<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/NCT03300570</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2017-01783</org_study_id>
    <secondary_id>NCI-2017-01783</secondary_id>
    <secondary_id>N01-CN-2012-00042</secondary_id>
    <secondary_id>MAY2017-09-01</secondary_id>
    <secondary_id>MAY2017-09-01</secondary_id>
    <secondary_id>N01CN00042</secondary_id>
    <secondary_id>P30CA015083</secondary_id>
    <nct_id>NCT03300570</nct_id>
  </id_info>
  <brief_title>Dolcanatide in Preventing Colorectal Cancer in Healthy Volunteers</brief_title>
  <official_title>Phase I Double-Blind, Placebo-Controlled Trial of 27 mg Dolcanatide (SP-333) to Demonstrate Colorectal Bioactivity in Healthy Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies how well dolcanatide works in preventing colorectal cancer in&#xD;
      healthy participants. Dolcanatide is similar to a natural hormone released into the&#xD;
      intestine. It is thought that people who have low levels of the hormone are more likely to&#xD;
      get colon cancer. It may be possible to prevent colon cancer by giving a drug that is similar&#xD;
      to the hormone, such as dolcanatide.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To identify the ability of dolcanatide (SP333), when administered as a single daily dose&#xD;
      of 27 mg x 7 days, to induce a direct pharmacological effect on cGMP levels, based on biopsy&#xD;
      samples from the rectum obtained pre- and post-intervention, as compared to placebo.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess the pharmacodynamic (PD) response rate between arms (dolcanatide versus&#xD;
      placebo).&#xD;
&#xD;
      II. To confirm the safety and tolerability of dolcanatide, as compared to placebo.&#xD;
&#xD;
      OUTLINE: Participants are randomized to 1 of 2 arms.&#xD;
&#xD;
      ARM A: Participants receive dolcanatide orally (PO) once daily (QD) for 7 days.&#xD;
&#xD;
      ARM B: Participants receive placebo PO QD for 7 days.&#xD;
&#xD;
      After completion of study, participants are followed up at 21 and 51 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 27, 2018</start_date>
  <completion_date type="Actual">May 17, 2021</completion_date>
  <primary_completion_date type="Actual">January 2, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pharmacological Effect on Cyclic Guanosine Monophosphate (cGMP) Levels for Dolcanatide Arm Versus (vs.) Placebo, as Measured by the Differences in Mean cGMP Levels After 7 Days of Intervention</measure>
    <time_frame>Baseline to 7 days</time_frame>
    <description>Pharmacological effect on cyclic guanosine monophosphate (cGMP) levels for dolcanatide arm versus (vs.) placebo, where this effect is defined as the arithmetic difference in mean cGMP levels before and after 7 days of dolcanatide from subject biopsies. This represents the increase in cGMP stimulated by 7 days of dolcanatide in an individual subject. The mean cGMP value will be calculated based on 6 biopsies collected from the rectum during a flexible sigmoidoscopy procedure. Each biopsy was analyzed in triplicate using a commercially available EIA kit.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic (PD) Response Rate</measure>
    <time_frame>Baseline to 7 days</time_frame>
    <description>Each participant will be assessed for PD response. The calculation is based on the standardized difference in means for the pharmacological effect on cGMP levels at the participant level, where a subject with a z &gt;= 1.645 will be considered a PD responder. A participant with a z &lt; 1.645 will be considered a non-responder. The PD response rate (percentage) of patients are summarized below by arm.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Grade 3 or Higher Diarrhea Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0</measure>
    <time_frame>Up to 21 days</time_frame>
    <description>The overall adverse event rates (percentages) for grade 3 or higher adverse events regardless of attribution to treatment are reported below. The percentages below are summarized for Diarrhea.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">27</enrollment>
  <condition>Colorectal Carcinoma</condition>
  <arm_group>
    <arm_group_label>Arm A (dolcanatide)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants receive dolcanatide PO QD for 7 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B (placebo)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants receive placebo PO QD for 7 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dolcanatide</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm A (dolcanatide)</arm_group_label>
    <other_name>SP 333</other_name>
    <other_name>SP-333</other_name>
    <other_name>SP333</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Arm A (dolcanatide)</arm_group_label>
    <arm_group_label>Arm B (placebo)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo Administration</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm B (placebo)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Questionnaire Administration</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Arm A (dolcanatide)</arm_group_label>
