<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/NCT03008590</url>
  </required_header>
  <id_info>
    <org_study_id>NURB-008-16S</org_study_id>
    <nct_id>NCT03008590</nct_id>
  </id_info>
  <brief_title>Low Dose Naltrexone for Chronic Pain From Arthritis</brief_title>
  <acronym>LDN-VA</acronym>
  <official_title>Low Dose Naltrexone for Chronic Pain in Osteoarthritis and Inflammatory Arthritis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Over 100 million Americans report chronic pain. Veterans are disproportionately affected for&#xD;
      multiple reasons, including injuries and post-traumatic stress disorder. Treatment for&#xD;
      chronic pain is a priority research area for the VA. One of the most common causes of chronic&#xD;
      pain is osteoarthritis (OA). OA is attributable to &quot;wear and tear,&quot; but reasons for pain are&#xD;
      complex. Inflammatory arthritis (IA) includes multiple severe diseases that affect 2-3% of&#xD;
      persons and require treatment with immune-suppressive drugs to prevent joint destruction.&#xD;
      Pain often persists despite effective treatment. Pain in arthritis results from multiple&#xD;
      sources: inflammation, perception of pain in the joint, and interpretation of pain by the&#xD;
      brain. Unfortunately, management of pain in arthritis remains a challenge. Low dose&#xD;
      naltrexone is a widely used but unproven &quot;alternative&quot; approach to chronic pain. It is&#xD;
      attractive for study because it is safe and is proposed to work on all three pathways that&#xD;
      contribute to pain. A small but high-quality clinical trial is needed to determine whether to&#xD;
      invest in definitive studies.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Chronic pain affects over 100 million Americans, and arthritis is the most common cause.&#xD;
      Existing treatments for chronic arthritic pain are only mildly effective, and risks of&#xD;
      medications used to treat pain are numerous and continue to be discovered. Treatment of&#xD;
      chronic is a high priority research area for VA CSR&amp;D.&#xD;
&#xD;
      Naltrexone is an opioid antagonist that is FDA approved in an oral daily dose of 50 mg to&#xD;
      prevent recidivism in alcoholics. At much lower doses of 4 - 4.5 mg daily, however, it has&#xD;
      been shown in small, blinded, randomized trials to improve pain in fibromyalgia,&#xD;
      gastrointestinal symptoms in Crohn's disease, and quality of life in multiple sclerosis. The&#xD;
      only other published data are case reports in complex regional pain syndrome, low back pain,&#xD;
      and scleroderma. However, advocacy of low-dose naltrexone (LDN) by internet-based MDs and&#xD;
      patients is high, and since LDN can be prescribed off-label, its use greatly exceeds what is&#xD;
      justified by evidence. The drug can be prescribed only via compounding pharmacies, so its use&#xD;
      costs a patient ~$40/month.&#xD;
&#xD;
      Among the many unproven treatments that are widely used, LDN is of particular interest&#xD;
      because results of surveys of patients are particularly impressive, because it is quite safe,&#xD;
      and because its benefit is plausible pharmacologically. There is evidence both for modulation&#xD;
      of central pain-processing pathways and for down-regulation of inflammatory pathways in&#xD;
      microglia. Considering the diversity of conditions proposed to benefit from LDN and the&#xD;
      unequivocal need for better approaches to pain relief in chronic conditions, high-quality&#xD;
      clinical trials are needed in both inflammatory and non-inflammatory conditions. This small&#xD;
      but placebo-controlled study, powered to detect an effect size as small as that seen with&#xD;
      NSAIDs or the most beneficial non-pharmacologic approaches, is proposed as a prerequisite for&#xD;
      considering a pivotal trial through the VA Cooperative Studies Program.&#xD;
&#xD;
      The proposed study is a randomized, double-blinded, cross-over, placebo-controlled trial in&#xD;
      adults with osteoarthritis or inflammatory arthritis and persistent pain. Sixty patients will&#xD;
      be enrolled for 16 weeks, during which they will receive LDN for 8 weeks and placebo for 8&#xD;
      weeks. Widely accepted patient-reported outcome measures will be used. The co-primary&#xD;
      endpoints are reduction in pain severity or pain's interference with function during 8 weeks&#xD;
      of LDN compared to 8 weeks placebo, using the Brief Pain Inventory. Other patient-reported&#xD;
      data will be used both as secondary outcomes and as covariates in analyzing determinants of&#xD;
      response to treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 1, 2018</start_date>
  <completion_date type="Actual">December 31, 2019</completion_date>
  <primary_completion_date type="Actual">December 31, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Brief Pain Inventory - Pain Interference</measure>
    <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone or 8 weeks placebo</time_frame>
    <description>Sum of 7 questions (each on a 0-10 scale, therefore 0-70 total) on how much pain has interfered with general function, walking ability, mood, normal work, relations with other people, sleep, and enjoyment of life. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks of naltrexone, or after 8 weeks of placebo.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Brief Pain Inventory - Pain Severity</measure>
    <time_frame>8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
    <description>Average severity of pain in the past 7 days (0-10). Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, and after 8 weeks placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>painDETECT</measure>
    <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
