<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/NCT02260388</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY00001500</org_study_id>
    <secondary_id>PCORI-1306-02496</secondary_id>
    <nct_id>NCT02260388</nct_id>
  </id_info>
  <brief_title>Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations</brief_title>
  <acronym>PAIN-CONTRoLS</acronym>
  <official_title>Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Kansas Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Patient-Centered Outcomes Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Kansas Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this large comparative effectiveness study led by Richard J. Barohn, MD, of&#xD;
      the University of Kansas Medical Center, is to learn about the safety and effectiveness of&#xD;
      nortriptyline, duloxetine, pregabalin and mexiletine in treating cryptogenic sensory&#xD;
      polyneuropathy (CSPN).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The goal of this research project is to find the best drug for the treatment of pain in&#xD;
      patients with CSPN. While the pharmaceutical industry has focused attention on drugs for&#xD;
      treating diabetic sensory neuropathy (DSPN), and two drugs are now FDA approved, there have&#xD;
      not been any prospective trials in CSPN. And, because there are no studies with CSPN&#xD;
      patients, insurance carriers often reject authorizing prescriptions for some drugs for&#xD;
      patients with CSPN.&#xD;
&#xD;
      There are four drugs that will be tested in this study: nortriptyline, duloxetine, pregabalin&#xD;
      and mexiletine. These drugs are not approved by the FDA for the treatment of CSPN and are&#xD;
      considered &quot;investigational&quot; in this study.&#xD;
&#xD;
      There are two periods in this study: Screening/Baseline and Study Drug. During the&#xD;
      Screening/Baseline period the researchers will determine eligibility for potential subjects.&#xD;
      During the second period, eligible patients who consented to participate will take the study&#xD;
      drug. Participants will be randomized to receive one of the four drugs in this study.&#xD;
      Participants will know which drug they are taking. Participants will not be allowed to switch&#xD;
      groups and receive a different drug during the study.&#xD;
&#xD;
      This study uses an adaptive study design. This means the study can enroll less participants&#xD;
      and provide better conclusions. The study design allows the researchers the ability to make&#xD;
      changes to the approach of the study or to stop the study early if there are strong results.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2014</start_date>
  <completion_date type="Actual">September 2017</completion_date>
  <primary_completion_date type="Actual">September 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit</measure>
    <time_frame>12 weeks</time_frame>
    <description>The final outcome of the study is a combination of two endpoints, efficacy and quit or treatment discontinuation rates. The first endpoint was a patient responder-defined measure of efficacy. A patient was deemed efficacious if a 50% or more reduction was observed in the Likert pain-scale from the baseline visit to the 12 week visit (i.e. 6 at baseline to 3 or less at week 12). The second endpoint was the observed percentage of patients who discontinued treatment prior to the last follow up visit for any reason or were lost to follow up. The utility function, which combines efficacy and quit rates, was used to drive the adaptive randomization, stopping criteria, and final analysis conclusions.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>SF12 Health Composite Scores</measure>
    <time_frame>12 weeks</time_frame>
    <description>SF-12v2® Health Survey Standard The Optum™ SF-12v2® Health Survey is a shorter version of the SF-36v2® Health Survey that uses just 12 questions to measure functional health and well-being from the patient's point of view.&#xD;
Survey provides psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores.&#xD;
Scores are calibrated so that 50 is the average score or norm, standard deviation = 10.&#xD;
Higher scores indicate better health for both mental and physical component summary scores.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PROMIS Pain Interference Short Form v1.0 8a T Score</measure>
    <time_frame>12 weeks</time_frame>
    <description>Higher scores for pain interference represents worse outcome (more pain interference) T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.&#xD;
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PROMIS Fatigue Short Form v1.0 8a</measure>
    <time_frame>12 Weeks</time_frame>
    <description>Higher scores for fatigue represents worse outcome (more fatigue). T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.&#xD;
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PROMIS Sleep Disturbance Short Form v1.0 8a</measure>
    <time_frame>12 weeks</time_frame>
    <description>Higher scores for sleep disturbance represents worse outcome (more sleep disturbance).&#xD;
T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.&#xD;
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.&#xD;
Higher scores equals more of the concept being measured</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">402</enrollment>
  <condition>Cryptogenic Sensory Polyneuropathy</condition>
  <arm_group>
    <arm_group_label>Nortriptyline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Duloxetine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pregabalin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Mexiletine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nortriptyline</intervention_name>
