<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/NCT03761277</url>
  </required_header>
  <id_info>
    <org_study_id>MDT18026</org_study_id>
    <nct_id>NCT03761277</nct_id>
  </id_info>
  <brief_title>Embrace TDD: Post-Market Study to Evaluate Intrathecal Morphine as an Alternative to Systemic Opioids for Chronic Pain</brief_title>
  <official_title>Embrace TDD: Prospective, Multi-Center, Post Market Study to Evaluate Intrathecal (IT) Morphine as an Alternative to Systemic Opioids for the Treatment of Chronic, Intractable, Non-Malignant Primary Back Pain With or Without Leg Pain</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>MedtronicNeuro</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>MedtronicNeuro</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective, multi-center, post market study to evaluate Intrathecal (IT)&#xD;
      preservative-free morphine sulfate (PFMS) using the SynchroMed™ II infusion system as an&#xD;
      alternative to systemic opioids for the treatment of chronic, intractable, non-malignant&#xD;
      primary back pain with or without leg pain.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Subjects will be assessed for pain control and opioid-related side effects following a route&#xD;
      of delivery change from systemic opioids to IT morphine therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 16, 2019</start_date>
  <completion_date type="Actual">December 6, 2021</completion_date>
  <primary_completion_date type="Actual">December 6, 2021</primary_completion_date>
  <phase>Phase 4</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>Number of Participants With Clinical Success at the 6-Month Visit</measure>
    <time_frame>Baseline to 6-Month Visit</time_frame>
    <description>To characterize the number of subjects with Clinical Success at the 6-Month Visit. Clinical Success is defined as any of the following: 1) Reduced opioid-related side effects (at least a 20% reduction) with equal pain (less than 20% increase or decrease) 2) Reduced pain (at least a 20% reduction) with equal opioid-related side effects (less than 20% increase or decrease) 3) Reduced pain and reduced opioid-related side effects (at least a 20% reduction in both). The number of subjects with Clinical Success at the 6-Month Visit is presented.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Visual Analog Scale (VAS) Pain Intensity at the 6-Month Visit</measure>
    <time_frame>Baseline to 6-Month Visit</time_frame>
    <description>To demonstrate pain intensity scores (Visual Analog Scale, VAS) at the 6-Month Visit is non-inferior to VAS at Baseline, with a non-inferiority margin of 10mm. Pain was assessed using a Visual Analog Scale, ranging from 0-100, where 0 is no pain and 100 is the worst pain. The VAS is a 100mm line, with &quot;No pain&quot; on the left side of the line and &quot;Worst pain imaginable&quot; on the right side of the line. Subjects made a perpendicular mark on the VAS line that best describes their average pain in the last 24 hours. Change in VAS is calculated as 6-Months - Baseline, with a negative change indicating a reduction (i.e., improvement) in pain intensity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Numerical Opioid Side Effect (NOSE) Assessment Tool</measure>
    <time_frame>Baseline to 6-Month Visit</time_frame>
    <description>To characterize the change in opioid-related side effects scores (NOSE) from Baseline to the 6-Month Visit. The Numerical Opioid Side Effect (NOSE) Assessment Tool is a tool to evaluate 10 opioid-related side effects using a 11-point numerical scale. Subjects are asked to evaluate each of the 10 opioid-related side effects on a scale of 0 - 10 with 0 being &quot;not present&quot; and 10 being &quot;as bad as you can imagine&quot;. A total sum score can range from 0 - 100, where 0 is no opioid-related side effects and 100 is the worst opioid-related side effects. Change in NOSE is calculated as 6-Months - Baseline, with a negative change indicating a reduction (i.e., improvement) in opioid-related side effects.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Systemic Opioid Elimination Through the 6-Month Visit</measure>
    <time_frame>Baseline to 6-Month Visit</time_frame>
    <description>To characterize the number of subjects who eliminate systemic opioids through the 6-Month Visit. Four drug tests for systemic opioid use are administered from intrathecal therapy initiation through the 6-Month Visit. If all of the available drug tests are negative for systemic opioid use, the subject is counted as eliminating systemic opioids through the 6-Month Visit. The number of subjects who eliminated systemic opioids through the 6-Month Visit is presented.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">93</enrollment>
  <condition>Chronic Non-malignant Pain</condition>
  <condition>Chronic Pain</condition>
  <condition>Pain, Back</condition>
  <condition>Pain, Leg</condition>
  <arm_group>
    <arm_group_label>Intrathecal Therapy</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Enrolled subjects who successfully wean from all systemic opioids and have a successful intrathecal trial, proceed to the intervention phase. This includes implantation with a SynchroMed™ II infusion system in the intrathecal space for targeted drug delivery of preservative-free morphine sulfate (PFMS).</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Medtronic SynchroMed™ II infusion system</intervention_name>
    <description>Implanted infusion system consisting of a pump and catheter, as well as external components of a clinician programmer, refill and catheter access port kits, and the Personal Therapy Manager (myPTM™).</description>
    <arm_group_label>Intrathecal Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Preservative-free morphine sulfate (PFMS)</intervention_name>
    <description>The pharmacological agent used in the pump for this study is limited to a preservative-free morphine sulfate (PFMS).</description>
    <arm_group_label>Intrathecal Therapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Willing and able to provide a signed and dated (Medtronic and Institutional Review&#xD;