    <description>Measure of neuropathic pain (0-38). Lower score indicates nociceptive pain, higher score indicates neuropathic pain. Results are reported as change from baseline: after 8 weeks of naltrexone or after 8 weeks placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brief Fatigue Inventory</measure>
    <time_frame>8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
    <description>Questionnaire, severity of fatigue and fatigue's interference with activity (0-10 scales). Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone or after 8 weeks placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Beck Depression Inventory-II</measure>
    <time_frame>8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
    <description>Questionnaire measuring severity of depression (0-69). Used primarily during screening to exclude enrollment of patients with severe depression, but also as a safety outcome measure during the study. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks of naltrexone, or after 8 weeks of placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Global Impression of Severity (CGI-S)</measure>
    <time_frame>8 and16 weeks, ie after 8 weeks naltrexone and 8 weeks placebo</time_frame>
    <description>7-point scale (1-7) of patients' self-reporting of severity during the study. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, or after 8 weeks placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Global Impression of Improvement (CGI-I)</measure>
    <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
    <description>7-point scale (1-7) of patients' self-reporting of improvement or worsening during the study. A higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, or after 8 weeks placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient Reported Outcomes Measurement Information System Profile (PROMIS-29)</measure>
    <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
    <description>Questionnaire, survey of 29 questions assessing health-related quality of life across 8 domains. The subscores are not added to give a single score. Results would have been reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C Reactive Protein (CRP)</measure>
    <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
    <description>Blood test for inflammation. Plan was to reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Activity Score (DAS28)</measure>
    <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
    <description>Measure of disease activity in rheumatoid arthritis. Plan was to reported report results as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bath Ankylosing Spondylitis Activity Index (BASDAI)</measure>
    <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
    <description>Patient-reported index of disease activity for ankylosing spondylitis. Higher is more severe. Results would have been reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo) but data were not collected.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">29</enrollment>
  <condition>Osteoarthritis</condition>
  <condition>Arthritis, Rheumatoid</condition>
  <condition>Arthritis, Psoriatic</condition>
  <arm_group>
    <arm_group_label>Naltrexone first then placebo</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Naltrexone for 8 weeks, then placebo for 8 weeks, blinded cross-over design</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo first then naltrexone</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Placebo for 8 weeks, then naltrexone for 8 weeks, blinded cross-over design</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Naltrexone</intervention_name>
    <description>One 4.5 mg capsule each evening</description>
    <arm_group_label>Naltrexone first then placebo</arm_group_label>
    <arm_group_label>Placebo first then naltrexone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>One capsule each evening</description>
    <arm_group_label>Naltrexone first then placebo</arm_group_label>
    <arm_group_label>Placebo first then naltrexone</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients must meet all of the following criteria in order to be eligible for enrollment:&#xD;
&#xD;
          -  Veteran or otherwise eligible for VA benefits, able to travel to VA Boston&#xD;
&#xD;
          -  One or more of the following chronic conditions:&#xD;
&#xD;
               -  osteoarthritis&#xD;
&#xD;
               -  rheumatoid arthritis&#xD;
&#xD;
               -  non-axial spondyloarthritis&#xD;
&#xD;
          -  Average daily pain interference with function (average of the 7 parts of question 9 on&#xD;
             the Brief Pain Inventory) rated at least 4 on a scale of 0-10, and no higher than 9&#xD;
&#xD;
          -  No change in medication in the past 8 weeks made with the expectation of improving&#xD;
             pain&#xD;
&#xD;
          -  No plan to start another medication or a non-pharmacologic treatment regimen likely to&#xD;
             affect pain during the next 16 weeks&#xD;
&#xD;
          -  Age at least 18&#xD;
&#xD;
          -  Registered for medical care in the VA Boston Healthcare System&#xD;
&#xD;
          -  Capable of informed consent, and willingness to comply with study procedures,&#xD;
             including receipt of weekly phone calls from the study coordinator&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Any of the following requires exclusion from participation:&#xD;
&#xD;
          -  Current use of opioids including tramadol&#xD;
&#xD;
          -  Pregnant, breast feeding, or unwilling to engage in contraceptive practices if&#xD;
             sexually active and capable of conceiving&#xD;
&#xD;
          -  Schizophrenia, bipolar disorder, or poorly controlled depression or anxiety&#xD;
&#xD;
          -  Previous use of low-dose naltrexone&#xD;
&#xD;