    <arm_group_label>Nortriptyline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Duloxetine</intervention_name>
    <arm_group_label>Duloxetine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pregabalin</intervention_name>
    <arm_group_label>Pregabalin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mexiletine</intervention_name>
    <arm_group_label>Mexiletine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of cryptogenic sensory polyneuropathy.&#xD;
&#xD;
          -  Likert Pain Score of greater than or equal to 4.&#xD;
&#xD;
          -  Must not currently be on nortriptyline, duloxetine, pregabalin or mexiletine or&#xD;
             similar class of medication for at least 7 days from baseline study visit.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any medical condition or current medication that would prevent them from taking either&#xD;
             nortriptyline, duloxetine, pregabalin or mexiletine.&#xD;
&#xD;
          -  Unable to give consent.&#xD;
&#xD;
          -  Unable or not willing to comply with the study.&#xD;
&#xD;
          -  Other causes for polyneuropathy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Richard Barohn, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Kansas Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Barrow Neurological Institute</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85013</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Phoenix Neurological Associates</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85018</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cedars-Sinai Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>California Pacific Medical Center</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Colorado Denver Anschutz Campus</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Colorado Springs Neurological Associates</name>
      <address>
        <city>Colorado Springs</city>
        <state>Colorado</state>
        <zip>80907</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Florida - Gainesville</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>10236</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Florida Health Science Center - Jacksonville</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Miami Miller School of Medicine</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurological Services of Orlando Research</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of South Florida</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NorthShore Neurological Institute</name>
      <address>
        <city>Glenview</city>
        <state>Illinois</state>
        <zip>60026</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indiana University</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mercy Medical Center - Des Moines</name>
      <address>
        <city>Des Moines</city>
        <state>Iowa</state>
        <zip>50314</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Iowa Hospitals and Clinics</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hutchinson Clinic, PA</name>
      <address>
        <city>Hutchinson</city>
        <state>Kansas</state>
        <zip>67502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Medical Center</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Norton Neurology Services</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brigham and Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Henry Ford Hospital</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spectrum Health System</name>
      <address>
        <city>Grand Rapids</city>
        <state>Michigan</state>
        <zip>49525</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55414</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Louis University</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Nebraska Medical Center</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68198</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Buffalo School of Medicine and Biomedical Sciences</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Beth Israel</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Cincinnati</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45221</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Ohio State University Wexner Medical Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health &amp; Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Penn State Medical Center</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>17033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Austin Neuromuscular Center</name>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <zip>78703</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sara Austin, MD, PA</name>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <zip>78705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seton Brain and Spine Institute</name>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <zip>78705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Neurology</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75214</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Southwestern</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Health Science Center at Houton</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Grand Medical Clinic</name>
      <address>
        <city>Katy</city>
        <state>Texas</state>
        <zip>77494</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology Clinic of Central Texas</name>
      <address>
        <city>New Braunfels</city>
        <state>Texas</state>
        <zip>78132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Health Science Center in San Antonio</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Vermont Medical Center</name>
      <address>
        <city>Burlington</city>
        <state>Vermont</state>
