD;
      intake. The study personnel will then sign and date the completed forms. A follow-up MRI to&#xD;
      assess the effects on the treated neuroma(s) will be performed four months after treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">April 24, 2017</start_date>
  <completion_date type="Anticipated">April 2019</completion_date>
  <primary_completion_date type="Anticipated">April 2019</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>
    <intervention_model_description>A single group feasibility study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change from baseline in the average daily pain</measure>
    <time_frame>Up to 6 months</time_frame>
    <description>Change from baseline in the average daily pain intensity, measured for 3 consecutive days, on the Numerical Pain Scale (NPS), an 11-point numeric rating scale.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Phantom Limb Pain</condition>
  <condition>Residual Limbs</condition>
  <condition>Amputation</condition>
  <arm_group>
    <arm_group_label>Magnetic resonance-guided focused ultrasound (MRgFUS)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ten amputees will recieve magnetic resonance-guided focused ultrasound (MRgFUS) treatment aimed to ablate neromas, which are beleived to cuase phantom / residual limb pain</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Magnetic resonance-guided focused ultrasound</intervention_name>
    <description>Ten amputees wil recieve a magnetic resonance-guided focused ultrasound treatment aimed at ablating neuromas, which are believe to contribute to their phantom / residual limb pain</description>
    <arm_group_label>Magnetic resonance-guided focused ultrasound (MRgFUS)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Men and women amputees, aged 18 and older&#xD;
&#xD;
          2. Patients who are able and willing to give consent and able to attend all study visits&#xD;
&#xD;
          3. Patients who are suffering from post-amputation phantom/residual limb pain for at&#xD;
             least 3 months&#xD;
&#xD;
          4. Patient with average pain intensity on a 0-10 numerical pain scale (NPS) ≥ 4 during a&#xD;
             3 days period prior to enrollment irrespective of medication use&#xD;
&#xD;
          5. Patient whose targeted (treated) lesion is deeper than 10-mm from the skin&#xD;
&#xD;
          6. Targeted (treated) neuroma is clearly visible by non-contrast MRI, and ExAblate MRgFUS&#xD;
             device accessible&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with any acute or unstable medical condition (e.g., infection, cardiac&#xD;
             condition, uncontrolled diabetes mellitus, uncontrolled hypertension) that is expected&#xD;
             to hinder them from completing this study&#xD;
&#xD;
          2. Patients with standard contraindications for MR imaging such as non-MRI compatible&#xD;
             implanted metallic devices including cardiac pacemakers, size limitations (weight &gt;250&#xD;
             pounds (113kg), etc.&#xD;
&#xD;
          3. Known intolerance or allergies to the MRI contrast agent (e.g. Gadolinium or&#xD;
             Magnevist) including advanced kidney disease&#xD;
&#xD;
          4. Individuals who are not able or willing to tolerate the required prolonged stationary&#xD;
             position during treatment (approximately 3 hrs.)&#xD;
&#xD;
          5. Are participating or have participated in another clinical trial in the last 30 days&#xD;
&#xD;
          6. Patients with persistent undistinguishable pain (pain source unidentifiable)&#xD;
&#xD;
          7. Patients whose neuroma is &lt; 10-mm from the skin, blood vessels or bone&#xD;
&#xD;
          8. Patients with more than three neuromas in the affected limb&#xD;
&#xD;
          9. Targeted (treated) neuroma is NOT visible by non-contrast MRI&#xD;
&#xD;
         10. Targeted neuroma is not accessible to ExAblate due to scar tissue or any other reason&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Elon Eisenberg, Prof</last_name>
    <phone>972-4-7771931</phone>
    <email>e_eisenberg@rambam.health.gov.il</email>
  </overall_contact>
  <location>
    <facility>
      <name>Rambam Health Care Campus</name>
      <address>
        <city>Haifa</city>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Elon Eisenberg</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>August 17, 2017</study_first_submitted>
  <study_first_submitted_qc>August 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 21, 2017</study_first_posted>
  <last_update_submitted>April 1, 2019</last_update_submitted>
  <last_update_submitted_qc>April 1, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 2, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rambam Health Care Campus</investigator_affiliation>
    <investigator_full_name>Eisenberg Elon MD</investigator_full_name>
    <investigator_title>Head, Pain Research Unit</investigator_title>
  </responsible_party>
  <keyword>MRI</keyword>
  <keyword>Ultrasound</keyword>
  <keyword>Phantom Limb Pain</keyword>
  <keyword>Residual Limb Pain</keyword>
  <keyword>Neuroma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroma</mesh_term>
    <mesh_term>Neuralgia</mesh_term>
    <mesh_term>Phantom Limb</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03255395
org study id: 180-16
nct id: NCT03255395
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
AIM: To provide initial information on the efficacy (pain reduction) and safety of focused
      ultrasound surgery for the ablation of stump neuromas in amputees with chronic neuropathic
      pain.