    <arm_group_label>Arm B (placebo)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  PRE-REGISTRATION INCLUSION&#xD;
&#xD;
          -  Able to understand and willingness to sign a written informed consent document and&#xD;
             follow study procedures&#xD;
&#xD;
          -  Willing to abstain from grapefruit juice during study&#xD;
&#xD;
          -  Willing to employ adequate contraception for men and women of childbearing potential;&#xD;
             Note: acceptable methods include double barrier methods, intrauterine device (IUD),&#xD;
             postmenopausal status documented by serum follicle stimulating hormone (FSH), and/or&#xD;
             documentation of surgical sterilization&#xD;
&#xD;
          -  Willing to provide blood and tissue specimens for research purposes&#xD;
&#xD;
          -  REGISTRATION INCLUSION&#xD;
&#xD;
          -  Normal organ function and have normal laboratory findings without clinically&#xD;
             significant findings&#xD;
&#xD;
          -  Leukocytes &gt;= 3 x 10^3/microliter (B/L)&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1.5 x 10^3/microliter (B/L)&#xD;
&#xD;
          -  Platelets &gt;= 100 x 10^3/microliter (B/L)&#xD;
&#xD;
          -  Total bilirubin within normal institutional limits&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/&#xD;
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =&lt; 1.5 x&#xD;
             institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  Creatinine =&lt; institutional upper limit of normal&#xD;
&#xD;
          -  Body mass index &lt; 35 kg/m^2&#xD;
&#xD;
          -  No findings in the rectum of advanced adenoma, chronic inflammation, or cancer&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  PRE-REGISTRATION EXCLUSION&#xD;
&#xD;
          -  Documented history of advanced adenomas (&gt;= 1 cm in maximal diameter, &gt;= 3 in total&#xD;
             number, villous morphology, or high-grade dysplasia) or colorectal cancer&#xD;
&#xD;
          -  Family history of polyposis syndrome (e.g., familial adenomatous polyposis [FAP],&#xD;
             hereditary nonpolyposis colorectal cancer [HNPCC]) or colorectal cancer (first degree&#xD;
             relatives younger than 60 years old)&#xD;
&#xD;
          -  History of gastroparesis&#xD;
&#xD;
          -  History of surgery involving the luminal gastrointestinal (GI) tract, including&#xD;
             bariatric surgery; exception: prior appendectomy &gt;= 60 days prior to pre-registration&#xD;
             is not an exclusion criterion&#xD;
&#xD;
          -  History of celiac disease&#xD;
&#xD;
          -  Inflammatory bowel disease (Crohn's disease, ulcerative colitis)&#xD;
&#xD;
          -  Previous diagnosis of irritable bowel syndrome, chronic constipation, functional bowel&#xD;
             disorders, colonic motility disorder, or opioid-induced constipation&#xD;
&#xD;
          -  Any malignancy within 3 years of baseline; exception: participants with a history of&#xD;
             basal cell or squamous cell skin cancer may be enrolled at the discretion of the&#xD;
             investigator&#xD;
&#xD;
          -  Currently receiving any other investigational agents&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to dolcanatide or to any of the excipients&#xD;
&#xD;
          -  History of difficulty with sigmoidoscopy or abnormal colorectal anatomy&#xD;
&#xD;
          -  Uncontrolled current illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Current use of laxatives more than 3 times per week&#xD;
&#xD;
          -  Current use of &gt;= 5 cigarettes/day&#xD;
&#xD;
          -  Current use of &gt;= 3 alcoholic drinks/day&#xD;
&#xD;
          -  Use of anti-coagulants or anti-platelet agents within 5 days prior to anticipated&#xD;
             sigmoidoscopy; exception: individuals taking aspirin will not be excluded and will not&#xD;
             be subject to a wash-out period&#xD;
&#xD;
          -  History of bleeding/coagulation problems&#xD;
&#xD;
          -  Any medical condition reported by the participant or documented in the medical record&#xD;
             that is judged by the investigator to constitute a risk to safe participation&#xD;
&#xD;
          -  Known or suspected mechanical gastrointestinal obstruction&#xD;
&#xD;
          -  REGISTRATION EXCLUSION&#xD;
&#xD;
          -  Sigmoidoscopy finding requiring clinical intervention&#xD;
&#xD;
          -  Use of any illicit or illegal substances detected by urinary drug screen&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David S Weinberg</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Thomas Jefferson University Hospital</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>October 2, 2017</study_first_submitted>
  <study_first_submitted_qc>October 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 3, 2017</study_first_posted>
  <results_first_submitted>November 7, 2019</results_first_submitted>
  <results_first_submitted_qc>December 4, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">December 17, 2019</results_first_posted>