        <zip>05403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Virginia</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22908</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Toronto General Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2C4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>October 6, 2014</study_first_submitted>
  <study_first_submitted_qc>October 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 9, 2014</study_first_posted>
  <results_first_submitted>March 2, 2018</results_first_submitted>
  <results_first_submitted_qc>June 6, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">July 6, 2018</results_first_posted>
  <last_update_submitted>June 6, 2018</last_update_submitted>
  <last_update_submitted_qc>June 6, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 6, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CSPN</keyword>
  <keyword>neuropathy</keyword>
  <keyword>pain</keyword>
  <keyword>pain management</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Polyneuropathies</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mexiletine</mesh_term>
    <mesh_term>Pregabalin</mesh_term>
    <mesh_term>Duloxetine Hydrochloride</mesh_term>
    <mesh_term>Nortriptyline</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <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>February 15, 2015</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/88/NCT02260388/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Nortriptyline</title>
          <description>Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.&#xD;
Nortriptyline</description>
        </group>
        <group group_id="P2">
          <title>Duloxetine</title>
          <description>Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.&#xD;
Duloxetine</description>
        </group>
        <group group_id="P3">
          <title>Pregabalin</title>
          <description>Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.&#xD;
Pregabalin</description>
        </group>
        <group group_id="P4">
          <title>Mexiletine</title>
          <description>Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.&#xD;
Mexiletine</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="134"/>
                <participants group_id="P2" count="126"/>
                <participants group_id="P3" count="73"/>
                <participants group_id="P4" count="69"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="132"/>
                <participants group_id="P2" count="118"/>
                <participants group_id="P3" count="70"/>
                <participants group_id="P4" count="65"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Nortriptyline</title>
          <description>Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.&#xD;
Nortriptyline</description>
        </group>
        <group group_id="B2">
          <title>Duloxetine</title>
          <description>Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.&#xD;
Duloxetine</description>
        </group>
        <group group_id="B3">
          <title>Pregabalin</title>
          <description>Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.&#xD;
Pregabalin</description>
        </group>
        <group group_id="B4">
          <title>Mexiletine</title>
          <description>Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.&#xD;
Mexiletine</description>
        </group>
        <group group_id="B5">
          <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="134"/>
            <count group_id="B2" value="126"/>
            <count group_id="B3" value="73"/>
            <count group_id="B4" value="69"/>
            <count group_id="B5" value="402"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="91"/>
                    <measurement group_id="B2" value="86"/>
                    <measurement group_id="B3" value="50"/>
                    <measurement group_id="B4" value="41"/>
                    <measurement group_id="B5" value="268"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="43"/>
                    <measurement group_id="B2" value="40"/>
                    <measurement group_id="B3" value="23"/>
                    <measurement group_id="B4" value="28"/>
                    <measurement group_id="B5" value="134"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <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="60.3" spread="12.7"/>
                    <measurement group_id="B2" value="59.9" spread="14.0"/>
                    <measurement group_id="B3" value="59.5" spread="13.6"/>
                    <measurement group_id="B4" value="60.7" spread="13.7"/>
                    <measurement group_id="B5" value="60.1" spread="13.4"/>
                  </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="59"/>
                    <measurement group_id="B2" value="68"/>
                    <measurement group_id="B3" value="34"/>
                    <measurement group_id="B4" value="28"/>
                    <measurement group_id="B5" value="189"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="75"/>
                    <measurement group_id="B2" value="58"/>
                    <measurement group_id="B3" value="39"/>
                    <measurement group_id="B4" value="41"/>
                    <measurement group_id="B5" value="213"/>
                  </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="8"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="126"/>
                    <measurement group_id="B2" value="119"/>
                    <measurement group_id="B3" value="68"/>
                    <measurement group_id="B4" value="66"/>
                    <measurement group_id="B5" value="379"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                  </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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="17"/>