      PARTICIPANTS: The study will include 10 amputees (men/women age >18 years old) with chronic
      (>3 months) phantom/residual limb pain (NPS ≥ 4).

      DESIGN: Patients potentially qualifying for the study will be offered an Informed Consent to
      sign prior to further evaluation. Those who accept will sign the informed consent, complete
      study questionnaires and be evaluated in terms of inclusion/exclusion criteria. Specifically,
      a complete medical history will be obtained to determine the patient's general health status,
      current symptoms, frequency and dosage of their current analgesic intake etc. Baseline pain
      scores will be established. If not performed within six months prior to the evaluation, a
      contrast MRI of the stump will be performed. Patients not meeting the study criteria will be
      exited from the study as screen failures and not be included in analyses. All qualifying
      patients will complete a baseline MRI exam on treatment day. Any patient not meeting study
      criteria at Imaging will be exited as screen failures.

      After completion of the MRI exam, qualifying patients will proceed to the ExAblate treatment.
      These patients will then be followed for 6-months post-ExAblate treatment; the patients will
      complete study follow-up questionnaires at 1, 3 days, 1 and 2 weeks, and 1, 3 and 6 months
      after treatments. Follow-up visits will take place 1 week and 1, 3 and 6 months after
      treatment to assess their pain status, their quality of life and safety. Data regarding
      dosage and frequency of analgesic intake for the management of post amputation NP will be
      collected. Relevant cost data will be collected in order to enable an assessment of the total
      cost of the procedure.
I. BACKGROUND:

      In 2005, 1.6 million people were estimated to be living with limb loss (3). Up to 70% of the
      patients who undergo limb amputation develop chronic phantom/residual limb pain. A
      state-of-art understanding of the pathophysiologic basis underlying post-amputation pain
      suggests that neuroma formation by regenerative sprouting, leading to increased ectopic
      afferent input is the predominant mechanism involved in NP. Post-amputation pain is often
      persistent, resistant to treatment and leads to considerable disability. Therefore, new
      "anti-nueromas" treatments are required.

      Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive procedure that
      combines two technologies:

        -  Focused ultrasound (FUS) waves which are converted to thermal energy at precise focal
           point, causes tissue temperature increase, resulting in irreversible thermal ablation of
           the tissue.

        -  MRI: Three-dimensional imaging of the tissue and the ultrasound beam in real time
           enhances the safety and effectiveness of the procedure by allowing:

             -  Anatomical planning of the treatment.

             -  Real time thermal imaging enables of the and its surrounding tissues. The safety
                and effectiveness of MRgFUS has been shown in a prospective, randomized (3:1),
                two-arm, sham-controlled, multicenter, international clinical study with a
                sham-crossover option in patients with metastatic bone pain, who were not suitable
                candidates for radiation therapy. A much higher proportion of MRgFUS patients than
                controls were responders (65.2% vs 18.9%).

      II. AIMS:

      To provide initial information on the efficacy (pain reduction) and safety of focused
      ultrasound surgery for the ablation of stump neuromas in amputees with chronic neuropathic
      pain.

      III. PARTICIPANTS:

      The study will include 10 amputees with chronic phantom/residual limb pain.

      Inclusion Criteria

        1. Men and women amputees, aged 18 and older

        2. Patients who are able and willing to give consent and able to attend all study visits

        3. Patients who are suffering from post-amputation phantom/residual limb pain for at least
           3 months

        4. Patient with average pain intensity on a 0-10 numerical pain scale (NPS) ≥ 4 during a 3
           days period prior to enrollment irrespective of medication use

        5. Patient whose targeted (treated) lesion is deeper than 10-mm from the skin

        6. Targeted (treated) neuroma is clearly visible by non-contrast MRI, and ExAblate MRgFUS
           device accessible Exclusion Criteria

      1. Patients with any acute or unstable medical condition that is expected to hinder them from
      completing this study 2. Patients with standard contraindications for MR imaging. 3. Known
      intolerance or allergies to the MRI contrast agent (e.g. Gadolinium or Magnevist) including
      advanced kidney disease 4. Individuals who are not able or willing to tolerate the required
      prolonged stationary position during treatment 5. Are participating or have participated in
      another clinical trial in the last 30 days 6. Patients with persistent undistinguishable pain
      (pain source unidentifiable) 7. Patients whose neuroma is < 10-mm from the skin, blood
      vessels or bone 8. Patients with more than three neuromas in the affected limb 9. Targeted
      (treated) neuroma is NOT visible by non-contrast MRI 10. Targeted neuroma is not accessible
      to ExAblate due to scar tissue or any other reason

