<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/NCT01689441</url>
  </required_header>
  <id_info>
    <org_study_id>2012P001755</org_study_id>
    <nct_id>NCT01689441</nct_id>
  </id_info>
  <brief_title>Randomized Controlled Trial of Calcitriol vs. Placebo Among Critically-ill Patients With Sepsis</brief_title>
  <official_title>Randomized Controlled Trial of Calcitriol vs. Placebo Among Critically-ill Patients With Sepsis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Brigham and Women's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Brigham and Women's Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Observational studies among critically ill patients have shown strong associations between&#xD;
      vitamin D deficiency and adverse outcomes, including increased length of stay, infection, and&#xD;
      mortality. It is unknown whether vitamin D deficiency contributes directly to adverse&#xD;
      outcomes or whether it is simply a biomarker of severity of illness or overall health status.&#xD;
      However, vitamin D plays a key role in host defense, largely by stimulating production of the&#xD;
      anti-microbial peptide cathelicidin (LL-37). We will test the hypothesis that administration&#xD;
      of activated vitamin D (calcitriol) will increase serum levels of cathelicidin.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>February 2013</start_date>
  <completion_date type="Actual">February 2014</completion_date>
  <primary_completion_date type="Actual">February 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Plasma Cathelicidin (hCAP18) Protein Levels at 48 Hours</measure>
    <time_frame>48 hours</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma Interleukin-6 (IL-6) Levels at 48 Hours</measure>
    <time_frame>48 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL) / Creatinine Ratio at 48 Hours</measure>
    <time_frame>48 hours</time_frame>
    <description>NGAL is a urinary marker of renal tubular injury. NGAL levels were normalized to the urinary creatinine concentration to account for the influence of dilution on biomarker concentrations.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">67</enrollment>
  <condition>Severe Sepsis or Septic Shock</condition>
  <arm_group>
    <arm_group_label>Calcitriol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Calcitriol 2mcg IV x 1</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Normal saline 2cc IV x 1</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Calcitriol</intervention_name>
    <arm_group_label>Calcitriol</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  age ≥ 18&#xD;
&#xD;
          -  Severe sepsis or septic shock&#xD;
&#xD;
          -  Central venous catheter (for blood drawing)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Serum calcium ≥ 10.0 mg/dl or phosphate ≥ 6.0 mg/dl, assessed within previous 48 hours&#xD;
&#xD;
          -  Current or recent therapy (within previous 7 days) with nutritional vitamin D at doses&#xD;
             &gt;1,000 I.U. per day or activated vitamin D at any dose&#xD;
&#xD;
          -  History of solid organ or bone marrow transplant, primary parathyroid disease,&#xD;
             metabolic bone disease, or sarcoidosis&#xD;
&#xD;
          -  Expected to die or leave the ICU within 48 hours&#xD;
&#xD;
          -  History of hypersensitivity or any allergic reaction to calcitriol&#xD;
&#xD;
          -  End stage renal disease&#xD;
&#xD;
          -  Acute Kidney Injury receiving intermittent renal replacement therapy&#xD;
&#xD;
          -  Enrolled in a competing study&#xD;
&#xD;
          -  Pregnancy&#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>David E Leaf, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Brigham and Women's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Brigham and Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.ncbi.nlm.nih.gov/pubmed/25029202</url>
    <description>Link to manuscript in pubmed</description>
  </link>
  <results_reference>
    <citation>Leaf DE, Raed A, Donnino MW, Ginde AA, Waikar SS. Randomized controlled trial of calcitriol in severe sepsis. Am J Respir Crit Care Med. 2014 Sep 1;190(5):533-41. doi: 10.1164/rccm.201405-0988OC.</citation>
    <PMID>25029202</PMID>
  </results_reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>September 18, 2012</study_first_submitted>
  <study_first_submitted_qc>September 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 21, 2012</study_first_posted>
  <results_first_submitted>October 27, 2014</results_first_submitted>
  <results_first_submitted_qc>October 27, 2014</results_first_submitted_qc>
  <results_first_posted type="Estimate">October 30, 2014</results_first_posted>
  <last_update_submitted>November 5, 2020</last_update_submitted>
  <last_update_submitted_qc>November 5, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Brigham and Women's Hospital</investigator_affiliation>
    <investigator_full_name>David Leaf</investigator_full_name>
    <investigator_title>Assistant Professor of Medicine, Harvard Medical School</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sepsis</mesh_term>
    <mesh_term>Toxemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Calcitriol</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Calcitriol</title>
          <description>Calcitriol 2mcg IV x 1&#xD;
Calcitriol</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Normal saline 2cc IV x 1&#xD;
Placebo</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="36"/>
                <participants group_id="P2" count="31"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="36"/>
                <participants group_id="P2" count="31"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Calcitriol</title>
          <description>Calcitriol 2mcg IV x 1&#xD;
Calcitriol</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Normal saline 2cc IV x 1&#xD;
Placebo</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="36"/>
            <count group_id="B2" value="31"/>
            <count group_id="B3" value="67"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="68" lower_limit="54" upper_limit="70"/>
                    <measurement group_id="B2" value="58" lower_limit="49" upper_limit="69"/>
                    <measurement group_id="B3" value="64" lower_limit="50" upper_limit="70"/>