                  </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 group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="113"/>
                    <measurement group_id="B2" value="104"/>
                    <measurement group_id="B3" value="62"/>
                    <measurement group_id="B4" value="64"/>
                    <measurement group_id="B5" value="343"/>
                  </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 group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="15"/>
                  </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="134"/>
                    <measurement group_id="B2" value="126"/>
                    <measurement group_id="B3" value="73"/>
                    <measurement group_id="B4" value="69"/>
                    <measurement group_id="B5" value="402"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Patient-Reported Outcomes Measurement Information System (PROMIS) Scale T-Scores</title>
          <description>T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD). A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population&#xD;
PROMIS Pain Interference Short Form v1.0 8a: Higher scores for pain interference represents worse outcome (more pain interference) PROMIS Fatigue Short Form v1.0 8a Higher scores indicate more fatigue (worse outcome).&#xD;
PROMIS Sleep Disturbance Short Form v1.0 8a Higher scores indicate more sleep disturbance (worse outcome).</description>
          <units>T-Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>PROMIS Pain Interference T-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="63.1" spread="7.0"/>
                    <measurement group_id="B2" value="62.4" spread="6.8"/>
                    <measurement group_id="B3" value="63.3" spread="5.5"/>
                    <measurement group_id="B4" value="60.9" spread="7.9"/>
                    <measurement group_id="B5" value="62.5" spread="6.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PROMIS Fatigue T-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59.6" spread="3.4"/>
                    <measurement group_id="B2" value="59.7" spread="3.3"/>
                    <measurement group_id="B3" value="59.1" spread="3.7"/>
                    <measurement group_id="B4" value="59.7" spread="3.2"/>
                    <measurement group_id="B5" value="59.6" spread="3.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PROMIS Sleep Disturbance T-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59.1" spread="9.8"/>
                    <measurement group_id="B2" value="60.6" spread="8.3"/>
                    <measurement group_id="B3" value="59.8" spread="8.7"/>
                    <measurement group_id="B4" value="57.0" spread="11.4"/>
                    <measurement group_id="B5" value="59.3" spread="9.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>SF12 Health Component Scores</title>
          <description>SF-12v2® Health Survey Standard The Optum™ SF-12v2® Health Survey is a shorter version of the SF-36v2® Health Survey that uses just 12 questions to measure functional health and well-being from the patient's point of view.&#xD;
Survey provides psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores.&#xD;
Scores are calibrated so that 50 is the average score or norm, standard deviation = 10.&#xD;
Higher scores indicate better health for both mental and physical component summary scores.</description>
          <units>Norm-Based Standardization Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>Physical Component Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="38.0" spread="9.3"/>
                    <measurement group_id="B2" value="38.5" spread="9.3"/>
                    <measurement group_id="B3" value="37.9" spread="9.1"/>
                    <measurement group_id="B4" value="41.1" spread="10.1"/>
                    <measurement group_id="B5" value="38.7" spread="9.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Mental Component Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="48.0" spread="10.4"/>
                    <measurement group_id="B2" value="46.7" spread="10.1"/>
                    <measurement group_id="B3" value="46.8" spread="11.3"/>
                    <measurement group_id="B4" value="47.2" spread="11.1"/>
                    <measurement group_id="B5" value="47.2" spread="10.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Likert Pain Scale</title>
          <description>Likert Pain Scale - Incremental Scale 0 to 10 with 10 indicating most 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="6.9" spread="1.5"/>
                    <measurement group_id="B2" value="6.7" spread="1.6"/>
                    <measurement group_id="B3" value="6.4" spread="1.6"/>
                    <measurement group_id="B4" value="6.5" spread="1.7"/>
                    <measurement group_id="B5" value="6.7" spread="1.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit</title>
        <description>The final outcome of the study is a combination of two endpoints, efficacy and quit or treatment discontinuation rates. The first endpoint was a patient responder-defined measure of efficacy. A patient was deemed efficacious if a 50% or more reduction was observed in the Likert pain-scale from the baseline visit to the 12 week visit (i.e. 6 at baseline to 3 or less at week 12). The second endpoint was the observed percentage of patients who discontinued treatment prior to the last follow up visit for any reason or were lost to follow up. The utility function, which combines efficacy and quit rates, was used to drive the adaptive randomization, stopping criteria, and final analysis conclusions.</description>
        <time_frame>12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nortriptyline</title>
