<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/NCT03281538</url>
  </required_header>
  <id_info>
    <org_study_id>CR845-CLIN3101</org_study_id>
    <nct_id>NCT03281538</nct_id>
  </id_info>
  <brief_title>Extension Study to Evaluate IV CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus</brief_title>
  <official_title>An Open-Label, Multicenter, Extension Study to Evaluate the Long Term Safety of Intravenous CR845 in Hemodialysis Patients With Chronic Kidney Disease-Associated Pruritus</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cara Therapeutics, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cara Therapeutics, Inc.</source>
  <oversight_info>
    <has_dmc>No</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>
      This is an open-label multicenter, long-term extension safety study to evaluate the safety of&#xD;
      IV CR845 administered after each dialysis session over a Treatment Period of up to 52 weeks.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label multicenter, long-term extension safety study to evaluate the safety of&#xD;
      IV CR845 administered after each dialysis session over a Treatment Period of up to 52 weeks.&#xD;
      This study will consist of a Screening Visit, a 52 week Treatment Period, and a Follow-up&#xD;
      Visit. Informed consent will be obtained prior to performing any study-specific procedures.&#xD;
      All patients will have a Screening Visit, which can be performed anytime within 14 days prior&#xD;
      to the first dose of study drug, to confirm eligibility.&#xD;
&#xD;
      Clinical laboratory tests, electrocardiograms (ECGs), vital signs, adverse events, and&#xD;
      concomitant medications will be monitored throughout the study. Blood samples for&#xD;
      inflammatory biomarkers will be collected from all patients prior to dialysis on Day 1 and&#xD;
      periodically until the End of Treatment or Early Termination Visit. Blood samples will also&#xD;
      be collected periodically for clinical laboratory tests.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 14, 2017</start_date>
  <completion_date type="Actual">February 11, 2020</completion_date>
  <primary_completion_date type="Actual">February 11, 2020</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With AEs</measure>
    <time_frame>Up to 52 weeks</time_frame>
    <description>Assessed by physical examination, monitoring of adverse events, vital signs and laboratory assessments</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">288</enrollment>
  <condition>Uremic Pruritus</condition>
  <arm_group>
    <arm_group_label>CR845 0.5mcg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CR845 0.5mcg/kg IV medication administered three times/week after dialysis</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CR845</intervention_name>
    <description>IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)</description>
    <arm_group_label>CR845 0.5mcg/kg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        To be eligible for inclusion into the study, a patient must meet the following criteria:&#xD;
&#xD;
          1. Willing and able to provide written informed consent prior to participating in this&#xD;
             study;&#xD;
&#xD;
          2. Able to communicate clearly with the Investigator and staff, able to understand the&#xD;
             study procedures, and able and willing to comply with the study schedules and all&#xD;
             study requirements;&#xD;
&#xD;
          3. Males or females 18 years of age or older;&#xD;
&#xD;
          4. Currently on hemodialysis for end-stage renal disease and has been categorized as&#xD;
             experiencing moderate to severe uremic pruritus;&#xD;
&#xD;
          5. If female:&#xD;
&#xD;
               1. Is not of childbearing potential (surgically sterile or postmenopausal, as&#xD;
                  defined in Section 6.5.1.6); or&#xD;
&#xD;
               2. Has a negative serum pregnancy test at screening and agrees to use acceptable&#xD;
                  contraceptive measures (as defined in Section 6.5.1.6) from the time of informed&#xD;
                  consent until the safety Follow-up Visit or 7 days after the last dose of study&#xD;
                  drug, whichever is later.&#xD;
&#xD;
          6. If male, agrees not to donate sperm after the first dose of study drug until 7 days&#xD;
             after the last dose, and agrees to use a condom with spermicide or abstain from&#xD;
             heterosexual intercourse during the study until 7 days after study drug&#xD;
             administration. (Note: No restrictions are required for a vasectomized male provided&#xD;
             his vasectomy was performed ≥4 months prior to dosing);&#xD;
&#xD;
          7. Has a dry body weight of ≥40.0 kg at screening (prescription target dry body weight);&#xD;
&#xD;
          8. Has adequacy of dialysis, defined as meeting 1 of the following criteria during the 3&#xD;
             months prior to screening:&#xD;
&#xD;
               1. ≥2 single pool Kt/V measurements ≥1.2; or&#xD;
&#xD;
               2. ≥2 urea reduction ratio measurements ≥65%; or&#xD;
&#xD;
               3. 1 single pool Kt/V measurement ≥1.2 and 1 urea reduction ratio measurement ≥65%&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        A patient will be excluded from the study if any of the following criteria are met:&#xD;
&#xD;
          1. Received an investigational drugwithin 30 days prior to the first dose of study drug,&#xD;
             or is planning to participate in another interventional clinical study while enrolled&#xD;
             in this study.&#xD;
&#xD;
          2. Has a concomitant disease or any medical condition that, in the opinion of the&#xD;
             Investigator, could pose undue risk to the patient, impede completion of the study&#xD;
             procedures, or would compromise the validity of the study measurements, including, but&#xD;
             not limited to:&#xD;
&#xD;
               1. Known or suspected history of Diagnostic and Statistical Manual of Mental&#xD;
                  Disorders, Fifth Edition, -diagnosed alcohol, narcotic or other drug abuse, or&#xD;
                  substance dependence within 12 months prior to screening;&#xD;
&#xD;
               2. New York Heart Association Class IV congestive heart failure (Appendix 1, Section&#xD;
                  14.0);&#xD;
&#xD;
               3. Severe mental illness or cognitive impairment (eg, dementia);&#xD;
&#xD;
               4. Any other relevant acute or chronic medical or neuropsychiatric condition;&#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>Frederique Menzaghi</last_name>
    <role>Study Director</role>
    <affiliation>Cara Therapeutics</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Chula Vista</city>
        <state>California</state>
        <zip>91990</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>El Centro</city>
        <state>California</state>
        <zip>92243</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Long Beach</city>
        <state>California</state>
        <zip>90813</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Northridge</city>
        <state>California</state>
        <zip>91324</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Hollywood</city>
        <state>Florida</state>
        <zip>33024</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33614</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Winter Park</city>
        <state>Florida</state>
        <zip>32789</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Albany</city>
        <state>Georgia</state>
        <zip>31701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Augusta</city>
        <state>Georgia</state>
        <zip>30909</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Meridian</city>
        <state>Idaho</state>
        <zip>83642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Springfield</city>
        <state>Massachusetts</state>
        <zip>01107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Roseville</city>
        <state>Michigan</state>
        <zip>48066</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64131</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Albuquerque</city>
        <state>New Mexico</state>
        <zip>87109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Gallup</city>
        <state>New Mexico</state>
        <zip>87301</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Mineola</city>
        <state>New York</state>
        <zip>11501</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Ridgewood</city>
        <state>New York</state>
        <zip>11385</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Bethlehem</city>
        <state>Pennsylvania</state>
        <zip>18017</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Knoxville</city>