             Board (IRB) approved) Informed Consent Form (ICF) and Health Insurance Portability and&#xD;
             Accountability Act (HIPAA) Authorization Form prior to any study procedures being&#xD;
             performed&#xD;
&#xD;
          2. A candidate per labeling for the Intrathecal Drug Delivery System (IDDS)&#xD;
&#xD;
          3. A diagnosis of chronic, intractable, non-malignant primary back pain with or without&#xD;
             leg pain, treatable with the IDDS&#xD;
&#xD;
          4. Current daily systemic opioid dose of &gt;0 and ≤ 120 Morphine Milligram Equivalents&#xD;
             (MME)&#xD;
&#xD;
          5. A Visual Analogue Scale (VAS) of ≥50 mm for pain intensity at the Baseline Visit&#xD;
             and/or a Numerical Opioid Side Effect (NOSE) Assessment Tool ≥40 for intolerable side&#xD;
             effects at the Baseline Visit&#xD;
&#xD;
          6. Psychological evaluation or investigator assessment of patient psychological&#xD;
             suitability for study participation&#xD;
&#xD;
          7. Has an MRI or CT prior to enrollment verifying patent spinal canal and no clinical&#xD;
             change in status since last imaging&#xD;
&#xD;
          8. At least 18 years old at time of enrollment&#xD;
&#xD;
          9. Willing and able to attend visits and comply with the study protocol&#xD;
&#xD;
         10. Male or non-pregnant, non-lactating female. Females must be post-menopausal or&#xD;
             surgically sterile; or be utilizing a medically acceptable form of birth control (i.e.&#xD;
             a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, or condom&#xD;
             with spermicide) for the duration of the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previously trialed or implanted with an IDDS&#xD;
&#xD;
          2. Concomitant stimulation device implanted for the treatment of pain&#xD;
&#xD;
          3. Any ongoing health condition that would be expected to interfere with pain and/or&#xD;
             quality of life ratings (i.e. active malignancy, other painful conditions not&#xD;
             treatable with IT therapy, etc.)&#xD;
&#xD;
          4. Psychological or other health conditions, financial and/or legal concerns that would&#xD;
             interfere with the subject's ability to fulfill the requirements of the protocol as&#xD;
             per the investigator's discretion&#xD;
&#xD;
          5. Substance Use Disorder (SUD) within the last 2 years or current Medication Assisted&#xD;
             Treatment (MAT) for substance use disorder&#xD;
&#xD;
          6. Currently using cannabinoids or illicit drugs&#xD;
&#xD;
          7. History of allergy or significant adverse reaction to morphine per investigator&#xD;
             discretion&#xD;
&#xD;
          8. Currently participating or plans to participate in another investigational study&#xD;
             unless written approval is provided by Medtronic Study Team&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Neuroversion</name>
      <address>
        <city>Anchorage</city>
        <state>Alaska</state>
        <zip>99508</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Coastal Pain and Spinal Diagnostics</name>
      <address>
        <city>Carlsbad</city>
        <state>California</state>
        <zip>92009</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Napa Valley Orthopaedic Medical Group</name>
      <address>
        <city>Napa</city>
        <state>California</state>
        <zip>94558</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Florida Pain Institute</name>
      <address>
        <city>Merritt Island</city>
        <state>Florida</state>
        <zip>32935</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Regional Brain &amp; Spine, LLC</name>
      <address>
        <city>Cape Girardeau</city>
        <state>Missouri</state>
        <zip>63701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Christian Hospital Pain Management</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Comprehensive and Interventional Pain Management</name>
      <address>
        <city>Henderson</city>
        <state>Nevada</state>
        <zip>89052</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Pain Management Center</name>
      <address>
        <city>Voorhees</city>
        <state>New Jersey</state>
        <zip>08043</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Premier Pain Treatment Institute</name>
      <address>
        <city>Mount Orab</city>
        <state>Ohio</state>
        <zip>45154</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Investigations, LLC</name>
      <address>
        <city>Edmond</city>
        <state>Oklahoma</state>
        <zip>73013</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moss Rehabilitation-Einstein Healthcare Network</name>
      <address>
        <city>Elkins Park</city>
        <state>Pennsylvania</state>
        <zip>19027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Medical Branch</name>
      <address>
        <city>Galveston</city>
        <state>Texas</state>
        <zip>77555</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Precision Spine Care</name>
      <address>
        <city>Tyler</city>
        <state>Texas</state>
        <zip>75701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Virginia Pain Management Center</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22908</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Eastern Virginia Medical School</name>
      <address>
        <city>Norfolk</city>
        <state>Virginia</state>
        <zip>23507</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwest Pain Care, Inc.</name>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <zip>99201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://manuals.medtronic.com/manuals/main/region</url>
    <description>Applicable Product Manual(s) for the SynchroMed II infusion system</description>
  </link>
  <reference>
    <citation>Smith TJ, Staats PS, Deer T, Stearns LJ, Rauck RL, Boortz-Marx RL, Buchser E, Catala E, Bryce DA, Coyne PJ, Pool GE; Implantable Drug Delivery Systems Study Group. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002 Oct 1;20(19):4040-9. doi: 10.1200/JCO.2002.02.118.</citation>