            <description>Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.&#xD;
Nortriptyline</description>
          </group>
          <group group_id="O2">
            <title>Duloxetine</title>
            <description>Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.&#xD;
Duloxetine</description>
          </group>
          <group group_id="O3">
            <title>Pregabalin</title>
            <description>Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.&#xD;
Pregabalin</description>
          </group>
          <group group_id="O4">
            <title>Mexiletine</title>
            <description>Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.&#xD;
Mexiletine</description>
          </group>
        </group_list>
        <measure>
          <title>Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit</title>
          <description>The final outcome of the study is a combination of two endpoints, efficacy and quit or treatment discontinuation rates. The first endpoint was a patient responder-defined measure of efficacy. A patient was deemed efficacious if a 50% or more reduction was observed in the Likert pain-scale from the baseline visit to the 12 week visit (i.e. 6 at baseline to 3 or less at week 12). The second endpoint was the observed percentage of patients who discontinued treatment prior to the last follow up visit for any reason or were lost to follow up. The utility function, which combines efficacy and quit rates, was used to drive the adaptive randomization, stopping criteria, and final analysis conclusions.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="134"/>
                <count group_id="O2" value="126"/>
                <count group_id="O3" value="73"/>
                <count group_id="O4" value="69"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Efficacious and Non-Quit</title>
                  <measurement_list>
                    <measurement group_id="O1" value="34"/>
                    <measurement group_id="O2" value="29"/>
                    <measurement group_id="O3" value="11"/>
                    <measurement group_id="O4" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Non-Efficacious and Non-Quit</title>
                  <measurement_list>
                    <measurement group_id="O1" value="49"/>
                    <measurement group_id="O2" value="50"/>
                    <measurement group_id="O3" value="31"/>
                    <measurement group_id="O4" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Quit</title>
                  <measurement_list>
                    <measurement group_id="O1" value="51"/>
                    <measurement group_id="O2" value="47"/>
                    <measurement group_id="O3" value="31"/>
                    <measurement group_id="O4" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>SF12 Health Composite Scores</title>
        <description>SF-12v2® Health Survey Standard The Optum™ SF-12v2® Health Survey is a shorter version of the SF-36v2® Health Survey that uses just 12 questions to measure functional health and well-being from the patient's point of view.&#xD;
Survey provides psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores.&#xD;
Scores are calibrated so that 50 is the average score or norm, standard deviation = 10.&#xD;
Higher scores indicate better health for both mental and physical component summary scores.</description>
        <time_frame>12 weeks</time_frame>
        <population>No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Nortriptyline</title>
            <description>Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.&#xD;
Nortriptyline</description>
          </group>
          <group group_id="O2">
            <title>Duloxetine</title>
            <description>Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.&#xD;
Duloxetine</description>
          </group>
          <group group_id="O3">
            <title>Pregabalin</title>
            <description>Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.&#xD;
Pregabalin</description>
          </group>
          <group group_id="O4">
            <title>Mexiletine</title>
            <description>Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.&#xD;
Mexiletine</description>
          </group>
        </group_list>
        <measure>
          <title>SF12 Health Composite Scores</title>
          <description>SF-12v2® Health Survey Standard The Optum™ SF-12v2® Health Survey is a shorter version of the SF-36v2® Health Survey that uses just 12 questions to measure functional health and well-being from the patient's point of view.&#xD;
Survey provides psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores.&#xD;
Scores are calibrated so that 50 is the average score or norm, standard deviation = 10.&#xD;
Higher scores indicate better health for both mental and physical component summary scores.</description>
          <population>No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.</population>
          <units>Norm-Based Standardization Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="83"/>
                <count group_id="O2" value="79"/>
                <count group_id="O3" value="42"/>
                <count group_id="O4" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Mental Component Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.0" spread="8.9"/>
                    <measurement group_id="O2" value="50.9" spread="9.9"/>
                    <measurement group_id="O3" value="47.2" spread="11.2"/>
                    <measurement group_id="O4" value="51.3" spread="10.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Physical Component Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42.8" spread="8.7"/>
                    <measurement group_id="O2" value="42.1" spread="9.5"/>
