<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/NCT03234374</url>
  </required_header>
  <id_info>
    <org_study_id>INN-CB-022</org_study_id>
    <nct_id>NCT03234374</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics, Relative Bioavailability and Safety of INL-001 Compared to Marcaine After Open Hernioplasty</brief_title>
  <official_title>A Randomized, Single Blind Study to Investigate the PK, Relative Bioavailability and Safety of INL-001 Bupivacaine HCl Collagen-Matrix Implant 300 mg Compared to Marcaine™ 0.25% (Bupivacaine HCl) 175 mg Infiltration After Open Hernioplasty</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Innocoll</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Medpace, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Innocoll</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a multicenter randomized, single-blind, controlled study. The primary objectives of&#xD;
      this study are to obtain the pharmacokinetic profile and the relative bioavailability of the&#xD;
      INL-001 matrix during and after open hernioplasty compared to Marcaine™ 0.25% infiltration.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multicenter randomized, single-blind, controlled study. Prior to surgery on Day 1,&#xD;
      48 subjects who continue to meet study entry criteria will be randomized just prior to&#xD;
      surgery in a 2:1 ratio to receive either 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix&#xD;
      implants (total bupivacaine HCl dose 300 mg) or Marcaine 0.25% (bupivacaine HCl) 175 mg&#xD;
      infiltration. Subjects will then undergo open hernioplasty according to standard procedure.&#xD;
&#xD;
      Subjects will remain in the clinic at least until after the 72 hour blood sample has been&#xD;
      collected for PK analysis on Day 4. Subjects discharged after the 72 hour blood draw will be&#xD;
      instructed to return to the clinic to complete the 96 hour PK blood draw on Day 5. Follow-up&#xD;
      safety assessments will include clinic visits on Day 7, Day 15 and Day 30.&#xD;
&#xD;
      Pharmacokinetic blood samples will be collected from subjects before surgery and at&#xD;
      predetermined time points up to 96 hours after administration of study drug. Safety&#xD;
      assessments will include frequent assessment of vital signs through 72 hours, continuous&#xD;
      electrocardiogram (ECG) monitoring for at least 24 hours, oxygen saturation levels, and&#xD;
      adverse events (AEs) reporting with particular emphasis on the signs and symptoms of CNS and&#xD;
      cardiovascular bupivacaine toxicity. The surgical wound will be assessed frequently for&#xD;
      adverse events associated with altered wound healing.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 2, 2017</start_date>
  <completion_date type="Actual">August 15, 2017</completion_date>
  <primary_completion_date type="Actual">August 15, 2017</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>This is a single-blind study in which the study subject is blinded to treatment group. All precautions will be taken to ensure that the blinding of the treatment group is maintained throughout the study period. Unblinding to the subject will not be permitted unless it is deemed necessary for appropriate treatment of a medical emergency.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Cmax</measure>
    <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours.</time_frame>
    <description>Maximum (peak) plasma concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tmax</measure>
    <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
    <description>Time to maximum (peak) plasma concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tlag</measure>
    <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
    <description>Lag-time</description>
  </primary_outcome>
  <primary_outcome>
    <measure>t½ Terminal Half Life</measure>
    <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
    <description>Terminal half-life</description>
  </primary_outcome>
  <primary_outcome>
    <measure>λz</measure>
    <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
    <description>Terminal phase rate constant</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC</measure>
    <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
    <description>Area under the plasma concentration-time curve from Time 0 to last time of last quantifiable plasma concentration (AUC0-last)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-∞</measure>
    <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
    <description>AUC from Time 0 to infinity</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC Extrapolated</measure>
    <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
    <description>AUC = area under the plasma concentration-time curve;</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">52</enrollment>
  <condition>Hernioplasty</condition>
  <arm_group>
    <arm_group_label>INL-001</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Marcaine 0.25% infiltration</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).</description>
  </arm_group>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>INL-001 (bupivacaine HCl collagen implant)</intervention_name>
    <description>3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
    <arm_group_label>INL-001</arm_group_label>
    <other_name>INL-001</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Marcaine 0.25% infiltration</intervention_name>
    <description>Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
    <arm_group_label>Marcaine 0.25% infiltration</arm_group_label>
    <other_name>Marcaine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        To be eligible for inclusion into the study, subjects must:&#xD;
&#xD;
          -  Be a man or woman ≥18 years of age.&#xD;
&#xD;
          -  Be eligible for unilateral inguinal hernioplasty with mesh (open laparotomy,&#xD;
             tension-free technique) performed according to standard surgical technique under&#xD;
             general anesthesia. Repair of multiple hernias through a single incision is permitted.&#xD;
             If female of childbearing potential, have a negative pregnancy test at screening and&#xD;
             before randomization on Day 1 AND be using an effective contraception method (ie,&#xD;
             abstinence, intrauterine device [IUD], hormonal [estrogen/progestin] contraceptives,&#xD;
             or barrier control) for at least one menstrual cycle prior to study enrollment and for&#xD;
             the duration of the study, OR be surgically sterile, OR be a postmenopausal female (no&#xD;
             menses for at least 1 year or hysterectomy).&#xD;
&#xD;
          -  Has the ability and willingness to comply with the study procedures.&#xD;
&#xD;
          -  Be willing to use only permitted medications throughout the study.&#xD;
&#xD;
          -  Be willing to use opioid analgesia.&#xD;
&#xD;
          -  Be able to fluently speak and understand either English or Spanish and be able to&#xD;
             provide meaningful written informed consent for the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        A subject will be excluded from study participation if prior to surgery he/she:&#xD;
&#xD;
          -  Has a known hypersensitivity to amide local anesthetics, morphine, acetaminophen, or&#xD;
             bovine products.&#xD;
&#xD;