    <PMID>12351602</PMID>
  </reference>
  <reference>
    <citation>Hamza M, Doleys D, Wells M, Weisbein J, Hoff J, Martin M, Soteropoulos C, Barreto J, Deschner S, Ketchum J. Prospective study of 3-year follow-up of low-dose intrathecal opioids in the management of chronic nonmalignant pain. Pain Med. 2012 Oct;13(10):1304-13. doi: 10.1111/j.1526-4637.2012.01451.x. Epub 2012 Jul 30.</citation>
    <PMID>22845187</PMID>
  </reference>
  <reference>
    <citation>Grider JS, Etscheidt MA, Harned ME, Lee J, Smith B, Lamar C, Bux A. Trialing and Maintenance Dosing Using a Low-Dose Intrathecal Opioid Method for Chronic Nonmalignant Pain: A Prospective 36-Month Study. Neuromodulation. 2016 Feb;19(2):206-19. doi: 10.1111/ner.12352. Epub 2015 Oct 19.</citation>
    <PMID>26477685</PMID>
  </reference>
  <reference>
    <citation>Hamza M, Doleys DM, Saleh IA, Medvedovsky A, Verdolin MH, Hamza M. A Prospective, Randomized, Single-Blinded, Head-to-Head Long-Term Outcome Study, Comparing Intrathecal (IT) Boluses With Continuous Infusion Trialing Techniques Prior to Implantation of Drug Delivery Systems (DDS) for the Treatment of Severe Intractable Chronic Nonmalignant Pain. Neuromodulation. 2015 Oct;18(7):636-48; discussion 649. doi: 10.1111/ner.12342. Epub 2015 Aug 26.</citation>
    <PMID>26307558</PMID>
  </reference>
  <reference>
    <citation>Wilkes DM, Orillosa SJ, Hustak EC, Williams CG, Doulatram GR, Solanki DR, Garcia EA, Huang LM. Efficacy, Safety, and Feasibility of the Morphine Microdose Method in Community-Based Clinics. Pain Med. 2018 Sep 1;19(9):1782-1789. doi: 10.1093/pm/pnx132.</citation>
    <PMID>29016893</PMID>
  </reference>
  <reference>
    <citation>Grider JS, Harned ME, Etscheidt MA. Patient selection and outcomes using a low-dose intrathecal opioid trialing method for chronic nonmalignant pain. Pain Physician. 2011 Jul-Aug;14(4):343-51.</citation>
    <PMID>21785477</PMID>
  </reference>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>November 15, 2018</study_first_submitted>
  <study_first_submitted_qc>November 29, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 3, 2018</study_first_posted>
  <results_first_submitted>December 1, 2022</results_first_submitted>
  <results_first_submitted_qc>January 13, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">February 8, 2023</results_first_posted>
  <last_update_submitted>January 13, 2023</last_update_submitted>
  <last_update_submitted_qc>January 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pain</keyword>
  <keyword>Intrathecal</keyword>
  <keyword>Targeted Drug Delivery (TDD)</keyword>
  <keyword>Non-Malignant Pain</keyword>
  <keyword>Systemic Opioids</keyword>
  <keyword>Opioid Weaning</keyword>
  <keyword>Pain Pump</keyword>
  <keyword>Drug Pump</keyword>
  <keyword>Medtronic Pump</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chronic Pain</mesh_term>
    <mesh_term>Back Pain</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Morphine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 26, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/77/NCT03761277/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 3, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/77/NCT03761277/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Subjects were enrolled from 2019 through 2021 at 16 sites.</recruitment_details>
      <pre_assignment_details>Subjects are considered enrolled at the time the informed consent form is signed. At the Baseline Visit, consented subjects are assessed for eligibility to the study-specific inclusion and exclusion criteria. Subjects who meet all eligibility criteria begin the systemic opioid weaning process prior to initiating the intrathecal drug trial. Subjects with a successful intrathecal trial are eligible for an Intrathecal Drug Delivery System Implant. Non-implanted subjects are exited from the study.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Enrolled Subjects</title>
          <description>All consented subjects are considered enrolled in the study. Enrolled subjects do not receive a treatment intervention before Intrathecal Trial. Subjects who met eligibility criteria proceeded to the Intrathecal Trial procedure. The intrathecal drug trial was conducted according to the investigator's standard of care procedures. A successful intrathecal trial was determined by the investigator.&#xD;
Subjects with a successful intrathecal trial were eligible for implant of the Intrathecal Drug Delivery System (IDDS).&#xD;
Subjects who were implanted with the IDDS were treated via the IDDS with intrathecal preservative-free morphine sulfate (IT PFMS), at a concentration not exceeding 25 mg/mL and 0.9% solution of preservative-free sodium chloride injection (USP) for dilution. IT PFMS initiation and subsequent dosing adjustments were determined based on specific patient needs and clinician standard practices, with utilization of the lowest reasonable daily dose of IT PFMS.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Enrollment to Implant</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="93"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Intrathecal Trial</title>
              <participants_list>
                <participants group_id="P1" count="72"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="52"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="41"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Screen Failure</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Site Closure</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Sponsor Request</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Post-Implant to 6 Months</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="52"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="47"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Site Closure</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>6 Months to 12 Months</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="47"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="28"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Completed Study under Protocol v3</title>