          -  Back pain described by the patient as greater in severity than arthritic pain in a&#xD;
             non-axial location&#xD;
&#xD;
          -  Significant kidney disease, defined as glomerular filtration rate &lt; 30 ml/min&#xD;
&#xD;
          -  Liver cirrhosis. There is no specific screening procedure to exclude cirrhosis.&#xD;
&#xD;
          -  Painful peripheral neuropathy. There is no specific screening procedure.&#xD;
&#xD;
          -  Plan to have surgery during the next 16 weeks&#xD;
&#xD;
          -  Inconsistency in self-reporting at the screening visit. BPI, PainDETECT, WOMAC, and&#xD;
             PROMIS-29 all contain 0-10 scales of average pain intensity, although the times listed&#xD;
             vary from 1-4 weeks. The severity reported on these three scales cannot differ by more&#xD;
             than 1.&#xD;
&#xD;
          -  Other qualitative circumstances that the investigator feels would make the patient a&#xD;
             poor candidate for this clinical trial, such as an unstable social situation or&#xD;
             unreliable transportation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paul A. Monach, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02130</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>December 22, 2016</study_first_submitted>
  <study_first_submitted_qc>December 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 2, 2017</study_first_posted>
  <results_first_submitted>December 23, 2020</results_first_submitted>
  <results_first_submitted_qc>February 10, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">March 3, 2021</results_first_posted>
  <last_update_submitted>February 10, 2021</last_update_submitted>
  <last_update_submitted_qc>February 10, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pain management</keyword>
  <keyword>Naltrexone</keyword>
  <keyword>Controlled clinical trials, randomized</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Arthritis</mesh_term>
    <mesh_term>Osteoarthritis</mesh_term>
    <mesh_term>Arthritis, Rheumatoid</mesh_term>
    <mesh_term>Arthritis, Psoriatic</mesh_term>
    <mesh_term>Chronic Pain</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Naltrexone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>A de-identified, anonymized dataset containing all the primary study data will be created and shared per VA policies. This dataset will be included as a supplementary file attached to the published manuscript, which in turn will be available through PubMed Central per VA rules. In the event that the study has not been published, the dataset will be made available by other means within 3 years of study completion. The publicly available dataset will not include any identifiers, e.g. age will be included but not birthdate.</ipd_description>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>ICF to be posted within 3 months per VA policy. De-identified dataset to be included as supplementary material with publication, anticipated to be within 12 months of study completion.</ipd_time_frame>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 25, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/90/NCT03008590/ICF_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 9, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/90/NCT03008590/Prot_SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Naltrexone First Then Placebo</title>
          <description>Naltrexone for 8 weeks, then placebo for 8 weeks, blinded cross-over design&#xD;
Naltrexone: One 4.5 mg capsule each evening&#xD;
Placebo: One capsule each evening</description>
        </group>
        <group group_id="P2">
          <title>Placebo First Then Naltrexone</title>
          <description>Placebo for 8 weeks, then naltrexone for 8 weeks, blinded cross-over design&#xD;
Naltrexone: One 4.5 mg capsule each evening&#xD;
Placebo: One capsule each evening</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Patients who completed the study</population>
      <group_list>
        <group group_id="B1">
          <title>Naltrexone First</title>
          <description>Received naltrexone first, then placebo</description>
        </group>
        <group group_id="B2">
          <title>Placebo First</title>
          <description>Received placebo first, then naltrexone</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="11"/>
            <count group_id="B2" value="12"/>
            <count group_id="B3" value="23"/>
          </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="62" spread="8.2"/>
                    <measurement group_id="B2" value="64" spread="11.9"/>
                    <measurement group_id="B3" value="63" spread="10"/>
                  </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="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="19"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Diagnosis, OA or IA</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Osteoarthritis</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Inflammatory arthritis</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body mass index</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33" spread="7.9"/>
                    <measurement group_id="B2" value="35" spread="6.9"/>
                    <measurement group_id="B3" value="34" spread="7.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Brief Pain Inventory - Pain interference (sum of 7 subscales, each 0-10)</title>
          <units>units on a 0-70 scale (higher is worse)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="39" spread="9.5"/>
                    <measurement group_id="B2" value="42" spread="11.5"/>
                    <measurement group_id="B3" value="41" spread="10.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Brief Pain Inventory - Pain severity</title>
          <units>units on a 0-10 scale (higher is worse)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5.9" spread="1.2"/>