      IV. STUDY DESIGN Patients potentially qualifying for the study will be offered an Informed
      Consent to sign prior to further evaluation. Those who accept will sign the informed consent,
      complete study questionnaires and be evaluated in terms of inclusion/exclusion criteria.
      Specifically, a complete medical history will be obtained to determine the patient's general
      health status, current symptoms, frequency and dosage of their current analgesic intake etc.
      Baseline pain scores will be established. If not performed within six months prior to the
      evaluation, a contrast MRI of the stump will be performed. Patients not meeting the study
      criteria will be exited from the study as screen failures and not be included in analyses.
      All qualifying patients will complete a baseline MRI exam on treatment day. Any patient not
      meeting study criteria at Imaging will be exited as screen failures.

      Qualifying patients will proceed to the ExAblate treatment. These patients will then be
      followed for 6-months post-ExAblate treatment; patients will complete study follow-up
      questionnaires at 1, 3 days, 1 and 2 weeks, and 1, 3 and 6 months after treatments. Follow-up
      visits will take place 1 week and 1, 3 and 6 months after treatment to assess their pain
      status, their quality of life and safety. Data regarding dosage and frequency of analgesic
      intake for the management of post amputation NP will be collected.

      Outcome measures Primary endpoint: Change from baseline in the average daily pain intensity,
      measured for 3 consecutive days, on the Numerical Pain Scale (NPS), an 11-point numeric
      rating scale.

      Secondary endpoints:

        -  Change from baseline in the maximum daily pain intensity, measured for 3 consecutive
           days, on the NPS.

        -  Change from the baseline in the minimum daily pain intensity, measured for 3 consecutive
           days, on the NPS.

        -  Change from the baseline in the consumption of analgesic medications used for the post
           amputation NP (i.e., increase, unchanged, decreased).

        -  Change from baseline in Short-Form McGill Pain Questionnaire (SF-MPQ) score

        -  Change from the baseline in the Pittsburgh sleep quality index (PSQI).

        -  Change from the baseline in the European Quality of Life Five-Dimensional (EQ-5D)
           questionnaire.

        -  Change from the baseline in the Brief Pain Inventory (BPI).

        -  Clinician's Global Impression of Change from the baseline.

        -  Patient's Global Impression of Change from the baseline.

        -  Change from the baseline in MRI findings in the treated neuroma(s).

      Treatment Procedure

        -  Baseline MRI examinations (without contrast) will be performed to identify the neuroma
           size, location and extent and device accessibility as well as to evaluate the patient's
           ability to cooperate during the ExAblate procedure. If at this point it is determined
           that the patient does not meet all Inclusion and Exclusion criteria and cannot be
           treated, the patient will be exited from the study. These patients will be considered
           screening failures, and will not be included in any of the safety or efficacy endpoint
           analyses.

        -  If the patient meets all study criteria, the patient will have the ExAblate treatment
           during this same MRI examination session.

        -  An IV line will be positioned for the delivery of medications and will be maintained
           throughout the procedure. Monitoring of heart rate and pO2 will be maintained throughout
           the procedure using standard MR-compatible monitoring devices. The patients' skin will
           be closely examined for hair in the treatment path. If necessary, the hair will be
           removed around the treatment area and the skin will be cleaned, for example with
           alcohol, from any oil based skin product. Degassed water and possibly an acoustic gel
           pad will be placed atop of the transducers' window to generate acoustic coupling.

        -  Patients will be positioned on the ExAblate therapy bed in a selected position according
           to the planned treatment area. The patient's area of treatment may be placed in a
           special-purpose imaging coil and positioned in the magnet in the treatment position.

        -  An MRI scan will be performed with T2 and T1 weighted sequences in all three
           orientations to localize and measure the target neuroma(s) to be treated.

        -  Any prior scar will be identified on the image and the ultrasound treatment plan will be
           planned to avoid sonicating through the scar whenever possible.

        -  If the neuroma(s) to be treated is identifiable on the MR images, accessible by the
           device for treatment, and the patient meets all inclusion and exclusion criteria,
           treatment planning will begin.

        -  The physician will trace the neuroma(s) in the targeted area.

        -  The physician will draw the treatment volume using MR images from one or more scan
           orientations using the following guidelines:

        -  Up to three well defined neuromas can be treated.