              <participants_list>
                <participants group_id="P1" count="25"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The Baseline Analysis Population (n=52) is the subset of enrolled subjects who completed the intrathecal trial and were implanted with an Implantable Drug Delivery System (IDDS). Within the 93 enrolled subjects, 21 exited prior to the intrathecal trial, 20 exited after intrathecal trial and before IDDS implant, and 52 received an IDDS implant.</population>
      <group_list>
        <group group_id="B1">
          <title>Targeted Drug Delivery Subjects</title>
          <description>All subjects implanted with the Intrathecal Drug Delivery System (IDDS). Subjects were treated via the IDDS with intrathecal preservative-free morphine sulfate (IT PFMS), at a concentration not exceeding 25 mg/mL and 0.9% solution of preservative-free sodium chloride injection (USP) for dilution. IT PFMS initiation and subsequent dosing adjustments were determined based on specific patient needs and clinician standard practices, with the goal to maintain or improve pain control and/or opioid-related side effects (compared to Baseline) with utilization of the lowest reasonable daily dose of IT PFMS. The following IT PFMS dose initiation parameters were recommended: (1) A starting PFMS dose of 0.1 to 0.5 mg/day, or half the effective trial dose, with lower initial PFMS doses considered, and (2) a starting concentration to achieve an estimated pump refill interval of 120 days, but not to exceed 180 days. IT PFMS dose increases or decreases could be made any time throughout the duration of study.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="52"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="63.1" spread="12.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="39"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="50"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Pain (Visual Analog Scale, VAS, 0-100)</title>
          <description>Pain was assessed with the Visual Analog Scale, ranging from 0-100, where 0 is no pain and 100 is the worst pain.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="75.5" spread="13.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Numerical Opioid Side Effect Assessment (NOSE, 0-100)</title>
          <description>Opioid-related side effects were assessed using the Numerical Opioid Side Effect Assessment, ranging from 0-100, where 0 is no opioid-related side effects and 100 is the worst opioid-related side effects.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="21.3" spread="20.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Clinical Success at the 6-Month Visit</title>
        <description>To characterize the number of subjects with Clinical Success at the 6-Month Visit. Clinical Success is defined as any of the following: 1) Reduced opioid-related side effects (at least a 20% reduction) with equal pain (less than 20% increase or decrease) 2) Reduced pain (at least a 20% reduction) with equal opioid-related side effects (less than 20% increase or decrease) 3) Reduced pain and reduced opioid-related side effects (at least a 20% reduction in both). The number of subjects with Clinical Success at the 6-Month Visit is presented.</description>
        <time_frame>Baseline to 6-Month Visit</time_frame>
        <population>A subset of the Targeted Drug Delivery Subjects who maintained intrathecal morphine monotherapy (ITMM) and provided outcome data at both the Baseline and 6-Month (6M) Visit. Of the 52 implanted subjects, 47 completed the 6M Visit, and 42 maintained ITMM through the 6M Visit. Four of the subjects who did not maintain ITMM through the 6M Visit changed their intrathecal medication, and one subject was explanted prior to the 6M Visit and completed the 6M Visit post-explant.</population>
        <group_list>
          <group group_id="O1">
            <title>Targeted Drug Delivery Subjects</title>
            <description>All subjects implanted with the Intrathecal Drug Delivery System (IDDS). Subjects were treated via the IDDS with intrathecal preservative-free morphine sulfate (IT PFMS), at a concentration not exceeding 25 mg/mL and 0.9% solution of preservative-free sodium chloride injection (USP) for dilution. IT PFMS initiation and subsequent dosing adjustments were determined based on specific patient needs and clinician standard practices, with the goal to maintain or improve pain control and/or opioid-related side effects (compared to Baseline) with utilization of the lowest reasonable daily dose of IT PFMS.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Clinical Success at the 6-Month Visit</title>
          <description>To characterize the number of subjects with Clinical Success at the 6-Month Visit. Clinical Success is defined as any of the following: 1) Reduced opioid-related side effects (at least a 20% reduction) with equal pain (less than 20% increase or decrease) 2) Reduced pain (at least a 20% reduction) with equal opioid-related side effects (less than 20% increase or decrease) 3) Reduced pain and reduced opioid-related side effects (at least a 20% reduction in both). The number of subjects with Clinical Success at the 6-Month Visit is presented.</description>
          <population>A subset of the Targeted Drug Delivery Subjects who maintained intrathecal morphine monotherapy (ITMM) and provided outcome data at both the Baseline and 6-Month (6M) Visit. Of the 52 implanted subjects, 47 completed the 6M Visit, and 42 maintained ITMM through the 6M Visit. Four of the subjects who did not maintain ITMM through the 6M Visit changed their intrathecal medication, and one subject was explanted prior to the 6M Visit and completed the 6M Visit post-explant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Visual Analog Scale (VAS) Pain Intensity at the 6-Month Visit</title>