                    <measurement group_id="B2" value="5.9" spread="1.3"/>
                    <measurement group_id="B3" value="5.9" spread="1.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Brief Pain Inventory - Pain Interference</title>
        <description>Sum of 7 questions (each on a 0-10 scale, therefore 0-70 total) on how much pain has interfered with general function, walking ability, mood, normal work, relations with other people, sleep, and enjoyment of life. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks of naltrexone, or after 8 weeks of placebo.</description>
        <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone or 8 weeks placebo</time_frame>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>Brief Pain Inventory - Pain Interference</title>
          <description>Sum of 7 questions (each on a 0-10 scale, therefore 0-70 total) on how much pain has interfered with general function, walking ability, mood, normal work, relations with other people, sleep, and enjoyment of life. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks of naltrexone, or after 8 weeks of placebo.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-23" spread="19.4"/>
                    <measurement group_id="O2" value="-22" spread="19.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.90</p_value>
            <p_value_desc>Significance pre-specified at P&lt;0.05</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Brief Pain Inventory - Pain Severity</title>
        <description>Average severity of pain in the past 7 days (0-10). Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, and after 8 weeks placebo.</description>
        <time_frame>8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>Brief Pain Inventory - Pain Severity</title>
          <description>Average severity of pain in the past 7 days (0-10). Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, and after 8 weeks placebo.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.7" spread="1.87"/>
                    <measurement group_id="O2" value="-2.0" spread="2.17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.22</p_value>
            <p_value_desc>Significance pre-specified at P&lt;0.05</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>painDETECT</title>
        <description>Measure of neuropathic pain (0-38). Lower score indicates nociceptive pain, higher score indicates neuropathic pain. Results are reported as change from baseline: after 8 weeks of naltrexone or after 8 weeks placebo.</description>
        <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>painDETECT</title>
          <description>Measure of neuropathic pain (0-38). Lower score indicates nociceptive pain, higher score indicates neuropathic pain. Results are reported as change from baseline: after 8 weeks of naltrexone or after 8 weeks placebo.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.0" spread="6.26"/>
                    <measurement group_id="O2" value="-5.6" spread="5.73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <p_value_desc>Although significance was pre-specified at P&lt;0.05, it is suspected that this result is spurious due to multiple comparisons</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Brief Fatigue Inventory</title>
        <description>Questionnaire, severity of fatigue and fatigue's interference with activity (0-10 scales). Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone or after 8 weeks placebo.</description>
        <time_frame>8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>Brief Fatigue Inventory</title>
          <description>Questionnaire, severity of fatigue and fatigue's interference with activity (0-10 scales). Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone or after 8 weeks placebo.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.8" spread="1.61"/>
                    <measurement group_id="O2" value="-1.8" spread="2.71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3</p_value>
            <p_value_desc>Significance pre-specified at P&lt;0.05</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Beck Depression Inventory-II</title>
        <description>Questionnaire measuring severity of depression (0-69). Used primarily during screening to exclude enrollment of patients with severe depression, but also as a safety outcome measure during the study. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks of naltrexone, or after 8 weeks of placebo</description>
        <time_frame>8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>Beck Depression Inventory-II</title>
          <description>Questionnaire measuring severity of depression (0-69). Used primarily during screening to exclude enrollment of patients with severe depression, but also as a safety outcome measure during the study. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks of naltrexone, or after 8 weeks of placebo</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.0" spread="4.29"/>
                    <measurement group_id="O2" value="-1.7" spread="6.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.04</p_value>
            <p_value_desc>Although significance was pre-specified at P&lt;0.05, it is suspected that this result is spurious due to multiple comparisons</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Global Impression of Severity (CGI-S)</title>
        <description>7-point scale (1-7) of patients' self-reporting of severity during the study. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, or after 8 weeks placebo.</description>
        <time_frame>8 and16 weeks, ie after 8 weeks naltrexone and 8 weeks placebo</time_frame>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Global Impression of Severity (CGI-S)</title>
