<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/NCT02981082</url>
  </required_header>
  <id_info>
    <org_study_id>PRO16070614</org_study_id>
    <nct_id>NCT02981082</nct_id>
  </id_info>
  <brief_title>Dimethyl Fumarate (DMF) in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension</brief_title>
  <official_title>A Double-blinded, Placebo-controlled Pilot Study of Dimethyl Fumarate (DMF) in Pulmonary Arterial Hypertension (PAH) Associated With Systemic Sclerosis (SSc-PAH): The Effect of DMF on Clinical Disease and Biomarkers of Oxidative Stress.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Robert Lafyatis</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Biogen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      A double-blinded, placebo-controlled study of Dimethyl fumarate (DMF) in 34 Systemic&#xD;
      Sclerosis-Pulmonary Hypertension (SSc-PAH) patients. The study will determine safety and the&#xD;
      primary outcome variability for DMF in treating SSc-PAH; the primary outcome of clinical&#xD;
      efficacy in this pilot trial will be improvement in 6-minute walk distance (6MWD).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A double-blinded, placebo-controlled study of Dimethyl fumarate (DMF) in 34 Systemic&#xD;
      Sclerosis-Pulmonary Hypertension (SSc-PAH) patients. The study medication will be added to&#xD;
      stable background PAH medication(s). Subjects will be dosed for 24 weeks, will undergo&#xD;
      examination every 8 weeks, and will be finally evaluated 12 weeks after completion of&#xD;
      treatment. Dosage will begin at once daily oral doses of 120mg for the first 7 days and&#xD;
      follow the up-titration schedule to a maintenance dose of 240mg twice a day (or highest&#xD;
      tolerated dose of a minimum of 120mg twice a day by the start of Week 8) for the remainder of&#xD;
      the study. Participation will be for a total of 40 weeks, including a 4-week screening&#xD;
      period, 24 weeks of drug, and a safety follow-up 12 weeks after the last dose. The study will&#xD;
      determine the safety and the primary outcome variability for DMF in treating SSc-PAH; the&#xD;
      primary outcome of clinical efficacy in this pilot trial will be improvement in 6-minute walk&#xD;
      distance (6MWD).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Low recruitment&#xD;
  </why_stopped>
  <start_date>December 2016</start_date>
  <completion_date type="Actual">February 10, 2020</completion_date>
  <primary_completion_date type="Actual">February 10, 2020</primary_completion_date>
  <phase>Phase 1</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>6 Minute Walk Distance (6MWD)</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The primary outcome of clinical efficacy in this study is improvement in 6-minute walk distance (6MWD). Data depict the mean change (%) at end-of-study-treatment (Week 24) from baseline in both treatment groups, utilizing the Last Observation Carried Forward of withdrawn subjects.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical Worsening</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The change in time to clinical worsening in DMF compared to placebo treated patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Borg Dyspnea Index (BDI)</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The change in Borg Dyspnea Index (BDI) at 24 weeks from baseline in DMF compared to placebo treated patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum Markers of Oxidative Stress</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The change from baseline of serum markers of oxidative stress at 24 weeks, comparing DMF to placebo treated patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proteomic Biomarkers</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The change from baseline in proteomic biomarkers, including BNP, at 24 weeks, comparing DMF to placebo treated patients.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Systemic Sclerosis</condition>
  <condition>Pulmonary; Hypertension</condition>
  <arm_group>
    <arm_group_label>Dimethyl Fumarate (DMF)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Twice daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days followed by the maintenance dose of Dimethyl Fumarate (DMF) 240mg twice a day. Subjects will be dosed for 24 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Twice daily oral doses of placebo for 12 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dimethyl Fumarate (DMF)</intervention_name>
    <description>Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.</description>
    <arm_group_label>Dimethyl Fumarate (DMF)</arm_group_label>
    <other_name>Tecfidera</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed inform consent prior to any study-mandated procedures&#xD;
&#xD;
          2. Adult patients 18-80 years of age&#xD;
&#xD;
          3. World Health Organization Group 1 PAH associated with scleroderma (SSc-PAH)&#xD;
&#xD;
          4. WHO functional Class II-III&#xD;
&#xD;
          5. 6MWD 150 to 450 meters&#xD;
&#xD;
          6. Right heart catheterization demonstrating mPAP≥ 25 mmHg and PCWP or left ventricular&#xD;
             end diastolic pressure ≤15mm Hg and pulmonary vascular resistance ≥240 dynes/cm-5 (3&#xD;
             Wood units) within 12 weeks prior to study entry.&#xD;
&#xD;
          7. ACR defined systemic sclerosis&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pulmonary hypertension associated with&#xD;
&#xD;
               -  PAH of any etiology other than scleroderma&#xD;
&#xD;
               -  PH of any etiology other than WHO Group I PAH&#xD;
&#xD;
               -  Pulmonary venous hypertension defined as PCWP or LVEDP &gt;15 mHg&#xD;
&#xD;
               -  Untreated sleep apnea with AHI &gt;20 or SaO2 Nadir &lt;87%&#xD;
&#xD;
               -  Chronic thromboembolic disease&#xD;
&#xD;
               -  Sarcoidosis&#xD;
&#xD;
          2. Participation in a clinical investigational study within the previous 30 days&#xD;
&#xD;
          3. Moderate to severe hepatic impairment (e.g., Child-Pugh Class B or C)&#xD;