        <description>To demonstrate pain intensity scores (Visual Analog Scale, VAS) at the 6-Month Visit is non-inferior to VAS at Baseline, with a non-inferiority margin of 10mm. Pain was assessed using a Visual Analog Scale, ranging from 0-100, where 0 is no pain and 100 is the worst pain. The VAS is a 100mm line, with &quot;No pain&quot; on the left side of the line and &quot;Worst pain imaginable&quot; on the right side of the line. Subjects made a perpendicular mark on the VAS line that best describes their average pain in the last 24 hours. Change in VAS is calculated as 6-Months - Baseline, with a negative change indicating a reduction (i.e., improvement) in pain intensity.</description>
        <time_frame>Baseline to 6-Month Visit</time_frame>
        <population>A subset of the Targeted Drug Delivery Subjects who maintained intrathecal morphine monotherapy (ITMM) and provided outcome data at both the Baseline and 6-Month (6M) Visit. Of the 52 implanted subjects, 47 completed the 6M Visit, and 42 maintained ITMM through the 6M Visit. Four of the subjects who did not maintain ITMM through the 6M Visit changed their intrathecal medication, and one subject was explanted prior to the 6M Visit and completed the 6M Visit post-explant.</population>
        <group_list>
          <group group_id="O1">
            <title>Targeted Drug Delivery Subjects</title>
            <description>All subjects implanted with the Intrathecal Drug Delivery System (IDDS). Subjects were treated via the IDDS with intrathecal preservative-free morphine sulfate (IT PFMS), at a concentration not exceeding 25 mg/mL and 0.9% solution of preservative-free sodium chloride injection (USP) for dilution. IT PFMS initiation and subsequent dosing adjustments were determined based on specific patient needs and clinician standard practices, with the goal to maintain or improve pain control and/or opioid-related side effects (compared to Baseline) with utilization of the lowest reasonable daily dose of IT PFMS.</description>
          </group>
        </group_list>
        <measure>
          <title>Visual Analog Scale (VAS) Pain Intensity at the 6-Month Visit</title>
          <description>To demonstrate pain intensity scores (Visual Analog Scale, VAS) at the 6-Month Visit is non-inferior to VAS at Baseline, with a non-inferiority margin of 10mm. Pain was assessed using a Visual Analog Scale, ranging from 0-100, where 0 is no pain and 100 is the worst pain. The VAS is a 100mm line, with &quot;No pain&quot; on the left side of the line and &quot;Worst pain imaginable&quot; on the right side of the line. Subjects made a perpendicular mark on the VAS line that best describes their average pain in the last 24 hours. Change in VAS is calculated as 6-Months - Baseline, with a negative change indicating a reduction (i.e., improvement) in pain intensity.</description>
          <population>A subset of the Targeted Drug Delivery Subjects who maintained intrathecal morphine monotherapy (ITMM) and provided outcome data at both the Baseline and 6-Month (6M) Visit. Of the 52 implanted subjects, 47 completed the 6M Visit, and 42 maintained ITMM through the 6M Visit. Four of the subjects who did not maintain ITMM through the 6M Visit changed their intrathecal medication, and one subject was explanted prior to the 6M Visit and completed the 6M Visit post-explant.</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-15" lower_limit="-22.7" upper_limit="-7.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>This analysis was to demonstrate pain intensity scores (VAS) at the 6-Month Visit is non-inferior to VAS at Baseline, i.e., the change in pain intensity is not greater than 0 by more than 10 points from Baseline to the 6-Month Visit.</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>This analysis was to demonstrate pain intensity scores (VAS) at the 6-Month Visit is non-inferior to VAS at Baseline, i.e., the change in pain intensity is not greater than 0 by more than 10 points from Baseline to the 6-Month Visit, with change calculated as 6-Month - Baseline.</non_inferiority_desc>
            <p_value>&lt; 0.001</p_value>
            <method>Wilcoxon Signed Rank test</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-15</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>25.0</dispersion_value>
            <ci_percent>97.5</ci_percent>
            <ci_n_sides>1-Sided</ci_n_sides>
            <ci_upper_limit>-7.1</ci_upper_limit>
            <other_analysis_desc>Due to non-normality, the non-inferiority test was conducted using a Wilcoxon Signed Rank test, rather than a one-sample t-test. Mean reduction in VAS and the upper 97.5% confidence limit are presented, but the change from baseline was evaluated using non-parametric analysis methods.</other_analysis_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>This analysis was to demonstrate pain intensity scores (VAS) at the 6-Month Visit are less than VAS at Baseline, i.e., the reduction in pain intensity is less than 0 from Baseline to the 6-Month Visit.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>This analysis was to demonstrate pain intensity scores (VAS) at the 6-Month Visit are less than VAS at Baseline, i.e., the reduction in pain intensity is less than 0 from Baseline to the 6-Month Visit, with change calculated as 6-Month - Baseline.</non_inferiority_desc>
            <p_value>&lt; 0.001</p_value>
            <method>Wilcoxon Signed Rank test</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-15</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>25.0</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-22.7</ci_lower_limit>
            <ci_upper_limit>-7.1</ci_upper_limit>
            <other_analysis_desc>Due to non-normality, the superiority test was conducted using a Wilcoxon Signed Rank test, rather than a one-sample t-test. Mean reduction in VAS and 95% confidence interval are presented, but the change from baseline was evaluated using non-parametric analysis methods.</other_analysis_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Numerical Opioid Side Effect (NOSE) Assessment Tool</title>
        <description>To characterize the change in opioid-related side effects scores (NOSE) from Baseline to the 6-Month Visit. The Numerical Opioid Side Effect (NOSE) Assessment Tool is a tool to evaluate 10 opioid-related side effects using a 11-point numerical scale. Subjects are asked to evaluate each of the 10 opioid-related side effects on a scale of 0 - 10 with 0 being &quot;not present&quot; and 10 being &quot;as bad as you can imagine&quot;. A total sum score can range from 0 - 100, where 0 is no opioid-related side effects and 100 is the worst opioid-related side effects. Change in NOSE is calculated as 6-Months - Baseline, with a negative change indicating a reduction (i.e., improvement) in opioid-related side effects.</description>