          -  Is scheduled for bilateral inguinal hernioplasty or other significant concomitant&#xD;
             surgical procedure.&#xD;
&#xD;
          -  Has undergone major surgery within 3 months of the scheduled hernioplasty or plans to&#xD;
             undergo another laparotomy procedure within the 30 day postoperative period.&#xD;
&#xD;
          -  Has known or suspected history of alcohol or drug abuse or misuse within 3 years of&#xD;
             screening or evidence of tolerance or physical dependency on opioid analgesics or&#xD;
             sedative-hypnotic medications.&#xD;
&#xD;
          -  Has any clinically significant unstable cardiac, neurological, immunological, renal,&#xD;
             hepatic or hematological disease or any other condition that, in the opinion of the&#xD;
             investigator, could compromise the subject's welfare, ability to communicate with the&#xD;
             study staff or otherwise contraindicate study participation.&#xD;
&#xD;
          -  Has venous access difficulties that may preclude the frequent pharmacokinetic sampling&#xD;
             requirements of the study.&#xD;
&#xD;
          -  Has participated in a clinical trial (investigational or marketed product) within 30&#xD;
             days of surgery.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gwendolyn Niebler, D.O.</last_name>
    <role>Study Director</role>
    <affiliation>Innocoll</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Pinnacle Research Group</name>
      <address>
        <city>Anniston</city>
        <state>Alabama</state>
        <zip>36207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Park Place Surgery Center</name>
      <address>
        <city>Longwood</city>
        <state>Florida</state>
        <zip>32750</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Concepts</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77004</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Concepts GP, LLC - Houston</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jean Brown Research</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84124</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>June 28, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <results_first_submitted>October 1, 2020</results_first_submitted>
  <results_first_submitted_qc>December 7, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">December 31, 2020</results_first_posted>
  <last_update_submitted>July 14, 2021</last_update_submitted>
  <last_update_submitted_qc>July 14, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 30, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Bioavailability</keyword>
  <keyword>Safety</keyword>
  <keyword>Bupivacaine</keyword>
  <keyword>Collagen</keyword>
  <keyword>Implant</keyword>
  <keyword>Marcaine</keyword>
  <keyword>Hernioplasty</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bupivacaine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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 17, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/74/NCT03234374/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>INL-001</title>
          <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
        </group>
        <group group_id="P2">
          <title>Marcaine 0.25% Infiltration</title>
          <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="35"/>
                <participants group_id="P2" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="34"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Safety &amp; PK Population</population>
      <group_list>
        <group group_id="B1">
          <title>INL-001</title>
          <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
        </group>
        <group group_id="B2">
          <title>Marcaine 0.25% Infiltration</title>
          <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</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="34"/>
            <count group_id="B2" value="16"/>
            <count group_id="B3" value="50"/>
          </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="45.6" spread="14.84"/>
                    <measurement group_id="B2" value="41.6" spread="12.18"/>
                    <measurement group_id="B3" value="44.3" spread="14.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="49"/>
                  </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="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="46"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Cmax</title>
        <description>Maximum (peak) plasma concentration</description>
        <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours.</time_frame>
        <population>Per-Protocol PK Population</population>
        <group_list>
          <group group_id="O1">
            <title>INL-001</title>
            <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
          </group>
          <group group_id="O2">
            <title>Marcaine 0.25% Infiltration</title>
            <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax</title>
          <description>Maximum (peak) plasma concentration</description>
          <population>Per-Protocol PK Population</population>
          <units>ng/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="663.412" spread="263.826"/>
                    <measurement group_id="O2" value="641.000" spread="262.684"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Tmax</title>
        <description>Time to maximum (peak) plasma concentration</description>
        <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
        <population>Summary of Plasma Bupivacaine PK Parameters by Treatment - Per-Protocol PK Population</population>
        <group_list>
          <group group_id="O1">
            <title>INL-001</title>
            <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
          </group>
          <group group_id="O2">
            <title>Marcaine 0.25% Infiltration</title>
            <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax</title>
          <description>Time to maximum (peak) plasma concentration</description>
          <population>Summary of Plasma Bupivacaine PK Parameters by Treatment - Per-Protocol PK Population</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.03" lower_limit="1.48" upper_limit="24.02"/>
                    <measurement group_id="O2" value="1.01" lower_limit="0.53" upper_limit="3.97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Tlag</title>
        <description>Lag-time</description>
        <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
        <population>Per-Protocol PK Population</population>
        <group_list>
          <group group_id="O1">
            <title>INL-001</title>
            <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
          </group>
          <group group_id="O2">
            <title>Marcaine 0.25% Infiltration</title>
            <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
          </group>
        </group_list>
        <measure>
          <title>Tlag</title>
          <description>Lag-time</description>
          <population>Per-Protocol PK Population</population>
          <units>hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.51" spread="0.13"/>
                    <measurement group_id="O2" value="0.47" spread="0.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>t½ Terminal Half Life</title>
        <description>Terminal half-life</description>