&#xD;
          4. Renal failure defined as:&#xD;
&#xD;
               -  estimated creatinine clearance &lt;30 m/min&#xD;
&#xD;
               -  serum creatinine&gt;2.5 mg/dl&#xD;
&#xD;
          5. Serum aspartate aminotransferase (AST) and or alanine aminotransferase (ALT) &gt; 1.5&#xD;
             times the upper limit of normal&#xD;
&#xD;
          6. Systolic blood pressure &lt; 90mmHg&#xD;
&#xD;
          7. Recently started (&lt; 8 weeks prior to randomization) or planned cardiopulmonary&#xD;
             rehabilitation program based on exercise&#xD;
&#xD;
          8. Pregnant or lactating women&#xD;
&#xD;
          9. Need for HAART therapy&#xD;
&#xD;
         10. Planned treatment or treatment with another investigational drug within 1 month prior&#xD;
             to start&#xD;
&#xD;
         11. Moderate to severe interstitial lung disease, defined by FVC &lt; 80% or evidence on HRCT&#xD;
             of fibrosis or ground glass changes involving more than 30% of lung parenchyma&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Robert A Lafyatis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Jewish</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80206</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>John Hopkins</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boston University</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02118</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>November 30, 2016</study_first_submitted>
  <study_first_submitted_qc>November 30, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 2, 2016</study_first_posted>
  <results_first_submitted>October 26, 2021</results_first_submitted>
  <results_first_submitted_qc>March 15, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">March 17, 2022</results_first_posted>
  <last_update_submitted>March 15, 2022</last_update_submitted>
  <last_update_submitted_qc>March 15, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 17, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Robert Lafyatis</investigator_full_name>
    <investigator_title>Professor of Medicine and the Thomas Medsger Professor in Arthritis Research</investigator_title>
  </responsible_party>
  <keyword>Systemic Sclerosis, Scleroderma, PAH, Pulmonary Hypertension</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Arterial Hypertension</mesh_term>
    <mesh_term>Hypertension, Pulmonary</mesh_term>
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Scleroderma, Systemic</mesh_term>
    <mesh_term>Scleroderma, Diffuse</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dimethyl Fumarate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <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>May 14, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/82/NCT02981082/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <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>May 20, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/82/NCT02981082/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Dimethyl Fumarate (DMF)</title>
          <description>Once daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days, following a titration schedule reaching a minimum of 120mg DMF twice daily, maximum 240mg twice daily, by the start of week 8. Subjects will be dosed for 24 weeks.&#xD;
Dimethyl Fumarate (DMF): Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Twice daily oral doses of placebo for 12 weeks.&#xD;
Placebo Oral Tablet: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Met stopping rule of low absolute lymphocyte count (&lt;0.5L) at two visits</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Dimethyl Fumarate (DMF)</title>
          <description>Once daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days, following a titration schedule reaching a minimum of 120mg DMF twice daily, maximum 240mg twice daily, by the start of week 8. Subjects will be dosed for 24 weeks.&#xD;
Dimethyl Fumarate (DMF): Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Twice daily oral doses of placebo for 12 weeks.&#xD;
Placebo Oral Tablet: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)</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="4"/>
            <count group_id="B2" value="2"/>
            <count group_id="B3" value="6"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="66.4" lower_limit="45" upper_limit="71.7"/>
                    <measurement group_id="B2" value="72.5" lower_limit="70.6" upper_limit="74.3"/>
                    <measurement group_id="B3" value="69" lower_limit="45" upper_limit="74.3"/>
                  </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="4"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</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>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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</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>
                  <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="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="5"/>
                  </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>6-minute walk distance (6MWD)</title>
          <units>Mean 6MWD (meters)</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="305.5" lower_limit="183" upper_limit="400"/>
                    <measurement group_id="B2" value="243.5" lower_limit="183" upper_limit="304"/>
                    <measurement group_id="B3" value="284.83" lower_limit="183" upper_limit="400"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>6 Minute Walk Distance (6MWD)</title>
        <description>The primary outcome of clinical efficacy in this study is improvement in 6-minute walk distance (6MWD). Data depict the mean change (%) at end-of-study-treatment (Week 24) from baseline in both treatment groups, utilizing the Last Observation Carried Forward of withdrawn subjects.</description>
        <time_frame>Baseline to Week 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dimethyl Fumarate (DMF)</title>