        <time_frame>Baseline to 6-Month Visit</time_frame>
        <population>A subset of the Targeted Drug Delivery Subjects who maintained intrathecal morphine monotherapy (ITMM) and provided outcome data at both the Baseline and 6-Month (6M) Visit. Of the 52 implanted subjects, 47 completed the 6M Visit, and 42 maintained ITMM through the 6M Visit. Four of the subjects who did not maintain ITMM through the 6M Visit changed their intrathecal medication, and one subject was explanted prior to the 6M Visit and completed the 6M Visit post-explant.</population>
        <group_list>
          <group group_id="O1">
            <title>Targeted Drug Delivery Subjects</title>
            <description>All subjects implanted with the Intrathecal Drug Delivery System (IDDS). Subjects were treated via the IDDS with intrathecal preservative-free morphine sulfate (IT PFMS), at a concentration not exceeding 25 mg/mL and 0.9% solution of preservative-free sodium chloride injection (USP) for dilution. IT PFMS initiation and subsequent dosing adjustments were determined based on specific patient needs and clinician standard practices, with the goal to maintain or improve pain control and/or opioid-related side effects (compared to Baseline) with utilization of the lowest reasonable daily dose of IT PFMS.</description>
          </group>
        </group_list>
        <measure>
          <title>Numerical Opioid Side Effect (NOSE) Assessment Tool</title>
          <description>To characterize the change in opioid-related side effects scores (NOSE) from Baseline to the 6-Month Visit. The Numerical Opioid Side Effect (NOSE) Assessment Tool is a tool to evaluate 10 opioid-related side effects using a 11-point numerical scale. Subjects are asked to evaluate each of the 10 opioid-related side effects on a scale of 0 - 10 with 0 being &quot;not present&quot; and 10 being &quot;as bad as you can imagine&quot;. A total sum score can range from 0 - 100, where 0 is no opioid-related side effects and 100 is the worst opioid-related side effects. Change in NOSE is calculated as 6-Months - Baseline, with a negative change indicating a reduction (i.e., improvement) in opioid-related side effects.</description>
          <population>A subset of the Targeted Drug Delivery Subjects who maintained intrathecal morphine monotherapy (ITMM) and provided outcome data at both the Baseline and 6-Month (6M) Visit. Of the 52 implanted subjects, 47 completed the 6M Visit, and 42 maintained ITMM through the 6M Visit. Four of the subjects who did not maintain ITMM through the 6M Visit changed their intrathecal medication, and one subject was explanted prior to the 6M Visit and completed the 6M Visit post-explant.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9.4" lower_limit="-15.4" upper_limit="-3.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Systemic Opioid Elimination Through the 6-Month Visit</title>
        <description>To characterize the number of subjects who eliminate systemic opioids through the 6-Month Visit. Four drug tests for systemic opioid use are administered from intrathecal therapy initiation through the 6-Month Visit. If all of the available drug tests are negative for systemic opioid use, the subject is counted as eliminating systemic opioids through the 6-Month Visit. The number of subjects who eliminated systemic opioids through the 6-Month Visit is presented.</description>
        <time_frame>Baseline to 6-Month Visit</time_frame>
        <population>The subset of Targeted Drug Delivery Subjects who have a drug test at the 6-Month Visit and no more than 1 missing drug test through the 6-Month Visit. Of the 52 implanted subjects, 47 completed the 6M Visit, 42 maintained ITMM through the 6M Visit, and 41 completed a drug test at the 6-Month and had no more than 1 missing drug test through the 6-Month Visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Targeted Drug Delivery Subjects</title>
            <description>All subjects implanted with the Intrathecal Drug Delivery System (IDDS). Subjects were treated via the IDDS with intrathecal preservative-free morphine sulfate (IT PFMS), at a concentration not exceeding 25 mg/mL and 0.9% solution of preservative-free sodium chloride injection (USP) for dilution. IT PFMS initiation and subsequent dosing adjustments were determined based on specific patient needs and clinician standard practices, with the goal to maintain or improve pain control and/or opioid-related side effects (compared to Baseline) with utilization of the lowest reasonable daily dose of IT PFMS.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Systemic Opioid Elimination Through the 6-Month Visit</title>
          <description>To characterize the number of subjects who eliminate systemic opioids through the 6-Month Visit. Four drug tests for systemic opioid use are administered from intrathecal therapy initiation through the 6-Month Visit. If all of the available drug tests are negative for systemic opioid use, the subject is counted as eliminating systemic opioids through the 6-Month Visit. The number of subjects who eliminated systemic opioids through the 6-Month Visit is presented.</description>
          <population>The subset of Targeted Drug Delivery Subjects who have a drug test at the 6-Month Visit and no more than 1 missing drug test through the 6-Month Visit. Of the 52 implanted subjects, 47 completed the 6M Visit, 42 maintained ITMM through the 6M Visit, and 41 completed a drug test at the 6-Month and had no more than 1 missing drug test through the 6-Month Visit.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="41"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected from date of subject consent through study exit, up to 12 months following intrathecal therapy initiation after implant of the Intrathecal Drug Delivery System, if applicable.</time_frame>