        <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
        <population>Per-Protocol PK Population</population>
        <group_list>
          <group group_id="O1">
            <title>INL-001</title>
            <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
          </group>
          <group group_id="O2">
            <title>Marcaine 0.25% Infiltration</title>
            <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
          </group>
        </group_list>
        <measure>
          <title>t½ Terminal Half Life</title>
          <description>Terminal half-life</description>
          <population>Per-Protocol PK Population</population>
          <units>hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.04" spread="0.01"/>
                    <measurement group_id="O2" value="0.09" spread="0.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>λz</title>
        <description>Terminal phase rate constant</description>
        <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
        <population>Per protocol population</population>
        <group_list>
          <group group_id="O1">
            <title>INL-001</title>
            <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
          </group>
          <group group_id="O2">
            <title>Marcaine 0.25% Infiltration</title>
            <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
          </group>
        </group_list>
        <measure>
          <title>λz</title>
          <description>Terminal phase rate constant</description>
          <population>Per protocol population</population>
          <units>1/hour</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.95" spread="5.95"/>
                    <measurement group_id="O2" value="9.08" spread="3.75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC</title>
        <description>Area under the plasma concentration-time curve from Time 0 to last time of last quantifiable plasma concentration (AUC0-last)</description>
        <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
        <population>Per Protocol Population</population>
        <group_list>
          <group group_id="O1">
            <title>INL-001</title>
            <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
          </group>
          <group group_id="O2">
            <title>Marcaine 0.25% Infiltration</title>
            <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
          </group>
        </group_list>
        <measure>
          <title>AUC</title>
          <description>Area under the plasma concentration-time curve from Time 0 to last time of last quantifiable plasma concentration (AUC0-last)</description>
          <population>Per Protocol Population</population>
          <units>h*ng/[mL*mg]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18,186.9" spread="39.0"/>
                    <measurement group_id="O2" value="8836.9" spread="46.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC0-∞</title>
        <description>AUC from Time 0 to infinity</description>
        <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
        <population>Per protocol population</population>
        <group_list>
          <group group_id="O1">
            <title>INL-001</title>
            <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
          </group>
          <group group_id="O2">
            <title>Marcaine 0.25% Infiltration</title>
            <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
          </group>
        </group_list>
        <measure>
          <title>AUC0-∞</title>
          <description>AUC from Time 0 to infinity</description>
          <population>Per protocol population</population>
          <units>h*ng/[mL*mg]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19,012.5" spread="38.7"/>
                    <measurement group_id="O2" value="8920.1" spread="0.65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC Extrapolated</title>
        <description>AUC = area under the plasma concentration-time curve;</description>
        <time_frame>0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>INL-001</title>
            <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
          </group>
          <group group_id="O2">
            <title>Marcaine 0.25% Infiltration</title>
            <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
          </group>
        </group_list>
        <measure>
          <title>AUC Extrapolated</title>
          <description>AUC = area under the plasma concentration-time curve;</description>
          <units>(h*ng/mL)</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.96" spread="120.9"/>
                    <measurement group_id="O2" value="0.65" spread="122.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>30 days</time_frame>
      <desc>Safety Population</desc>
      <group_list>
        <group group_id="E1">
          <title>INL-001</title>
          <description>3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.&#xD;
INL-001 (bupivacaine HCl collagen implant): 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)</description>
        </group>
        <group group_id="E2">
          <title>Marcaine 0.25% Infiltration</title>
          <description>Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).&#xD;
Marcaine 0.25% infiltration: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (18.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="33" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="34"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="34"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="34"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="34"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia oral</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="34"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="34"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Paraesthesia oral</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="34"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Incision site complication</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="34"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="19" subjects_affected="19" subjects_at_risk="34"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="12" subjects_affected="12" subjects_at_risk="34"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="34"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="34"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="34"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Restlessness</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="34"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="34"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="16"/>
              </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>Charlene A. Tucker, MS Executive Director, Medical Writing and Document Management</name_or_title>
      <organization>Innocoll</organization>
      <phone>484-406-5211</phone>
      <email>ctucker@innocoll.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/NCT03234374
org study id: INN-CB-022
nct id: NCT03234374
lead sponsor: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
This is a multicenter randomized, single-blind, controlled study. The primary objectives of
      this study are to obtain the pharmacokinetic profile and the relative bioavailability of the
      INL-001 matrix during and after open hernioplasty compared to Marcaine™ 0.25% infiltration.
