<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/NCT04491604</url>
  </required_header>
  <id_info>
    <org_study_id>B-VEC-03</org_study_id>
    <nct_id>NCT04491604</nct_id>
  </id_info>
  <brief_title>Ph 3 Efficacy and Safety of B-VEC for the Treatment of DEB</brief_title>
  <acronym>GEM-3</acronym>
  <official_title>A Phase III Efficacy and Safety Study of Beremagene Geperpavec (B-VEC, Previously &quot;KB103&quot;) for the Treatment of Dystrophic Epidermolysis Bullosa (DEB)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Krystal Biotech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Krystal Biotech, Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To determine whether administration of topical B-VEC improves wound healing as compared to&#xD;
      placebo, and to evaluate durability, repeat dosing (Primary Endpoint) and further obtain&#xD;
      safety and tolerability data.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Thirty-one (31) participants with DEB, aged 6 months or older at time of consent were&#xD;
      enrolled for this Phase III study. The trial duration for each subject was about 6 months,&#xD;
      with administration occurring once weekly. A Safety Follow-up Visit occurring 30 days from&#xD;
      the date of final treatment with the Investigational Product also occurred. Each subject&#xD;
      provided one pair of primary target wounds, with one wound from each pair randomized to be&#xD;
      treated with B-VEC and the other wound with placebo. In addition to the primary target wound&#xD;
      pair(s), additional wounds (secondary wounds) were selected to be treated with B-VEC.&#xD;
      Throughout the study, participants complete questionnaires, had images captured of their&#xD;
      study wounds, underwent physical exams, had vital signs and safety labs monitored.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 17, 2020</start_date>
  <completion_date type="Actual">January 14, 2022</completion_date>
  <primary_completion_date type="Actual">October 29, 2021</primary_completion_date>
  <phase>Phase 3</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>
    <intervention_model_description>An intra-subject parallel study. Primary wounds are randomized within each subject, such that one wound receives B-VEC and the other wound receives placebo. Secondary wounds are selected to receive B-VEC only.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26</measure>
    <time_frame>26 weeks post-baseline</time_frame>
    <description>The primary wound was defined as a responder wound that met either of the following conditions:&#xD;
Complete wound healing on Week 22 and Week 24, or&#xD;
Complete wound healing on Week 24 and Week 26.&#xD;
For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12</measure>
    <time_frame>12 weeks post-baseline</time_frame>
    <description>The primary wound was defined as a responder wound that met either of the following conditions:&#xD;
Complete wound healing on Week 8 and Week 10, or&#xD;
Complete wound healing on Week 10 and Week 12.&#xD;
For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26.</measure>
    <time_frame>26 weeks post-baseline</time_frame>
    <description>Changes from baseline at Weeks 22, 24, and 26 in primary wound pain severity (visual analog scale (VAS)) for ages 6 and above subjects. The Visual Analog Scale scores from 0 (no pain) to 10 (the worst possible pain). Negative values in changes from baseline mean improvement in pain severity.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">31</enrollment>
  <condition>Dystrophic Epidermolysis Bullosa</condition>
  <condition>Recessive Dystrophic Epidermolysis Bullosa</condition>
  <condition>Dominant Dystrophic Epidermolysis Bullosa</condition>
  <arm_group>
    <arm_group_label>B-VEC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Matching masked inactive topical gel</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Topical Beremagene Geperpavec</intervention_name>
    <description>Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein</description>
    <arm_group_label>B-VEC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Matching masked inactive topical gel</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The subject or legally appointed and authorized representative must have read,&#xD;
             understood and signed an Institutional Review Board/Ethics Committee (IRB/EC) approved&#xD;
             Informed Consent or Assent Form and must be able to and willing to follow study&#xD;
             procedures and instructions.&#xD;
&#xD;
          2. Age ≥ 6 months and older at the time of Informed Consent.&#xD;
&#xD;
          3. Clinical diagnosis of the Dystrophic Epidermolysis Bullosa.&#xD;
&#xD;
          4. Confirmation of DEB diagnosis (either DDEB or RDEB) by genetic testing including&#xD;
             COL7A1.&#xD;
&#xD;
          5. Two (2) cutaneous wounds meeting the following criteria:&#xD;
&#xD;
               1. Location: similar in size, located in similar anatomical regions, and have&#xD;
                  similar appearance&#xD;
&#xD;
               2. Appearance: clean with adequate granulation tissue, excellent vascularization,&#xD;
                  and do not appear infected.&#xD;
&#xD;
          6. Subjects and caregivers who, in the opinion of the Investigator, are able to&#xD;
             understand the study, co-operate with the study procedures and are willing to return&#xD;
             to the clinic for all the required follow-up visits.&#xD;
&#xD;
          7. Male or Female of childbearing potential must use a reliable birth control method&#xD;
             throughout the duration of the study and for three (3) months post last dose of B-VEC.&#xD;
&#xD;
          8. Negative pregnancy test at Visit 1 (Week 1), if applicable.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Medical instability limiting ability to travel to the Investigative Center.&#xD;
&#xD;
          2. Diseases or conditions that could interfere with the assessment of safety and efficacy&#xD;
             of the study treatment and compliance of the subject with study visits/procedures, as&#xD;
             determined by the Investigator.&#xD;
&#xD;
          3. Current evidence or a history of squamous cell carcinoma in the area that will undergo&#xD;