      <desc>Any adverse event (AE) meeting the definition of systemic opioid weaning-related, device-related, intrathecal drug-related, and procedure-related, all serious adverse events and deaths (regardless of relatedness) for all subjects from consent to the 12-Month Visit, were collected. Subjects were assessed for adverse events by the investigator at each scheduled and unscheduled study visit.</desc>
      <group_list>
        <group group_id="E1">
          <title>Enrolled Subjects</title>
          <description>All consented subjects are considered enrolled in the study. Enrolled subjects do not receive a treatment intervention before Intrathecal Trial. Subjects who met eligibility criteria proceeded to the Intrathecal Trial procedure. The intrathecal drug trial was conducted according to the investigator's standard of care procedures. A successful intrathecal trial was determined by the investigator.&#xD;
Subjects with a successful intrathecal trial were eligible for implant of the Intrathecal Drug Delivery System (IDDS).&#xD;
Subjects who were implanted with the IDDS were treated via the IDDS with intrathecal preservative-free morphine sulfate (IT PFMS), at a concentration not exceeding 25 mg/mL and 0.9% solution of preservative-free sodium chloride injection (USP) for dilution. IT PFMS initiation and subsequent dosing adjustments were determined based on specific patient needs and clinician standard practices, with the goal to maintain or improve pain control and/or opioid-related side effects (compared to Baseline) with utilization of the lowest reasonable daily dose of IT PFMS.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (24.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Ventricular tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Drug withdrawal syndrome</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>COVID-19</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Implant site infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Intervertebral discitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Wound infection pseudomonas</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fibula fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Upper limb fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Vascular graft occlusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood glucose increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Osteoarthritis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Mental status changes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Renal failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (24.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Adverse drug reaction</sub_title>
                <counts group_id="E1" events="14" subjects_affected="9" subjects_at_risk="93"/>
              </event>
              <event>
                <sub_title>Drug withdrawal syndrome</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="93"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>No manuscripts, abstracts, or case reports that jeopardize the primary publication will be submitted prior to the submission of the primary publication. It is required that all publications undergo review at Medtronic for confidential information and technical accuracy prior to publication.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Protocol V3.0 revised the last study visit from the 12-Month Visit to the 6-Month Visit at a point in the study where some subjects, but not all, had already progressed beyond the 6-Month Visit. Thus, subjects consented under Protocol V3.0 may complete the study without completing the 12-Month Visit. This protocol revision did not impact the Primary and Secondary endpoints, which are evaluated at 6 months.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Pain Therapies Clinical Research Director</name_or_title>
      <organization>Medtronic Neuromodulation Clinical Research</organization>
      <phone>763-514-4000</phone>
      <email>rs.embracetdd@medtronic.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03761277
org study id: MDT18026
nct id: NCT03761277
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: Yes
is us export: No
This is a prospective, multi-center, post market study to evaluate Intrathecal (IT)
      preservative-free morphine sulfate (PFMS) using the SynchroMed™ II infusion system as an
      alternative to systemic opioids for the treatment of chronic, intractable, non-malignant
      primary back pain with or without leg pain.
Subjects will be assessed for pain control and opioid-related side effects following a route
      of delivery change from systemic opioids to IT morphine therapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Clinical Success at the 6-Month Visit
time frame: Baseline to 6-Month Visit
description: To characterize the number of subjects with Clinical Success at the 6-Month Visit. Clinical Success is defined as any of the following: 1) Reduced opioid-related side effects (at least a 20% reduction) with equal pain (less than 20% increase or decrease) 2) Reduced pain (at least a 20% reduction) with equal opioid-related side effects (less than 20% increase or decrease) 3) Reduced pain and reduced opioid-related side effects (at least a 20% reduction in both). The number of subjects with Clinical Success at the 6-Month Visit is presented.
measure: Visual Analog Scale (VAS) Pain Intensity at the 6-Month Visit
time frame: Baseline to 6-Month Visit
description: To demonstrate pain intensity scores (Visual Analog Scale, VAS) at the 6-Month Visit is non-inferior to VAS at Baseline, with a non-inferiority margin of 10mm. Pain was assessed using a Visual Analog Scale, ranging from 0-100, where 0 is no pain and 100 is the worst pain. The VAS is a 100mm line, with "No pain" on the left side of the line and "Worst pain imaginable" on the right side of the line. Subjects made a perpendicular mark on the VAS line that best describes their average pain in the last 24 hours. Change in VAS is calculated as 6-Months - Baseline, with a negative change indicating a reduction (i.e., improvement) in pain intensity.