This is a multicenter randomized, single-blind, controlled study. Prior to surgery on Day 1,
      48 subjects who continue to meet study entry criteria will be randomized just prior to
      surgery in a 2:1 ratio to receive either 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix
      implants (total bupivacaine HCl dose 300 mg) or Marcaine 0.25% (bupivacaine HCl) 175 mg
      infiltration. Subjects will then undergo open hernioplasty according to standard procedure.

      Subjects will remain in the clinic at least until after the 72 hour blood sample has been
      collected for PK analysis on Day 4. Subjects discharged after the 72 hour blood draw will be
      instructed to return to the clinic to complete the 96 hour PK blood draw on Day 5. Follow-up
      safety assessments will include clinic visits on Day 7, Day 15 and Day 30.

      Pharmacokinetic blood samples will be collected from subjects before surgery and at
      predetermined time points up to 96 hours after administration of study drug. Safety
      assessments will include frequent assessment of vital signs through 72 hours, continuous
      electrocardiogram (ECG) monitoring for at least 24 hours, oxygen saturation levels, and
      adverse events (AEs) reporting with particular emphasis on the signs and symptoms of CNS and
      cardiovascular bupivacaine toxicity. The surgical wound will be assessed frequently for
      adverse events associated with altered wound healing.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: Single (Participant)
masking description: This is a single-blind study in which the study subject is blinded to treatment group. All precautions will be taken to ensure that the blinding of the treatment group is maintained throughout the study period. Unblinding to the subject will not be permitted unless it is deemed necessary for appropriate treatment of a medical emergency.
measure: Cmax
time frame: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours.
description: Maximum (peak) plasma concentration
measure: Tmax
time frame: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours
description: Time to maximum (peak) plasma concentration
measure: Tlag
time frame: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours
description: Lag-time
measure: t½ Terminal Half Life
time frame: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours
description: Terminal half-life
measure: λz
time frame: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours
description: Terminal phase rate constant
measure: AUC
time frame: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours
description: Area under the plasma concentration-time curve from Time 0 to last time of last quantifiable plasma concentration (AUC0-last)
measure: AUC0-∞
time frame: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours
description: AUC from Time 0 to infinity
measure: AUC Extrapolated
time frame: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 18, 24, 36, 48 and 72 hours
description: AUC = area under the plasma concentration-time curve;
arm group label: INL-001
arm group type: Experimental
description: 3 x 100 mg INL-001 (bupivacaine HCl collagen implants). Total bupivacaine HCl dose 300 mg.
arm group label: Marcaine 0.25% infiltration
arm group type: Active Comparator
description: Marcaine 0.25% infiltration (bupivacaine HCl 175 mg).
intervention type: Combination Product
intervention name: INL-001 (bupivacaine HCl collagen implant)
description: 3 x 100 mg INL-001 bupivacaine HCl collagen-matrix implants (total bupivacaine HCl dose 300 mg)
arm group label: INL-001
other name: INL-001
intervention type: Drug
intervention name: Marcaine 0.25% infiltration
description: Marcaine 0.25% (bupivacaine HCl) 175 mg infiltration
arm group label: Marcaine 0.25% infiltration
other name: Marcaine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gwendolyn Niebler, D.O.
role: Study Director
affiliation: Innocoll
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Bupivacaine
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 