          <description>7-point scale (1-7) of patients' self-reporting of severity during the study. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, or after 8 weeks placebo.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.1" spread="1.59"/>
                    <measurement group_id="O2" value="-1.1" spread="1.83"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.78</p_value>
            <p_value_desc>Significance pre-specified at P&lt;0.05</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Global Impression of Improvement (CGI-I)</title>
        <description>7-point scale (1-7) of patients' self-reporting of improvement or worsening during the study. A higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, or after 8 weeks placebo.</description>
        <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Global Impression of Improvement (CGI-I)</title>
          <description>7-point scale (1-7) of patients' self-reporting of improvement or worsening during the study. A higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, or after 8 weeks placebo.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.3" spread="1.2"/>
                    <measurement group_id="O2" value="-0.2" spread="1.71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Data from the primary or secondary outcome measures were the dependent variables. The patient was the random effect. Dependent fixed effects variables included treatment at the time of data collection (naltrexone or placebo), group (naltrexone first or placebo first), and week (4, 8, 12, and 16).</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.92</p_value>
            <p_value_desc>Significance pre-specified at P&lt;0.05</p_value_desc>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Patient Reported Outcomes Measurement Information System Profile (PROMIS-29)</title>
        <description>Questionnaire, survey of 29 questions assessing health-related quality of life across 8 domains. The subscores are not added to give a single score. Results would have been reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.</description>
        <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
        <population>Data not collected</population>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>Patient Reported Outcomes Measurement Information System Profile (PROMIS-29)</title>
          <description>Questionnaire, survey of 29 questions assessing health-related quality of life across 8 domains. The subscores are not added to give a single score. Results would have been reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.</description>
          <population>Data not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>C Reactive Protein (CRP)</title>
        <description>Blood test for inflammation. Plan was to reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.</description>
        <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
        <population>Data were not collected</population>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>C Reactive Protein (CRP)</title>
          <description>Blood test for inflammation. Plan was to reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.</description>
          <population>Data were not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Disease Activity Score (DAS28)</title>
        <description>Measure of disease activity in rheumatoid arthritis. Plan was to reported report results as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.</description>
        <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
        <population>Data not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>Disease Activity Score (DAS28)</title>
          <description>Measure of disease activity in rheumatoid arthritis. Plan was to reported report results as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.</description>
          <population>Data not collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Bath Ankylosing Spondylitis Activity Index (BASDAI)</title>
        <description>Patient-reported index of disease activity for ankylosing spondylitis. Higher is more severe. Results would have been reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo) but data were not collected.</description>
        <time_frame>8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo</time_frame>
        <population>Data not collected</population>
        <group_list>
          <group group_id="O1">
            <title>At End of 8 Weeks Naltrexone Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
          <group group_id="O2">
            <title>At End of 8 Weeks Placebo Treatment</title>
            <description>Data from naltrexone periods were pooled for presentation purposes, but period (first or second) was included as a variable in the statistical analysis. Results shown are change from baseline.</description>
          </group>
        </group_list>
        <measure>
          <title>Bath Ankylosing Spondylitis Activity Index (BASDAI)</title>
          <description>Patient-reported index of disease activity for ankylosing spondylitis. Higher is more severe. Results would have been reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo) but data were not collected.</description>
          <population>Data not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>16 weeks (8 weeks each naltrexone and placebo)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>During Naltrexone Treatment</title>
          <description>Adverse events during naltrexone</description>
        </group>
        <group group_id="E2">
          <title>During Placebo Treatment</title>
          <description>Adverse events during placebo</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-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="0" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="29"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Anaplasmosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Shortness of breath</sub_title>