measure: Numerical Opioid Side Effect (NOSE) Assessment Tool
time frame: Baseline to 6-Month Visit
description: To characterize the change in opioid-related side effects scores (NOSE) from Baseline to the 6-Month Visit. The Numerical Opioid Side Effect (NOSE) Assessment Tool is a tool to evaluate 10 opioid-related side effects using a 11-point numerical scale. Subjects are asked to evaluate each of the 10 opioid-related side effects on a scale of 0 - 10 with 0 being "not present" and 10 being "as bad as you can imagine". A total sum score can range from 0 - 100, where 0 is no opioid-related side effects and 100 is the worst opioid-related side effects. Change in NOSE is calculated as 6-Months - Baseline, with a negative change indicating a reduction (i.e., improvement) in opioid-related side effects.
measure: Number of Participants With Systemic Opioid Elimination Through the 6-Month Visit
time frame: Baseline to 6-Month Visit
description: To characterize the number of subjects who eliminate systemic opioids through the 6-Month Visit. Four drug tests for systemic opioid use are administered from intrathecal therapy initiation through the 6-Month Visit. If all of the available drug tests are negative for systemic opioid use, the subject is counted as eliminating systemic opioids through the 6-Month Visit. The number of subjects who eliminated systemic opioids through the 6-Month Visit is presented.
arm group label: Intrathecal Therapy
arm group type: Other
description: Enrolled subjects who successfully wean from all systemic opioids and have a successful intrathecal trial, proceed to the intervention phase. This includes implantation with a SynchroMed™ II infusion system in the intrathecal space for targeted drug delivery of preservative-free morphine sulfate (PFMS).
intervention type: Device
intervention name: Medtronic SynchroMed™ II infusion system
description: Implanted infusion system consisting of a pump and catheter, as well as external components of a clinician programmer, refill and catheter access port kits, and the Personal Therapy Manager (myPTM™).
arm group label: Intrathecal Therapy
intervention type: Drug
intervention name: Preservative-free morphine sulfate (PFMS)
description: The pharmacological agent used in the pump for this study is limited to a preservative-free morphine sulfate (PFMS).
arm group label: Intrathecal Therapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
url: http://manuals.medtronic.com/manuals/main/region
description: Applicable Product Manual(s) for the SynchroMed II infusion system
citation: Smith TJ, Staats PS, Deer T, Stearns LJ, Rauck RL, Boortz-Marx RL, Buchser E, Catala E, Bryce DA, Coyne PJ, Pool GE; Implantable Drug Delivery Systems Study Group. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002 Oct 1;20(19):4040-9. doi: 10.1200/JCO.2002.02.118.
PMID: 12351602
citation: Hamza M, Doleys D, Wells M, Weisbein J, Hoff J, Martin M, Soteropoulos C, Barreto J, Deschner S, Ketchum J. Prospective study of 3-year follow-up of low-dose intrathecal opioids in the management of chronic nonmalignant pain. Pain Med. 2012 Oct;13(10):1304-13. doi: 10.1111/j.1526-4637.2012.01451.x. Epub 2012 Jul 30.
PMID: 22845187
citation: Grider JS, Etscheidt MA, Harned ME, Lee J, Smith B, Lamar C, Bux A. Trialing and Maintenance Dosing Using a Low-Dose Intrathecal Opioid Method for Chronic Nonmalignant Pain: A Prospective 36-Month Study. Neuromodulation. 2016 Feb;19(2):206-19. doi: 10.1111/ner.12352. Epub 2015 Oct 19.
PMID: 26477685
citation: Hamza M, Doleys DM, Saleh IA, Medvedovsky A, Verdolin MH, Hamza M. A Prospective, Randomized, Single-Blinded, Head-to-Head Long-Term Outcome Study, Comparing Intrathecal (IT) Boluses With Continuous Infusion Trialing Techniques Prior to Implantation of Drug Delivery Systems (DDS) for the Treatment of Severe Intractable Chronic Nonmalignant Pain. Neuromodulation. 2015 Oct;18(7):636-48; discussion 649. doi: 10.1111/ner.12342. Epub 2015 Aug 26.
PMID: 26307558
citation: Wilkes DM, Orillosa SJ, Hustak EC, Williams CG, Doulatram GR, Solanki DR, Garcia EA, Huang LM. Efficacy, Safety, and Feasibility of the Morphine Microdose Method in Community-Based Clinics. Pain Med. 2018 Sep 1;19(9):1782-1789. doi: 10.1093/pm/pnx132.
PMID: 29016893
citation: Grider JS, Harned ME, Etscheidt MA. Patient selection and outcomes using a low-dose intrathecal opioid trialing method for chronic nonmalignant pain. Pain Physician. 2011 Jul-Aug;14(4):343-51.
PMID: 21785477
responsible party type: Sponsor
mesh term: Chronic Pain
mesh term: Back Pain
mesh term: Morphine
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Protocol V3.0 revised the last study visit from the 12-Month Visit to the 6-Month Visit at a point in the study where some subjects, but not all, had already progressed beyond the 6-Month Visit. Thus, subjects consented under Protocol V3.0 may complete the study without completing the 12-Month Visit. This protocol revision did not impact the Primary and Secondary endpoints, which are evaluated at 6 months.
point of contact: 