        <state>Tennessee</state>
        <zip>37920</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>El Paso</city>
        <state>Texas</state>
        <zip>79902</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78221</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Saint George</city>
        <state>Utah</state>
        <zip>84790</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>Wauwatosa</city>
        <state>Wisconsin</state>
        <zip>53326</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cara Therapeutics Study Site</name>
      <address>
        <city>San Juan</city>
        <zip>00926</zip>
        <country>Puerto Rico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Puerto Rico</country>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>June 20, 2017</study_first_submitted>
  <study_first_submitted_qc>September 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 13, 2017</study_first_posted>
  <results_first_submitted>September 21, 2021</results_first_submitted>
  <results_first_submitted_qc>September 21, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">October 14, 2021</results_first_posted>
  <disposition_first_submitted>February 10, 2021</disposition_first_submitted>
  <disposition_first_submitted_qc>February 10, 2021</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">February 12, 2021</disposition_first_posted>
  <last_update_submitted>September 21, 2021</last_update_submitted>
  <last_update_submitted_qc>September 21, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CR845</keyword>
  <keyword>difelikefalin</keyword>
  <keyword>Pruritus</keyword>
  <keyword>Chronic Itch</keyword>
  <keyword>Itch</keyword>
  <keyword>Itching</keyword>
  <keyword>hemodialysis</keyword>
  <keyword>Uremic Pruritus</keyword>
  <keyword>Dialysis</keyword>
  <keyword>CKD</keyword>
  <keyword>CKD-associated pruritus</keyword>
  <keyword>CKD-aP</keyword>
  <keyword>ESRD (end stage renal disease)</keyword>
  <keyword>Chronic Kidney Disease</keyword>
  <keyword>Kidney failure, chronic</keyword>
  <keyword>Kidney dysfunction</keyword>
  <keyword>Generalized pruritus</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pruritus</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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 26, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/38/NCT03281538/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>March 9, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/38/NCT03281538/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>CR845 0.5mcg/kg</title>
          <description>CR845 0.5mcg/kg IV medication administered three times/week after dialysis&#xD;
CR845: IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="288"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="133"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="155"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>CR845 0.5mcg/kg</title>
          <description>CR845 0.5mcg/kg IV medication administered three times/week after dialysis&#xD;
CR845: IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="288"/>
          </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="57.4" spread="12.61"/>
                  </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="115"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="173"/>
                  </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="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="148"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="114"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With AEs</title>
        <description>Assessed by physical examination, monitoring of adverse events, vital signs and laboratory assessments</description>
        <time_frame>Up to 52 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CR845 0.5mcg/kg</title>
            <description>CR845 0.5mcg/kg IV medication administered three times/week after dialysis&#xD;
CR845: IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With AEs</title>
          <description>Assessed by physical examination, monitoring of adverse events, vital signs and laboratory assessments</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="288"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="240"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 52 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>CR845 0.5mcg/kg</title>
          <description>CR845 0.5mcg/kg IV medication administered three times/week after dialysis&#xD;
CR845: IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)</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="17" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="148" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Angina pectoris</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Cardiac arrest</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Coronary artery disease</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Mitral valve incompetence</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Acute left ventricular failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Arteriosclerosis coronary artery</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Cardiac failure acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Cardiac tamponade</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Cardiogenic shock</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Chronic left ventricular failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Left ventricular failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Myocardia ischaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Pericarditis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Pericardial effusion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Diplopia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Visual impairment</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Upper gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Discoloured vomit</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Enterocolitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Erosive oesophagitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Gastric haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Gastric ulcer haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Haematemesis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Intestinal ischaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Intestinal perforation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Irritable bowel syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Oesophageal ulcer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Pancreatitis acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Proctitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Rectal ulcer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Impaired healing</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Catheter site thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Complication associated with device</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Drug interaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Sudden death</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Vascular stent restenosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Cholelithiasis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Hepatic cirrhosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Bacteraemia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Osteomyelitis</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Clostridium difficile colitis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Gangrene</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Septic shock</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Infected skin ulcer</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Staphylococcal sepsis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Abscess limb</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Appendicitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Ateriovenous fistula site infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Ateriovenous graft site abscess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Bronchitis viral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Cardiac valve vegetation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Catheter site infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Device related sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Klebsiella sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Latent tuberculosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Otitis externa</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Perirectal abscess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Pneumonia bacterial</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Postoperative wound infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Respiratory syncytial virus bronchiolitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Serratia sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Staphylococcal bacteraemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Staphylococcal infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Subacute endocarditis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Subcutaneous abscess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Vascular access site infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Arteriovenous fistula thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Vascular access malfunction</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Vascular access site thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Vascular graft complication</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Abdominal injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Arteriovenous fistula site complication</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Arteriovenous graft site haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Arteriovenous graft thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Chemical burn of respiratory tract</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Fibula fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Gun shot wound</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Head injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Hip fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Limb injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Rib fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Shunt malfunction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Skin injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Skin wound</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Tibia fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Wound haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Shunt thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood pressure increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Cardiac stress test abnormal</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Electrocardiogram T wave inversion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Fluid overload</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Hypocalcaemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Diabetic ketoacidosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Calciphylaxis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Metabolic acidosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Osteoarthritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Synovitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Bening lung neoplasm</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Ovarian cancer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Brain stem infarction</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Cerebrovascular accident</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Brain injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Hypertensive encephalopathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Metabolic encephalopathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Neurological symptom</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Neuropathy peripheral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Status epilepticus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Transient ischaemic attack</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Unresponsive to stimuli</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Product Issues</title>
            <event_list>
              <event>
                <sub_title>Device expulsion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Mental status changes</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Confusional state</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Hallucination, visual</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Major depression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Suicidal ideation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal colic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Genital lesion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Pulmonary oedema</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Acute pulmonary oedema</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Asthma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Atelectasis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Pneumonia apsiration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Respiratory acidosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Decubitus ulcer</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Angioedema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Skin ulcer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Hypertensive emergency</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Hypertensive crisis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Shock haemorrhagic</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Steal syndrome</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Accelerated hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Aortic stenosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Arterial stenosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Jugular vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Orthostatic hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Peripheral arterial occlusive disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Peripheral artery occlusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Peripheral ischaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Peripheral venous disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="288"/>
              </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="139" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="48" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="44" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="38" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="42" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="288"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="288"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="288"/>
              </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 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>Frédérique Menzaghi, PhD</name_or_title>
      <organization>Cara Therapeutics</organization>
      <phone>203-406-3700</phone>
      <email>clinicaltrials.gov@caratherapeutics.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/NCT03281538
org study id: CR845-CLIN3101
nct id: NCT03281538
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This is an open-label multicenter, long-term extension safety study to evaluate the safety of
      IV CR845 administered after each dialysis session over a Treatment Period of up to 52 weeks.
This is an open-label multicenter, long-term extension safety study to evaluate the safety of
      IV CR845 administered after each dialysis session over a Treatment Period of up to 52 weeks.
      This study will consist of a Screening Visit, a 52 week Treatment Period, and a Follow-up
      Visit. Informed consent will be obtained prior to performing any study-specific procedures.
      All patients will have a Screening Visit, which can be performed anytime within 14 days prior
      to the first dose of study drug, to confirm eligibility.

      Clinical laboratory tests, electrocardiograms (ECGs), vital signs, adverse events, and
      concomitant medications will be monitored throughout the study. Blood samples for
      inflammatory biomarkers will be collected from all patients prior to dialysis on Day 1 and
      periodically until the End of Treatment or Early Termination Visit. Blood samples will also
      be collected periodically for clinical laboratory tests.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With AEs
time frame: Up to 52 weeks
description: Assessed by physical examination, monitoring of adverse events, vital signs and laboratory assessments
arm group label: CR845 0.5mcg/kg
arm group type: Experimental
description: CR845 0.5mcg/kg IV medication administered three times/week after dialysis
intervention type: Drug
intervention name: CR845
description: IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)
arm group label: CR845 0.5mcg/kg
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Frederique Menzaghi
role: Study Director
affiliation: Cara Therapeutics
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country: Puerto Rico
country: United States
responsible party type: Sponsor
mesh term: Pruritus
sharing ipd: Undecided
provided document: 
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participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 