                <description>Shortness of breath of unknown origin, led to hospitalization, resolved</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-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="7" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal / GI symptoms</sub_title>
                <description>Nausea, vomiting, bloating</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Lip and tongue swelling</sub_title>
                <description>Suspected allergic reaction</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infections, minor viral or bacterial</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Ankle injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Reduced renal function</sub_title>
                <description>Mild, transient reduction in GFR, unknown cause</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermatitis</sub_title>
                <description>One case poison ivy, another unknown, both resolved</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr Paul Monach, Chief, Rheumatology Section</name_or_title>
      <organization>VA Boston Healthcare System</organization>
      <phone>857-364-5552</phone>
      <email>Paul.Monach@va.gov</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/NCT03008590
org study id: NURB-008-16S
nct id: NCT03008590
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Over 100 million Americans report chronic pain. Veterans are disproportionately affected for
      multiple reasons, including injuries and post-traumatic stress disorder. Treatment for
      chronic pain is a priority research area for the VA. One of the most common causes of chronic
      pain is osteoarthritis (OA). OA is attributable to "wear and tear," but reasons for pain are
      complex. Inflammatory arthritis (IA) includes multiple severe diseases that affect 2-3% of
      persons and require treatment with immune-suppressive drugs to prevent joint destruction.
      Pain often persists despite effective treatment. Pain in arthritis results from multiple
      sources: inflammation, perception of pain in the joint, and interpretation of pain by the
      brain. Unfortunately, management of pain in arthritis remains a challenge. Low dose
      naltrexone is a widely used but unproven "alternative" approach to chronic pain. It is
      attractive for study because it is safe and is proposed to work on all three pathways that
      contribute to pain. A small but high-quality clinical trial is needed to determine whether to
      invest in definitive studies.
Chronic pain affects over 100 million Americans, and arthritis is the most common cause.
      Existing treatments for chronic arthritic pain are only mildly effective, and risks of
      medications used to treat pain are numerous and continue to be discovered. Treatment of
      chronic is a high priority research area for VA CSR&D.

      Naltrexone is an opioid antagonist that is FDA approved in an oral daily dose of 50 mg to
      prevent recidivism in alcoholics. At much lower doses of 4 - 4.5 mg daily, however, it has
      been shown in small, blinded, randomized trials to improve pain in fibromyalgia,
      gastrointestinal symptoms in Crohn's disease, and quality of life in multiple sclerosis. The
      only other published data are case reports in complex regional pain syndrome, low back pain,
      and scleroderma. However, advocacy of low-dose naltrexone (LDN) by internet-based MDs and
      patients is high, and since LDN can be prescribed off-label, its use greatly exceeds what is
      justified by evidence. The drug can be prescribed only via compounding pharmacies, so its use
      costs a patient ~$40/month.

      Among the many unproven treatments that are widely used, LDN is of particular interest
      because results of surveys of patients are particularly impressive, because it is quite safe,
      and because its benefit is plausible pharmacologically. There is evidence both for modulation
      of central pain-processing pathways and for down-regulation of inflammatory pathways in
      microglia. Considering the diversity of conditions proposed to benefit from LDN and the
      unequivocal need for better approaches to pain relief in chronic conditions, high-quality
      clinical trials are needed in both inflammatory and non-inflammatory conditions. This small
      but placebo-controlled study, powered to detect an effect size as small as that seen with
      NSAIDs or the most beneficial non-pharmacologic approaches, is proposed as a prerequisite for
      considering a pivotal trial through the VA Cooperative Studies Program.

      The proposed study is a randomized, double-blinded, cross-over, placebo-controlled trial in
      adults with osteoarthritis or inflammatory arthritis and persistent pain. Sixty patients will
      be enrolled for 16 weeks, during which they will receive LDN for 8 weeks and placebo for 8
      weeks. Widely accepted patient-reported outcome measures will be used. The co-primary
      endpoints are reduction in pain severity or pain's interference with function during 8 weeks
      of LDN compared to 8 weeks placebo, using the Brief Pain Inventory. Other patient-reported
      data will be used both as secondary outcomes and as covariates in analyzing determinants of
      response to treatment.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Brief Pain Inventory - Pain Interference
time frame: 8 and 16 weeks, ie after 8 weeks naltrexone or 8 weeks placebo
description: Sum of 7 questions (each on a 0-10 scale, therefore 0-70 total) on how much pain has interfered with general function, walking ability, mood, normal work, relations with other people, sleep, and enjoyment of life. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks of naltrexone, or after 8 weeks of placebo.