  <last_update_submitted>May 19, 2021</last_update_submitted>
  <last_update_submitted_qc>May 19, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dolcanatide</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 6, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/70/NCT03300570/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>37 patients were pre-registered, where 10 were screen failures, leaving 27 patients who proceeded to randomization.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Arm A (Placebo)</title>
          <description>Participants receive placebo PO QD for 7 days. All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with placebo.</description>
        </group>
        <group group_id="P2">
          <title>Arm B (Dolcanatide)</title>
          <description>Participants receive dolcanatide PO QD for 7 days. All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with dolcanatide.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Inadequate bowel prep</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Arm A (Placebo)</title>
          <description>Participants receive placebo PO QD for 7 days. All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with placebo.</description>
        </group>
        <group group_id="B2">
          <title>Arm B (Dolcanatide)</title>
          <description>Participants receive dolcanatide PO QD for 7 days.All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with dolcanatide.</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="13"/>
            <count group_id="B2" value="14"/>
            <count group_id="B3" value="27"/>
          </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="44.2" spread="11.67"/>
                    <measurement group_id="B2" value="48.7" spread="5.72"/>
                    <measurement group_id="B3" value="46.6" spread="9.19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ECOG Performance Status = 0</title>
          <description>Eastern Cooperative Oncology Group PS Scale: 0)Fully active, able to carry on all pre-disease performance without restriction; 1)Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2)Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3)Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4)Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Pharmacological Effect on Cyclic Guanosine Monophosphate (cGMP) Levels for Dolcanatide Arm Versus (vs.) Placebo, as Measured by the Differences in Mean cGMP Levels After 7 Days of Intervention</title>
        <description>Pharmacological effect on cyclic guanosine monophosphate (cGMP) levels for dolcanatide arm versus (vs.) placebo, where this effect is defined as the arithmetic difference in mean cGMP levels before and after 7 days of dolcanatide from subject biopsies. This represents the increase in cGMP stimulated by 7 days of dolcanatide in an individual subject. The mean cGMP value will be calculated based on 6 biopsies collected from the rectum during a flexible sigmoidoscopy procedure. Each biopsy was analyzed in triplicate using a commercially available EIA kit.</description>
        <time_frame>Baseline to 7 days</time_frame>
        <population>Only patients who completed the study in the Participant Flow are included in this analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm B (Dolcanatide)</title>
            <description>Participants receive dolcanatide PO QD for 7 days.All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with dolcanatide.</description>
          </group>
          <group group_id="O2">
            <title>Arm A (Placebo)</title>
            <description>Participants receive placebo PO QD for 7 days. All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacological Effect on Cyclic Guanosine Monophosphate (cGMP) Levels for Dolcanatide Arm Versus (vs.) Placebo, as Measured by the Differences in Mean cGMP Levels After 7 Days of Intervention</title>
          <description>Pharmacological effect on cyclic guanosine monophosphate (cGMP) levels for dolcanatide arm versus (vs.) placebo, where this effect is defined as the arithmetic difference in mean cGMP levels before and after 7 days of dolcanatide from subject biopsies. This represents the increase in cGMP stimulated by 7 days of dolcanatide in an individual subject. The mean cGMP value will be calculated based on 6 biopsies collected from the rectum during a flexible sigmoidoscopy procedure. Each biopsy was analyzed in triplicate using a commercially available EIA kit.</description>
          <population>Only patients who completed the study in the Participant Flow are included in this analysis.</population>
          <units>pmol/mg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.42" spread="0.43"/>
                    <measurement group_id="O2" value="-0.22" spread="0.29"/>
                  </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</non_inferiority_type>
            <p_value>0.15</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pharmacodynamic (PD) Response Rate</title>