                    <measurement group_id="O3" value="40.0" spread="8.2"/>
                    <measurement group_id="O4" value="43.7" spread="9.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PROMIS Pain Interference Short Form v1.0 8a T Score</title>
        <description>Higher scores for pain interference represents worse outcome (more pain interference) T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.&#xD;
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.</description>
        <time_frame>12 weeks</time_frame>
        <population>No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Nortriptyline</title>
            <description>Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.&#xD;
Nortriptyline</description>
          </group>
          <group group_id="O2">
            <title>Duloxetine</title>
            <description>Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.&#xD;
Duloxetine</description>
          </group>
          <group group_id="O3">
            <title>Pregabalin</title>
            <description>Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.&#xD;
Pregabalin</description>
          </group>
          <group group_id="O4">
            <title>Mexiletine</title>
            <description>Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.&#xD;
Mexiletine</description>
          </group>
        </group_list>
        <measure>
          <title>PROMIS Pain Interference Short Form v1.0 8a T Score</title>
          <description>Higher scores for pain interference represents worse outcome (more pain interference) T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.&#xD;
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.</description>
          <population>No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.</population>
          <units>T-Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="83"/>
                <count group_id="O2" value="79"/>
                <count group_id="O3" value="42"/>
                <count group_id="O4" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="56.4" spread="8.4"/>
                    <measurement group_id="O2" value="56.5" spread="8.3"/>
                    <measurement group_id="O3" value="60.0" spread="7.5"/>
                    <measurement group_id="O4" value="54.5" spread="8.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PROMIS Fatigue Short Form v1.0 8a</title>
        <description>Higher scores for fatigue represents worse outcome (more fatigue). T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.&#xD;
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.</description>
        <time_frame>12 Weeks</time_frame>
        <population>No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Nortriptyline</title>
            <description>Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.&#xD;
Nortriptyline</description>
          </group>
          <group group_id="O2">
            <title>Duloxetine</title>
            <description>Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.&#xD;
Duloxetine</description>
          </group>
          <group group_id="O3">
            <title>Pregabalin</title>
            <description>Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.&#xD;
Pregabalin</description>
          </group>
          <group group_id="O4">
            <title>Mexiletine</title>
            <description>Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.&#xD;
Mexiletine</description>
          </group>
        </group_list>
        <measure>
          <title>PROMIS Fatigue Short Form v1.0 8a</title>
          <description>Higher scores for fatigue represents worse outcome (more fatigue). T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.&#xD;
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.</description>
          <population>No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.</population>
          <units>T-Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="83"/>
                <count group_id="O2" value="79"/>
                <count group_id="O3" value="42"/>
                <count group_id="O4" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53.6" spread="9.5"/>
                    <measurement group_id="O2" value="55.4" spread="10.2"/>
                    <measurement group_id="O3" value="56.7" spread="10.6"/>
                    <measurement group_id="O4" value="51.6" spread="10.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PROMIS Sleep Disturbance Short Form v1.0 8a</title>
        <description>Higher scores for sleep disturbance represents worse outcome (more sleep disturbance).&#xD;
T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.&#xD;
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.&#xD;
Higher scores equals more of the concept being measured</description>
        <time_frame>12 weeks</time_frame>
        <population>No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Nortriptyline</title>
            <description>Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.&#xD;
Nortriptyline</description>
          </group>
          <group group_id="O2">
            <title>Duloxetine</title>
            <description>Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.&#xD;
Duloxetine</description>
          </group>
          <group group_id="O3">
            <title>Pregabalin</title>
            <description>Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.&#xD;
Pregabalin</description>
          </group>
          <group group_id="O4">
            <title>Mexiletine</title>
            <description>Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.&#xD;
Mexiletine</description>
          </group>
        </group_list>
        <measure>
          <title>PROMIS Sleep Disturbance Short Form v1.0 8a</title>
          <description>Higher scores for sleep disturbance represents worse outcome (more sleep disturbance).&#xD;