             treatment.&#xD;
&#xD;
          4. Subjects actively receiving chemotherapy or immunotherapy at Visit 1 (Week 1).&#xD;
&#xD;
          5. Active drug or alcohol addiction as determined by the Investigator.&#xD;
&#xD;
          6. Hypersensitivity to local anesthesia (lidocaine/prilocaine cream).&#xD;
&#xD;
          7. Participation in an interventional clinical trial within the past three (3) months&#xD;
             (not including BVEC administration).&#xD;
&#xD;
          8. Receipt of a skin graft in the past three (3) months.&#xD;
&#xD;
          9. Pregnant or nursing women.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Mission Dermatology Center</name>
      <address>
        <city>Rancho Santa Margarita</city>
        <state>California</state>
        <zip>92688</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pediatric Skin Research, LLC</name>
      <address>
        <city>Coral Gables</city>
        <state>Florida</state>
        <zip>33146</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.krystalbio.com/patients-and-families/patient-advocacy/</url>
    <description>Krystal Biotech, Inc. Patient and Family Advocacy Site</description>
  </link>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>July 22, 2020</study_first_submitted>
  <study_first_submitted_qc>July 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 29, 2020</study_first_posted>
  <results_first_submitted>December 8, 2022</results_first_submitted>
  <results_first_submitted_qc>January 25, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">February 17, 2023</results_first_posted>
  <last_update_submitted>January 25, 2023</last_update_submitted>
  <last_update_submitted_qc>January 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>DEB</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epidermolysis Bullosa</mesh_term>
    <mesh_term>Epidermolysis Bullosa Dystrophica</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 21, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/04/NCT04491604/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 25, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/04/NCT04491604/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>All Participants (&quot;Topical Beremagene Geperpavec (B-VEC)&quot;, and &quot;Placebo&quot;)</title>
          <description>Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="31">Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo. The total primary wounds selected were 62 (=2x31), in which 31 each received B-VEC and Placebo, respectively. Additional wounds (&quot;Secondary Wounds&quot;) were selected using the remaining weekly B-VEC dose. The number of Secondary Wounds treated depended on wound areas. The Secondary Wounds related data were not analyzed per protocol.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>B-VEC</title>
              <participants_list>
                <participants group_id="P1" count="31"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Placebo</title>
              <participants_list>
                <participants group_id="P1" count="31"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="28"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Safety Population</population>
      <group_list>
        <group group_id="B1">
          <title>All Participants (&quot;Topical Beremagene Geperpavec (B-VEC)&quot;, and &quot;Placebo&quot;)</title>
          <description>Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="31"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17.2" spread="10.70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;= 12 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt; 12 and &lt;= 18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt; 18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </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="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </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="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>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="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Primary Wound Area(cm^2) B-VEC</title>
          <units>cm^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14.354" spread="12.6930"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Primary Wound Area(cm^2) Placebo</title>
          <units>cm^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15.565" spread="12.1315"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26</title>
        <description>The primary wound was defined as a responder wound that met either of the following conditions:&#xD;
Complete wound healing on Week 22 and Week 24, or&#xD;
Complete wound healing on Week 24 and Week 26.&#xD;
For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).</description>
        <time_frame>26 weeks post-baseline</time_frame>
        <population>The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not.</population>
        <group_list>
          <group group_id="O1">
            <title>B-VEC</title>
            <description>Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching masked inactive topical gel</description>
          </group>
        </group_list>
        <measure>
          <title>Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26</title>
          <description>The primary wound was defined as a responder wound that met either of the following conditions:&#xD;
Complete wound healing on Week 22 and Week 24, or&#xD;
Complete wound healing on Week 24 and Week 26.&#xD;
For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).</description>
          <population>The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not.</population>
          <units>number of wounds with complete healing</units>
          <param>Number</param>
          <units_analyzed>Wounds</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="31"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>Wounds</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="31"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.9"/>