measure: Brief Pain Inventory - Pain Severity
time frame: 8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
description: Average severity of pain in the past 7 days (0-10). Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, and after 8 weeks placebo.
measure: painDETECT
time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
description: Measure of neuropathic pain (0-38). Lower score indicates nociceptive pain, higher score indicates neuropathic pain. Results are reported as change from baseline: after 8 weeks of naltrexone or after 8 weeks placebo.
measure: Brief Fatigue Inventory
time frame: 8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
description: Questionnaire, severity of fatigue and fatigue's interference with activity (0-10 scales). Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone or after 8 weeks placebo.
measure: Beck Depression Inventory-II
time frame: 8 and16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
description: Questionnaire measuring severity of depression (0-69). Used primarily during screening to exclude enrollment of patients with severe depression, but also as a safety outcome measure during the study. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks of naltrexone, or after 8 weeks of placebo
measure: Clinical Global Impression of Severity (CGI-S)
time frame: 8 and16 weeks, ie after 8 weeks naltrexone and 8 weeks placebo
description: 7-point scale (1-7) of patients' self-reporting of severity during the study. Higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, or after 8 weeks placebo.
measure: Clinical Global Impression of Improvement (CGI-I)
time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
description: 7-point scale (1-7) of patients' self-reporting of improvement or worsening during the study. A higher score is a worse outcome. Results are reported as change from baseline: after 8 weeks naltrexone, or after 8 weeks placebo.
measure: Patient Reported Outcomes Measurement Information System Profile (PROMIS-29)
time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
description: Questionnaire, survey of 29 questions assessing health-related quality of life across 8 domains. The subscores are not added to give a single score. Results would have been reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.
measure: C Reactive Protein (CRP)
time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
description: Blood test for inflammation. Plan was to reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.
measure: Disease Activity Score (DAS28)
time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
description: Measure of disease activity in rheumatoid arthritis. Plan was to reported report results as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo), but data were not collected.
measure: Bath Ankylosing Spondylitis Activity Index (BASDAI)
time frame: 8 and 16 weeks, ie after 8 weeks naltrexone and after 8 weeks placebo
description: Patient-reported index of disease activity for ankylosing spondylitis. Higher is more severe. Results would have been reported as change from baseline (after 8 weeks naltrexone, or after 8 weeks placebo) but data were not collected.
arm group label: Naltrexone first then placebo
arm group type: Other
description: Naltrexone for 8 weeks, then placebo for 8 weeks, blinded cross-over design
arm group label: Placebo first then naltrexone
arm group type: Other
description: Placebo for 8 weeks, then naltrexone for 8 weeks, blinded cross-over design
intervention type: Drug
intervention name: Naltrexone
description: One 4.5 mg capsule each evening
arm group label: Naltrexone first then placebo
arm group label: Placebo first then naltrexone
intervention type: Drug
intervention name: Placebo
description: One capsule each evening
arm group label: Naltrexone first then placebo
arm group label: Placebo first then naltrexone
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Paul A. Monach, MD PhD
role: Principal Investigator
affiliation: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
facility: 
country: United States
responsible party type: Sponsor
mesh term: Arthritis
mesh term: Osteoarthritis
mesh term: Arthritis, Rheumatoid
mesh term: Arthritis, Psoriatic
mesh term: Chronic Pain
mesh term: Naltrexone
sharing ipd: Yes
ipd description: A de-identified, anonymized dataset containing all the primary study data will be created and shared per VA policies. This dataset will be included as a supplementary file attached to the published manuscript, which in turn will be available through PubMed Central per VA rules. In the event that the study has not been published, the dataset will be made available by other means within 3 years of study completion. The publicly available dataset will not include any identifiers, e.g. age will be included but not birthdate.
ipd info type: Informed Consent Form (ICF)
ipd time frame: ICF to be posted within 3 months per VA policy. De-identified dataset to be included as supplementary material with publication, anticipated to be within 12 months of study completion.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 