        -  A central point on the neuroma (depending on patient anatomy) will be sonicated with a
           low thermal dose, to verify targeting accuracy in the patient. Target placement and
           transducer positioning will be adjusted as necessary.

        -  If at this point it is determined that the patient cannot be treated, he or she will be
           withdrawn from the magnet and the IV line and pulse oximeter will be removed. The
           patient will be taken to the recovery area for observation and release. Follow-up will
           consist of a phone call at 1-week post treatment. These patients will be considered
           screen failures and will not be included in the efficacy analysis.

        -  Prior to the delivery of any treatment sonications the patient will receive analgesia
           and sedation or other measures to reduce pain and limit patient motion, and help
           alleviate anxiety and claustrophobia. Monitoring of heart rate and pO2 saturation will
           be maintained throughout the procedure.

        -  Treatment will begin. Sonications will be performed on successive points [sonication
           duration between 15 - 60 sec]. The effect of each sonication will be measured by MR
           using phase map imaging, reflecting the temperature-dependent change in the proton
           resonance frequency. Acoustic power will be adjusted throughout the treatment, to
           achieve temperature between 65 and 85 degrees from MR thermal images at the targeted
           neuroma.

        -  Sonications will continue until the prescribed targeted area has been treated. The goal
           is that the total time from 1st to last sonication will be limited to 180-minutes, or to
           patient tolerance.

        -  If no more than 3 planned sonications can be performed using therapeutic energies, then
           these patients will be considered as screen failures, and will not be included in the
           intent-to-treat analysis. However, they will be added to the Safety analyses. Criteria
           to terminate treatment include patient intolerance to the treatment, targeting
           difficulties due to patient motion or a decision of the treating physician.

        -  Immediately post-treatment, a series of MR scans will be performed. The scanning will
           include T2 weighted sequences and T1 weighted contrast enhanced sequences to evaluate
           general anatomy and to assess treatment effect.

        -  The patient will be taken off the therapeutic table and escorted to a recovery area for
           observation period pending release from hospital.

        -  All MR exams taken during the study will be archived for later analyses.

        -  If during the treatment session, the physician did not complete the planned treatment,
           and determines that it would be to the benefit of the patient to continue treatment at a
           second session, a second treatment session may be completed within two (2) weeks of the
           first treatment. However, up to three painful neuromas can be treated under this
           protocol and the purpose of the second treatment is to complete the original treatment
           plan. This protocol does not allow for a second treatment due to continued pain at the
           treated site or the treatment of additional painful lesions. The preparation procedures
           for the second treatment will be the same as the first. No more than two treatments
           should be performed within a two (2) week period.

      Follow-up Telephone follow-up visits will be completed at 1 and 3 days, and 2 weeks post
      treatment. Clinic visits will be completed at 1 week and 1, 3 and 6 months post-ExAblate
      treatment. Patients will be evaluated for general health, efficacy measurements as well as
      for device/procedure related AEs that may have occurred during the follow-up period.
      Additional data regarding dosage and frequency of analgesic intake for the management of NP
      will also be collected. For phone visits, study personnel will contact the patient, inquire
      about AEs and question the patient according to the pain questionnaire, pain medication
      intake. The study personnel will then sign and date the completed forms. A follow-up MRI to
      assess the effects on the treated neuroma(s) will be performed four months after treatment.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: A single group feasibility study
primary purpose: Treatment
masking: None (Open Label)
measure: Change from baseline in the average daily pain
time frame: Up to 6 months
description: Change from baseline in the average daily pain intensity, measured for 3 consecutive days, on the Numerical Pain Scale (NPS), an 11-point numeric rating scale.
arm group label: Magnetic resonance-guided focused ultrasound (MRgFUS)
arm group type: Experimental
description: Ten amputees will recieve magnetic resonance-guided focused ultrasound (MRgFUS) treatment aimed to ablate neromas, which are beleived to cuase phantom / residual limb pain
intervention type: Device
intervention name: Magnetic resonance-guided focused ultrasound
description: Ten amputees wil recieve a magnetic resonance-guided focused ultrasound treatment aimed at ablating neuromas, which are believe to contribute to their phantom / residual limb pain
arm group label: Magnetic resonance-guided focused ultrasound (MRgFUS)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Elon Eisenberg, Prof
phone: 972-4-7771931
email: e_eisenberg@rambam.health.gov.il
facility: 
status: Recruiting
investigator: 
country: Israel
responsible party type: Principal Investigator
investigator affiliation: Rambam Health Care Campus
investigator full name: Eisenberg Elon MD
investigator title: Head, Pain Research Unit
mesh term: Neuroma
mesh term: Neuralgia
mesh term: Phantom Limb
sharing ipd: Undecided