                    <measurement group_id="O2" value="6.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis of interest was the absence of a treatment effect on wound healing and the alternative hypothesis is the presence of a treatment effect on wound healing. The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data. For subjects with missing primary wound healing data, a multiple imputation approach was used.</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data.</non_inferiority_desc>
            <p_value>0.00192</p_value>
            <method>McNemar</method>
            <method_desc>The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data. A multiple imputation approach was used for missing data.</method_desc>
            <param_type>responder rate difference</param_type>
            <param_value>45.8</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>23.6</ci_lower_limit>
            <ci_upper_limit>68.0</ci_upper_limit>
            <estimate_desc>The difference is the treatment/discordance difference in percentage of responders (primary wounds with complete healing), which is the same as the difference in the percentage of treatment responders and the percentage of placebo responders.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12</title>
        <description>The primary wound was defined as a responder wound that met either of the following conditions:&#xD;
Complete wound healing on Week 8 and Week 10, or&#xD;
Complete wound healing on Week 10 and Week 12.&#xD;
For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).</description>
        <time_frame>12 weeks post-baseline</time_frame>
        <population>The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not.</population>
        <group_list>
          <group group_id="O1">
            <title>B-VEC</title>
            <description>Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching masked inactive topical gel</description>
          </group>
        </group_list>
        <measure>
          <title>Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12</title>
          <description>The primary wound was defined as a responder wound that met either of the following conditions:&#xD;
Complete wound healing on Week 8 and Week 10, or&#xD;
Complete wound healing on Week 10 and Week 12.&#xD;
For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).</description>
          <population>The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not.</population>
          <units>number of wounds with complete healing</units>
          <param>Number</param>
          <units_analyzed>Wounds</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="31"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>Wounds</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="31"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.9"/>
                    <measurement group_id="O2" value="6.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis of interest was the absence of a treatment effect on wound healing and the alternative hypothesis is the presence of a treatment effect on wound healing. The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data. For subjects with missing primary wound healing data, a multiple imputation approach was used.</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data.</non_inferiority_desc>
            <p_value>0.00047</p_value>
            <p_value_desc>There is no multiplicity adjustment needed since the hypothesis testing are hierarchical.</p_value_desc>
            <method>McNemar</method>
            <method_desc>The Hypothesis was tested by exact McNemar's test on the paired primary wound healing data. A multiple imputation approach was used for missing data.</method_desc>
            <param_type>responder rate difference</param_type>
            <param_value>51.0</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>29.3</ci_lower_limit>
            <ci_upper_limit>72.6</ci_upper_limit>
            <estimate_desc>The difference is the treatment/discordance difference in percentage of responders (complete wound healing), which is the same as the difference in the percentage of treatment responders and the percentage of placebo responders.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26.</title>
        <description>Changes from baseline at Weeks 22, 24, and 26 in primary wound pain severity (visual analog scale (VAS)) for ages 6 and above subjects. The Visual Analog Scale scores from 0 (no pain) to 10 (the worst possible pain). Negative values in changes from baseline mean improvement in pain severity.</description>
        <time_frame>26 weeks post-baseline</time_frame>
        <population>The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not. For pain severity, only subjects ages 6 and above were evaluated (n=27). The analyses were based on observed data where missing data were not imputed, therefore the numbers of available data for analyses could be less than the total.</population>
        <group_list>
          <group group_id="O1">
            <title>B-VEC</title>
            <description>Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching masked inactive topical gel</description>
          </group>
        </group_list>
        <measure>
          <title>Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26.</title>
          <description>Changes from baseline at Weeks 22, 24, and 26 in primary wound pain severity (visual analog scale (VAS)) for ages 6 and above subjects. The Visual Analog Scale scores from 0 (no pain) to 10 (the worst possible pain). Negative values in changes from baseline mean improvement in pain severity.</description>
          <population>The intent-to-treat (ITT) population included subjects whose primary wounds were randomized regardless of whether they received randomized treatment or not. For pain severity, only subjects ages 6 and above were evaluated (n=27). The analyses were based on observed data where missing data were not imputed, therefore the numbers of available data for analyses could be less than the total.</population>
          <units>score on a scale of 0 to 10</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="27"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 22</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="24"/>
                    <count group_id="O2" value="24"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.88" spread="2.346"/>