        <description>Each participant will be assessed for PD response. The calculation is based on the standardized difference in means for the pharmacological effect on cGMP levels at the participant level, where a subject with a z &gt;= 1.645 will be considered a PD responder. A participant with a z &lt; 1.645 will be considered a non-responder. The PD response rate (percentage) of patients are summarized below by arm.</description>
        <time_frame>Baseline to 7 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm B (Dolcanatide)</title>
            <description>Participants receive dolcanatide PO QD for 7 days. All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with dolcanatide.</description>
          </group>
          <group group_id="O2">
            <title>Arm A (Placebo)</title>
            <description>Participants receive placebo PO QD for 7 days. All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacodynamic (PD) Response Rate</title>
          <description>Each participant will be assessed for PD response. The calculation is based on the standardized difference in means for the pharmacological effect on cGMP levels at the participant level, where a subject with a z &gt;= 1.645 will be considered a PD responder. A participant with a z &lt; 1.645 will be considered a non-responder. The PD response rate (percentage) of patients are summarized below by arm.</description>
          <units>percentage of patients</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Grade 3 or Higher Diarrhea Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0</title>
        <description>The overall adverse event rates (percentages) for grade 3 or higher adverse events regardless of attribution to treatment are reported below. The percentages below are summarized for Diarrhea.</description>
        <time_frame>Up to 21 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm B (Dolcanatide)</title>
            <description>Participants receive dolcanatide PO QD for 7 days. All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with dolcanatide.</description>
          </group>
          <group group_id="O2">
            <title>Arm A (Placebo)</title>
            <description>Participants receive placebo PO QD for 7 days. All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Grade 3 or Higher Diarrhea Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0</title>
          <description>The overall adverse event rates (percentages) for grade 3 or higher adverse events regardless of attribution to treatment are reported below. The percentages below are summarized for Diarrhea.</description>
          <units>percentage of patients</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 21 days</time_frame>
      <desc>Each CTCAE term is a representation of a specific event used for medical documentation &amp; analysis &amp; is a single MedDRA Lowest Level Term (LLT). Serious AE (SAE) reports may include any secondary serious or non-serious events considered related to the primary event (the reason for filing an expedited report); collectively, these events are referred to as Expedited AEs, &amp; appear in the SAE table.</desc>
      <group_list>
        <group group_id="E1">
          <title>Arm A (Placebo)</title>
          <description>Participants receive placebo PO QD for 7 days. All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing withplacebo.</description>
        </group>
        <group group_id="E2">
          <title>Arm B (Dolcanatide)</title>
          <description>Participants receive dolcanatide PO QD for 7 days. All participants will undergo sigmoidoscopies at baseline and after seven days of daily dosing with dolcanatide.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA 12</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="48" subjects_affected="11" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="5" subjects_affected="1" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </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" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="14"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin and subcut tissue disord - Oth spec</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="4" subjects_affected="1" subjects_at_risk="14"/>
              </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>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>David Weinberg, M.D., M.Sc.</name_or_title>
      <organization>Fox Chase Cancer Center</organization>
      <phone>215-214-1424</phone>
      <email>david.weinberg@fccc.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03300570
org study id: NCI-2017-01783
secondary id: NCI-2017-01783
secondary id: N01-CN-2012-00042
secondary id: MAY2017-09-01
secondary id: MAY2017-09-01
secondary id: N01CN00042
secondary id: P30CA015083
nct id: NCT03300570
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies how well dolcanatide works in preventing colorectal cancer in
      healthy participants. Dolcanatide is similar to a natural hormone released into the
      intestine. It is thought that people who have low levels of the hormone are more likely to
      get colon cancer. It may be possible to prevent colon cancer by giving a drug that is similar
      to the hormone, such as dolcanatide.