            <description>Once daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days, following a titration schedule reaching a minimum of 120mg DMF twice daily, maximum 240mg twice daily, by the start of week 8. Subjects will be dosed for 24 weeks.&#xD;
Dimethyl Fumarate (DMF): Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Twice daily oral doses of placebo for 12 weeks.&#xD;
Placebo Oral Tablet: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)</description>
          </group>
        </group_list>
        <measure>
          <title>6 Minute Walk Distance (6MWD)</title>
          <description>The primary outcome of clinical efficacy in this study is improvement in 6-minute walk distance (6MWD). Data depict the mean change (%) at end-of-study-treatment (Week 24) from baseline in both treatment groups, utilizing the Last Observation Carried Forward of withdrawn subjects.</description>
          <units>percent change</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-7.07" lower_limit="-24.69" upper_limit="8.20"/>
                    <measurement group_id="O2" value="-14.97" lower_limit="-29.93" upper_limit="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Worsening</title>
        <description>The change in time to clinical worsening in DMF compared to placebo treated patients.</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Insufficient data collection due to low recruitment and early termination of study.</population>
        <group_list>
          <group group_id="O1">
            <title>Dimethyl Fumarate (DMF)</title>
            <description>Once daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days, following a titration schedule reaching a minimum of 120mg DMF twice daily, maximum 240mg twice daily, by the start of week 8. Subjects will be dosed for 24 weeks.&#xD;
Dimethyl Fumarate (DMF): Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Twice daily oral doses of placebo for 12 weeks.&#xD;
Placebo Oral Tablet: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Worsening</title>
          <description>The change in time to clinical worsening in DMF compared to placebo treated patients.</description>
          <population>Insufficient data collection due to low recruitment and early termination of study.</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>Borg Dyspnea Index (BDI)</title>
        <description>The change in Borg Dyspnea Index (BDI) at 24 weeks from baseline in DMF compared to placebo treated patients</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Insufficient data collection due to low recruitment and early termination of study.</population>
        <group_list>
          <group group_id="O1">
            <title>Dimethyl Fumarate (DMF)</title>
            <description>Once daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days, following a titration schedule reaching a minimum of 120mg DMF twice daily, maximum 240mg twice daily, by the start of week 8. Subjects will be dosed for 24 weeks.&#xD;
Dimethyl Fumarate (DMF): Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Twice daily oral doses of placebo for 12 weeks.&#xD;
Placebo Oral Tablet: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)</description>
          </group>
        </group_list>
        <measure>
          <title>Borg Dyspnea Index (BDI)</title>
          <description>The change in Borg Dyspnea Index (BDI) at 24 weeks from baseline in DMF compared to placebo treated patients</description>
          <population>Insufficient data collection due to low recruitment and early termination of study.</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>Serum Markers of Oxidative Stress</title>
        <description>The change from baseline of serum markers of oxidative stress at 24 weeks, comparing DMF to placebo treated patients.</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Insufficient data collection due to low recruitment and early termination of study.</population>
        <group_list>
          <group group_id="O1">
            <title>Dimethyl Fumarate (DMF)</title>
            <description>Once daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days, following a titration schedule reaching a minimum of 120mg DMF twice daily, maximum 240mg twice daily, by the start of week 8. Subjects will be dosed for 24 weeks.&#xD;
Dimethyl Fumarate (DMF): Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Twice daily oral doses of placebo for 12 weeks.&#xD;
Placebo Oral Tablet: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)</description>
          </group>
        </group_list>
        <measure>
          <title>Serum Markers of Oxidative Stress</title>
          <description>The change from baseline of serum markers of oxidative stress at 24 weeks, comparing DMF to placebo treated patients.</description>
          <population>Insufficient data collection due to low recruitment and early termination of study.</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>Proteomic Biomarkers</title>
        <description>The change from baseline in proteomic biomarkers, including BNP, at 24 weeks, comparing DMF to placebo treated patients.</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Insufficient data collection due to low recruitment and early termination of study.</population>
        <group_list>
          <group group_id="O1">
            <title>Dimethyl Fumarate (DMF)</title>
            <description>Once daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days, following a titration schedule reaching a minimum of 120mg DMF twice daily, maximum 240mg twice daily, by the start of week 8. Subjects will be dosed for 24 weeks.&#xD;
Dimethyl Fumarate (DMF): Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Twice daily oral doses of placebo for 12 weeks.&#xD;
Placebo Oral Tablet: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)</description>
          </group>
        </group_list>
        <measure>
          <title>Proteomic Biomarkers</title>
          <description>The change from baseline in proteomic biomarkers, including BNP, at 24 weeks, comparing DMF to placebo treated patients.</description>