                    <measurement group_id="O2" value="-0.71" spread="2.476"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 24</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="25"/>
                    <count group_id="O2" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.64" spread="2.325"/>
                    <measurement group_id="O2" value="-0.08" spread="2.548"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 26</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="24"/>
                    <count group_id="O2" value="24"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.63" spread="2.123"/>
                    <measurement group_id="O2" value="-0.38" spread="2.871"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>All Participants (&quot;Topical Beremagene Geperpavec (B-VEC)&quot;, and &quot;Placebo&quot;)</title>
          <description>Each subject provided one pair of primary target wounds, with one wound from each pair randomized to be treated with B-VEC and the other wound with placebo. Due to the 'split-person'/intrasubject design, each subject received both B-VEC and Placebo. Therefore, the safety assessments were reported at subject level, but not per intervention.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <description>severe anemia</description>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <description>Diarrhoea</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <description>cellulitis of the right leg</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood culture positive</sub_title>
                <description>Blood culture positive</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Squamous cell carcinoma</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="31"/>
              </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="2" subjects_affected="2" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="31"/>
              </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="4" subjects_affected="3" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="31"/>
              </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. Hubert Chen, MD, Senior Vice President of Clinical Development</name_or_title>
      <organization>Krystal Biotech</organization>
      <phone>(412) 586-5830</phone>
      <email>inquiries@krystalbio.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04491604
org study id: B-VEC-03
nct id: NCT04491604
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
To determine whether administration of topical B-VEC improves wound healing as compared to
      placebo, and to evaluate durability, repeat dosing (Primary Endpoint) and further obtain
      safety and tolerability data.
Thirty-one (31) participants with DEB, aged 6 months or older at time of consent were
      enrolled for this Phase III study. The trial duration for each subject was about 6 months,
      with administration occurring once weekly. A Safety Follow-up Visit occurring 30 days from
      the date of final treatment with the Investigational Product also occurred. Each subject
      provided one pair of primary target wounds, with one wound from each pair randomized to be
      treated with B-VEC and the other wound with placebo. In addition to the primary target wound
      pair(s), additional wounds (secondary wounds) were selected to be treated with B-VEC.
      Throughout the study, participants complete questionnaires, had images captured of their
      study wounds, underwent physical exams, had vital signs and safety labs monitored.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: An intra-subject parallel study. Primary wounds are randomized within each subject, such that one wound receives B-VEC and the other wound receives placebo. Secondary wounds are selected to receive B-VEC only.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 22 and 24 or Weeks 24 and 26
time frame: 26 weeks post-baseline
description: The primary wound was defined as a responder wound that met either of the following conditions:
Complete wound healing on Week 22 and Week 24, or
Complete wound healing on Week 24 and Week 26.
For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).
measure: Primary Wound With Complete Wound Healing (100% Wound Closure) on Weeks 8 and 10 or Weeks 10 and 12
time frame: 12 weeks post-baseline
description: The primary wound was defined as a responder wound that met either of the following conditions:
Complete wound healing on Week 8 and Week 10, or
Complete wound healing on Week 10 and Week 12.
For subjects with missing primary wound healing data, a multiple imputation approach (10 repliates) was used. The total numbers of primary wounds with complete healing for B-VEC and Placebo presented below were the average of those from the multiple imputation replicates, and therefore, they would not be whole numbers (integers).
measure: Primary Wound Pain Severity (Visual Analog Scale (VAS)) Change for Ages 6 and Above Subjects at Weeks 22, 24, and 26.
time frame: 26 weeks post-baseline
description: Changes from baseline at Weeks 22, 24, and 26 in primary wound pain severity (visual analog scale (VAS)) for ages 6 and above subjects. The Visual Analog Scale scores from 0 (no pain) to 10 (the worst possible pain). Negative values in changes from baseline mean improvement in pain severity.
arm group label: B-VEC
arm group type: Experimental
description: Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein
arm group label: Placebo
arm group type: Placebo Comparator
description: Matching masked inactive topical gel
intervention type: Biological
intervention name: Topical Beremagene Geperpavec
description: Topical gel of non-integrating, replication-incompetent HSV-1 expressing the human collagen VII protein
arm group label: B-VEC
intervention type: Other
intervention name: Placebo
description: Matching masked inactive topical gel
arm group label: Placebo
criteria: 
gender: All
minimum age: 6 Months
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
country: United States
url: https://www.krystalbio.com/patients-and-families/patient-advocacy/
description: Krystal Biotech, Inc. Patient and Family Advocacy Site
responsible party type: Sponsor
mesh term: Epidermolysis Bullosa
mesh term: Epidermolysis Bullosa Dystrophica
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 