T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.&#xD;
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.&#xD;
Higher scores equals more of the concept being measured</description>
          <population>No secondary data were collected for participants who 'Quit' taking the study medication prior to study completion. Thus, only participants that were deemed efficacious and non-quit, or non-efficacious and non-quit at the primary outcome were collected and analyzed for the secondary outcome measure.</population>
          <units>T-Score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="83"/>
                <count group_id="O2" value="79"/>
                <count group_id="O3" value="42"/>
                <count group_id="O4" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="58.9" spread="2.5"/>
                    <measurement group_id="O2" value="58.9" spread="2.6"/>
                    <measurement group_id="O3" value="58.3" spread="2.3"/>
                    <measurement group_id="O4" value="59.1" spread="2.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>12 Weeks Post Randomization</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Nortriptyline</title>
          <description>Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.&#xD;
Nortriptyline</description>
        </group>
        <group group_id="E2">
          <title>Duloxetine</title>
          <description>Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.&#xD;
Duloxetine</description>
        </group>
        <group group_id="E3">
          <title>Pregabalin</title>
          <description>Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.&#xD;
Pregabalin</description>
        </group>
        <group group_id="E4">
          <title>Mexiletine</title>
          <description>Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.&#xD;
Mexiletine</description>
        </group>
      </group_list>
      <serious_events>
        <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="134"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="69"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="134"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="69"/>
              </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="75" subjects_at_risk="134"/>
                <counts group_id="E2" subjects_affected="59" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="29" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="27" subjects_at_risk="69"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="134"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="69"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating/Constipation</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="134"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="69"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="134"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="69"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dry Mouth</sub_title>
                <counts group_id="E1" subjects_affected="27" subjects_at_risk="134"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="69"/>
              </event>
              <event>
                <sub_title>Drowsiness/Sleepiness</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="134"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="69"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="134"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="69"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="134"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="69"/>
              </event>
              <event>
                <sub_title>Other</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="134"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="126"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="73"/>
                <counts group_id="E4" subjects_affected="9" subjects_at_risk="69"/>
              </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>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. Richard Barohn</name_or_title>
      <organization>University of Kansas Medical Center</organization>
      <phone>9139459943</phone>
      <email>rbarohn@kumc.edu</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/NCT02260388
org study id: STUDY00001500
secondary id: PCORI-1306-02496
nct id: NCT02260388
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this large comparative effectiveness study led by Richard J. Barohn, MD, of
      the University of Kansas Medical Center, is to learn about the safety and effectiveness of
      nortriptyline, duloxetine, pregabalin and mexiletine in treating cryptogenic sensory
      polyneuropathy (CSPN).
The goal of this research project is to find the best drug for the treatment of pain in
      patients with CSPN. While the pharmaceutical industry has focused attention on drugs for
      treating diabetic sensory neuropathy (DSPN), and two drugs are now FDA approved, there have
      not been any prospective trials in CSPN. And, because there are no studies with CSPN
      patients, insurance carriers often reject authorizing prescriptions for some drugs for
      patients with CSPN.

      There are four drugs that will be tested in this study: nortriptyline, duloxetine, pregabalin
      and mexiletine. These drugs are not approved by the FDA for the treatment of CSPN and are
      considered "investigational" in this study.

      There are two periods in this study: Screening/Baseline and Study Drug. During the
      Screening/Baseline period the researchers will determine eligibility for potential subjects.
      During the second period, eligible patients who consented to participate will take the study
      drug. Participants will be randomized to receive one of the four drugs in this study.