          <population>Insufficient data collection due to low recruitment and early termination of study.</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>36 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Dimethyl Fumarate (DMF)</title>
          <description>Once daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days, following a titration schedule reaching a minimum of 120mg DMF twice daily, maximum 240mg twice daily, by the start of week 8. Subjects will be dosed for 24 weeks.&#xD;
Dimethyl Fumarate (DMF): Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Twice daily oral doses of placebo for 12 weeks.&#xD;
Placebo Oral Tablet: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)</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="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Worsening of heart failure and shortness of breath secondary to anemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="2"/>
              </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="4" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Small bowel bacteria overgrowth</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Shingles</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Pneumonina</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Decreased CD4 lymphocytes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>High cholesterol</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Joint effusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Ankle swelling at night</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Right rotator cuff tendinopathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hemoptysis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </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>
    <limitations_and_caveats>Early study termination due to low recruitment; not enough participants for statistically reliable analyses.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Robert Lafyatis</name_or_title>
      <organization>University of Pittsburgh</organization>
      <phone>412-648-7040</phone>
      <email>lafyatis@pitt.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/NCT02981082
org study id: PRO16070614
nct id: NCT02981082
lead sponsor: 
collaborator: 
has dmc: Yes
A double-blinded, placebo-controlled study of Dimethyl fumarate (DMF) in 34 Systemic
      Sclerosis-Pulmonary Hypertension (SSc-PAH) patients. The study will determine safety and the
      primary outcome variability for DMF in treating SSc-PAH; the primary outcome of clinical
      efficacy in this pilot trial will be improvement in 6-minute walk distance (6MWD).
A double-blinded, placebo-controlled study of Dimethyl fumarate (DMF) in 34 Systemic
      Sclerosis-Pulmonary Hypertension (SSc-PAH) patients. The study medication will be added to
      stable background PAH medication(s). Subjects will be dosed for 24 weeks, will undergo
      examination every 8 weeks, and will be finally evaluated 12 weeks after completion of
      treatment. Dosage will begin at once daily oral doses of 120mg for the first 7 days and
      follow the up-titration schedule to a maintenance dose of 240mg twice a day (or highest
      tolerated dose of a minimum of 120mg twice a day by the start of Week 8) for the remainder of
      the study. Participation will be for a total of 40 weeks, including a 4-week screening
      period, 24 weeks of drug, and a safety follow-up 12 weeks after the last dose. The study will
      determine the safety and the primary outcome variability for DMF in treating SSc-PAH; the
      primary outcome of clinical efficacy in this pilot trial will be improvement in 6-minute walk
      distance (6MWD).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: 6 Minute Walk Distance (6MWD)
time frame: Baseline to Week 24
description: The primary outcome of clinical efficacy in this study is improvement in 6-minute walk distance (6MWD). Data depict the mean change (%) at end-of-study-treatment (Week 24) from baseline in both treatment groups, utilizing the Last Observation Carried Forward of withdrawn subjects.
measure: Clinical Worsening
time frame: Baseline to Week 24
description: The change in time to clinical worsening in DMF compared to placebo treated patients.
measure: Borg Dyspnea Index (BDI)
time frame: Baseline to Week 24
description: The change in Borg Dyspnea Index (BDI) at 24 weeks from baseline in DMF compared to placebo treated patients
measure: Serum Markers of Oxidative Stress
time frame: Baseline to Week 24
description: The change from baseline of serum markers of oxidative stress at 24 weeks, comparing DMF to placebo treated patients.
measure: Proteomic Biomarkers
time frame: Baseline to Week 24
description: The change from baseline in proteomic biomarkers, including BNP, at 24 weeks, comparing DMF to placebo treated patients.
arm group label: Dimethyl Fumarate (DMF)
arm group type: Active Comparator
description: Twice daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days followed by the maintenance dose of Dimethyl Fumarate (DMF) 240mg twice a day. Subjects will be dosed for 24 weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: Twice daily oral doses of placebo for 12 weeks
intervention type: Drug
intervention name: Dimethyl Fumarate (DMF)
description: Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.
arm group label: Dimethyl Fumarate (DMF)
other name: Tecfidera
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Robert A Lafyatis, MD
role: Principal Investigator
affiliation: University of Pittsburgh
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Robert Lafyatis
investigator title: Professor of Medicine and the Thomas Medsger Professor in Arthritis Research
mesh term: Pulmonary Arterial Hypertension
mesh term: Hypertension, Pulmonary
mesh term: Hypertension
mesh term: Scleroderma, Systemic
mesh term: Scleroderma, Diffuse
mesh term: Sclerosis
mesh term: Dimethyl Fumarate
sharing ipd: Undecided
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Early study termination due to low recruitment; not enough participants for statistically reliable analyses.
point of contact: 