PRIMARY OBJECTIVES:

      I. To identify the ability of dolcanatide (SP333), when administered as a single daily dose
      of 27 mg x 7 days, to induce a direct pharmacological effect on cGMP levels, based on biopsy
      samples from the rectum obtained pre- and post-intervention, as compared to placebo.

      SECONDARY OBJECTIVES:

      I. To assess the pharmacodynamic (PD) response rate between arms (dolcanatide versus
      placebo).

      II. To confirm the safety and tolerability of dolcanatide, as compared to placebo.

      OUTLINE: Participants are randomized to 1 of 2 arms.

      ARM A: Participants receive dolcanatide orally (PO) once daily (QD) for 7 days.

      ARM B: Participants receive placebo PO QD for 7 days.

      After completion of study, participants are followed up at 21 and 51 days.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Investigator)
measure: Pharmacological Effect on Cyclic Guanosine Monophosphate (cGMP) Levels for Dolcanatide Arm Versus (vs.) Placebo, as Measured by the Differences in Mean cGMP Levels After 7 Days of Intervention
time frame: Baseline to 7 days
description: Pharmacological effect on cyclic guanosine monophosphate (cGMP) levels for dolcanatide arm versus (vs.) placebo, where this effect is defined as the arithmetic difference in mean cGMP levels before and after 7 days of dolcanatide from subject biopsies. This represents the increase in cGMP stimulated by 7 days of dolcanatide in an individual subject. The mean cGMP value will be calculated based on 6 biopsies collected from the rectum during a flexible sigmoidoscopy procedure. Each biopsy was analyzed in triplicate using a commercially available EIA kit.
measure: Pharmacodynamic (PD) Response Rate
time frame: Baseline to 7 days
description: Each participant will be assessed for PD response. The calculation is based on the standardized difference in means for the pharmacological effect on cGMP levels at the participant level, where a subject with a z >= 1.645 will be considered a PD responder. A participant with a z < 1.645 will be considered a non-responder. The PD response rate (percentage) of patients are summarized below by arm.
measure: Percentage of Participants With Grade 3 or Higher Diarrhea Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
time frame: Up to 21 days
description: The overall adverse event rates (percentages) for grade 3 or higher adverse events regardless of attribution to treatment are reported below. The percentages below are summarized for Diarrhea.
arm group label: Arm A (dolcanatide)
arm group type: Experimental
description: Participants receive dolcanatide PO QD for 7 days.
arm group label: Arm B (placebo)
arm group type: Placebo Comparator
description: Participants receive placebo PO QD for 7 days.
intervention type: Drug
intervention name: Dolcanatide
description: Given PO
arm group label: Arm A (dolcanatide)
other name: SP 333
other name: SP-333
other name: SP333
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Arm A (dolcanatide)
arm group label: Arm B (placebo)
intervention type: Other
intervention name: Placebo Administration
description: Given PO
arm group label: Arm B (placebo)
intervention type: Other
intervention name: Questionnaire Administration
description: Ancillary studies
arm group label: Arm A (dolcanatide)
arm group label: Arm B (placebo)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: David S Weinberg
role: Principal Investigator
affiliation: Mayo Clinic
facility: 
country: United States
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Dolcanatide
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 