      Participants will know which drug they are taking. Participants will not be allowed to switch
      groups and receive a different drug during the study.

      This study uses an adaptive study design. This means the study can enroll less participants
      and provide better conclusions. The study design allows the researchers the ability to make
      changes to the approach of the study or to stop the study early if there are strong results.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Co-Primary Measures: Percent of Patients With at Least a 50% Decrease in Likert Pain Scale From Baseline to Week 12 Follow Up and Percent of Patients That Quit
time frame: 12 weeks
description: The final outcome of the study is a combination of two endpoints, efficacy and quit or treatment discontinuation rates. The first endpoint was a patient responder-defined measure of efficacy. A patient was deemed efficacious if a 50% or more reduction was observed in the Likert pain-scale from the baseline visit to the 12 week visit (i.e. 6 at baseline to 3 or less at week 12). The second endpoint was the observed percentage of patients who discontinued treatment prior to the last follow up visit for any reason or were lost to follow up. The utility function, which combines efficacy and quit rates, was used to drive the adaptive randomization, stopping criteria, and final analysis conclusions.
measure: SF12 Health Composite Scores
time frame: 12 weeks
description: SF-12v2® Health Survey Standard The Optum™ SF-12v2® Health Survey is a shorter version of the SF-36v2® Health Survey that uses just 12 questions to measure functional health and well-being from the patient's point of view.
Survey provides psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores.
Scores are calibrated so that 50 is the average score or norm, standard deviation = 10.
Higher scores indicate better health for both mental and physical component summary scores.
measure: PROMIS Pain Interference Short Form v1.0 8a T Score
time frame: 12 weeks
description: Higher scores for pain interference represents worse outcome (more pain interference) T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.
measure: PROMIS Fatigue Short Form v1.0 8a
time frame: 12 Weeks
description: Higher scores for fatigue represents worse outcome (more fatigue). T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.
measure: PROMIS Sleep Disturbance Short Form v1.0 8a
time frame: 12 weeks
description: Higher scores for sleep disturbance represents worse outcome (more sleep disturbance).
T-score metric: 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.
On the T-score metric: A score of 40 is one SD lower than the mean of the reference population; A score of 60 is one SD higher than the mean of the reference population.
Higher scores equals more of the concept being measured
arm group label: Nortriptyline
arm group type: Experimental
description: Nortriptyline - 25 mg daily for 1 week at bedtime, then 50 mg daily at bedtime for 1 week, then 75 mg daily at bedtime for the remainder of the study.
arm group label: Duloxetine
arm group type: Experimental
description: Duloxetine - 20 mg daily for 1 week, then 40 mg daily for 1 week, then 60 mg daily for the remainder of the study.
arm group label: Pregabalin
arm group type: Experimental
description: Pregabalin - 100 mg at bedtime for 1 week, then 100 mg 2 times per day for 1 week, then 100 mg 3 times per day for the remainder of the study.
arm group label: Mexiletine
arm group type: Experimental
description: Mexiletine - 200 mg at bedtime for 1 week, then 200 mg 2 times per day for 1 week, then 200 mg 3 times per day for the remainder of the study.
intervention type: Drug
intervention name: Nortriptyline
arm group label: Nortriptyline
intervention type: Drug
intervention name: Duloxetine
arm group label: Duloxetine
intervention type: Drug
intervention name: Pregabalin
arm group label: Pregabalin
intervention type: Drug
intervention name: Mexiletine
arm group label: Mexiletine
criteria: 
gender: All
minimum age: 30 Years
maximum age: N/A
healthy volunteers: No
last name: Richard Barohn, MD
role: Principal Investigator
affiliation: University of Kansas Medical Center
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country: Canada
country: United States
responsible party type: Sponsor
mesh term: Polyneuropathies
mesh term: Mexiletine
mesh term: Pregabalin
mesh term: Duloxetine Hydrochloride
mesh term: Nortriptyline
provided document: 
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