                  </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="14"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="37"/>
                  </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="36"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Plasma Cathelicidin (hCAP18) Protein Levels at 48 Hours</title>
        <time_frame>48 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Calcitriol</title>
            <description>Calcitriol 2mcg IV x 1&#xD;
Calcitriol</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Normal saline 2cc IV x 1&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Cathelicidin (hCAP18) Protein Levels at 48 Hours</title>
          <units>ng/ml</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="36"/>
                <count group_id="O2" value="31"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="76" lower_limit="60" upper_limit="94"/>
                    <measurement group_id="O2" value="82" lower_limit="70" upper_limit="100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.25</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Interleukin-6 (IL-6) Levels at 48 Hours</title>
        <time_frame>48 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Calcitriol</title>
            <description>Calcitriol 2mcg IV x 1&#xD;
Calcitriol</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Normal saline 2cc IV x 1&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Interleukin-6 (IL-6) Levels at 48 Hours</title>
          <units>pg/ml</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="36"/>
                <count group_id="O2" value="31"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41" lower_limit="25" upper_limit="92"/>
                    <measurement group_id="O2" value="32" lower_limit="21" upper_limit="85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.51</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL) / Creatinine Ratio at 48 Hours</title>
        <description>NGAL is a urinary marker of renal tubular injury. NGAL levels were normalized to the urinary creatinine concentration to account for the influence of dilution on biomarker concentrations.</description>
        <time_frame>48 hours</time_frame>
        <population>The discrepancy in &quot;number of participants analyzed&quot; for this outcome vs. other outcomes is due to urine samples not being available in all participants</population>
        <group_list>
          <group group_id="O1">
            <title>Calcitriol</title>
            <description>Calcitriol 2mcg IV x 1&#xD;
Calcitriol</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Normal saline 2cc IV x 1&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL) / Creatinine Ratio at 48 Hours</title>
          <description>NGAL is a urinary marker of renal tubular injury. NGAL levels were normalized to the urinary creatinine concentration to account for the influence of dilution on biomarker concentrations.</description>
          <population>The discrepancy in &quot;number of participants analyzed&quot; for this outcome vs. other outcomes is due to urine samples not being available in all participants</population>
          <units>mg/mg</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.6" lower_limit="0.2" upper_limit="3.1"/>
                    <measurement group_id="O2" value="0.7" lower_limit="0.3" upper_limit="2.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.54</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Calcitriol</title>
          <description>Calcitriol 2mcg IV x 1&#xD;
Calcitriol</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Normal saline 2cc IV x 1&#xD;
Placebo</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="36"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="36"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>David Leaf, MD, MMSc</name_or_title>
      <organization>Brigham and Women's Hospital</organization>
      <phone>617-732-5500</phone>
      <email>deleaf@partners.org</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/NCT01689441
org study id: 2012P001755
nct id: NCT01689441
lead sponsor: 
has dmc: No
Observational studies among critically ill patients have shown strong associations between
      vitamin D deficiency and adverse outcomes, including increased length of stay, infection, and
      mortality. It is unknown whether vitamin D deficiency contributes directly to adverse
      outcomes or whether it is simply a biomarker of severity of illness or overall health status.
      However, vitamin D plays a key role in host defense, largely by stimulating production of the
      anti-microbial peptide cathelicidin (LL-37). We will test the hypothesis that administration
      of activated vitamin D (calcitriol) will increase serum levels of cathelicidin.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Plasma Cathelicidin (hCAP18) Protein Levels at 48 Hours
time frame: 48 hours
measure: Plasma Interleukin-6 (IL-6) Levels at 48 Hours
time frame: 48 hours
measure: Urinary Neutrophil Gelatinase-associated Lipocalin (NGAL) / Creatinine Ratio at 48 Hours
time frame: 48 hours
description: NGAL is a urinary marker of renal tubular injury. NGAL levels were normalized to the urinary creatinine concentration to account for the influence of dilution on biomarker concentrations.
arm group label: Calcitriol
arm group type: Experimental
description: Calcitriol 2mcg IV x 1
arm group label: Placebo
arm group type: Placebo Comparator
description: Normal saline 2cc IV x 1
intervention type: Drug
intervention name: Calcitriol
arm group label: Calcitriol
intervention type: Drug
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: David E Leaf, M.D.
role: Principal Investigator
affiliation: Brigham and Women's Hospital
facility: 
country: United States
url: http://www.ncbi.nlm.nih.gov/pubmed/25029202
description: Link to manuscript in pubmed
citation: Leaf DE, Raed A, Donnino MW, Ginde AA, Waikar SS. Randomized controlled trial of calcitriol in severe sepsis. Am J Respir Crit Care Med. 2014 Sep 1;190(5):533-41. doi: 10.1164/rccm.201405-0988OC.
PMID: 25029202
responsible party type: Principal Investigator
investigator affiliation: Brigham and Women's Hospital
investigator full name: David Leaf
investigator title: Assistant Professor of Medicine, Harvard Medical School
mesh term: Sepsis
mesh term: Toxemia
mesh term: Calcitriol
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 