<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/NCT02992236</url>
  </required_header>
  <id_info>
    <org_study_id>VAS203/I/3/05</org_study_id>
    <nct_id>NCT02992236</nct_id>
  </id_info>
  <brief_title>Effects of the NO-synthase Inhibitor VAS203 on Renal Function in Healthy Volunteers</brief_title>
  <official_title>Effects of the NO-synthase Inhibitor VAS203 on Renal Function in Healthy Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>veriNOS operations GmbH</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Winicker Norimed GmbH</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>veriNOS operations GmbH</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Analysis of the effect of the NO-Synthase inhibitor VAS203 (6 hours infusion of 10 mg/kg) on&#xD;
      renal function and perfusion in 16 healthy subjects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Analysis of the effect of i.v. VAS203 on renal function and perfusion in healthy subjects.&#xD;
&#xD;
      Primary objective:&#xD;
&#xD;
      Possible adverse effect of VAS203 on the Renal Plasma Flow (RPF) and the Glomerular&#xD;
      Filtration Rate (GFR) during and after 6 hours of constant-rate iv. infusion of 10 mg/kg&#xD;
      VAS203.&#xD;
&#xD;
      Secondary objective:&#xD;
&#xD;
      To analyse the effects of VAS203 on&#xD;
&#xD;
        -  filtration fraction&#xD;
&#xD;
        -  hemodynamics (afferent and efferent resistance, intraglomerular pressure)&#xD;
&#xD;
        -  markers of kidney injury and renal function&#xD;
&#xD;
        -  systolic, mean and diastolic brachial blood pressure&#xD;
&#xD;
        -  Plasma Pharmacokinetic of VAS203 and its first metabolite.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2015</start_date>
  <completion_date type="Actual">November 2016</completion_date>
  <primary_completion_date type="Actual">May 2016</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Renal Plasma Flow</measure>
    <time_frame>0, 2h, 4h, 6h and 8 h after start of infusion</time_frame>
    <description>Renal plasma flow measurement by para-Amino-Hippuric-Acid Clearance Method</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Glomerular Filtration Rate</measure>
    <time_frame>0, 2h, 4h, 6h and 8 h after start of infusion</time_frame>
    <description>by para-Amino-Hippuric Acid Clearance Method</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Serum Creatinine Concentration</measure>
    <time_frame>0, 2h, 4h, 6h, 8h, 10h, 24h and 48h after start of infusion</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Renal Function Impairment in Healthy Volunteers</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Infusion (6 hours) of Saline</description>
  </arm_group>
  <arm_group>
    <arm_group_label>VAS203</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Infusion (6 hours) of VAS203 (10 mg/kg)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>VAS203</intervention_name>
    <description>Infusion of NO-Synthase inhibitor VAS203</description>
    <arm_group_label>VAS203</arm_group_label>
    <other_name>Ronopterin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Saline</intervention_name>
    <description>Infusion of saline</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>0.9% sodium chloride</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Informed consent in writing available.&#xD;
&#xD;
          2. Willing and able to comply with all requirements of the study.&#xD;
&#xD;
          3. Male, 18 and 45 years (inclusive).&#xD;
&#xD;
          4. Subject has a body weight between 60 kg and 100 kg, extremes included.&#xD;
&#xD;
          5. BMI 18 to 27 kg/m2.&#xD;
&#xD;
          6. Non-smoker&#xD;
&#xD;
          7. Serum creatinine within reference range (≤1.2 mg/dL) and Cockroft-Gault Clearance &gt; 90&#xD;
             ml/min&#xD;
&#xD;
          8. Good general health as judged by the Investigator, as determined by medical history,&#xD;
             physical examination, vital signs (systolic and diastolic blood pressure and pulse&#xD;
             rate) and clinical laboratory parameters (clinical chemistry, hematology, and&#xD;
             urinalysis)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Clinically significant abnormalities in physical examination, vital signs or clinical&#xD;
             laboratory parameters (according to the Investigator's judgment).&#xD;
&#xD;
          2. Serum glutamate oxaloacetate transaminase or glutamate-pyruvate transaminase &gt; 2-times&#xD;
             above the upper limit of normal range.&#xD;
&#xD;
          3. Subject with Cockcroft-Gault clearance &lt; 90 ml/min.&#xD;
&#xD;
          4. Clinically significant history of cardiovascular disease or any known present&#xD;
             cardiovascular disease.&#xD;
&#xD;
          5. History of clinically significant neurological, gastrointestinal, renal, hepatic,&#xD;
             psychological, pulmonary, metabolic, endocrine, hematological, or other major&#xD;
             disorders.&#xD;
&#xD;
          6. Office blood pressure at screening higher than 160/100 mmHg, or lower than 95/55 mmHg.&#xD;
&#xD;
          7. Office heart rate at screening after at least 5 minutes outside the range of 50- 99&#xD;
             beats per minute (inclusive).&#xD;
&#xD;
          8. Concomitant use of OTC medication within 1 week prior to dosing, except use of&#xD;
             paracetamol (up to 2 g/day).&#xD;
&#xD;
          9. Participation in any other clinical study within 30 days prior to inclusion in this -&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Roland E Schmieder, Prof. Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universitätsklinik Erlangen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Universitätsklinik Erlangen</name>
      <address>
        <city>Erlangen</city>
        <zip>91054</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>December 7, 2016</study_first_submitted>
  <study_first_submitted_qc>December 9, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 14, 2016</study_first_posted>
  <results_first_submitted>March 21, 2019</results_first_submitted>
  <results_first_submitted_qc>August 8, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">August 9, 2019</results_first_posted>
  <last_update_submitted>August 8, 2019</last_update_submitted>
  <last_update_submitted_qc>August 8, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 9, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Cross-over design, all subjects received VAS203 and placebo</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo, Then VAS203</title>
          <description>Participants first received Placebo (6 hours Infusion of Saline). After a washout period of 4 weeks, they then received VAS203 (6 hours Infusion of 10 mg/kg VAS203).</description>
        </group>
        <group group_id="P2">
          <title>VAS203, Then Placebo</title>
          <description>Participants first received VAS203 (6 hours Infusion of 10 mg/kg VAS203). After a washout period of 4 weeks, they then received Placebo (6 hours Infusion of Saline).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </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>Placebo, Then VAS203</title>
          <description>Participants first received Placebo (6 hours Infusion of Saline). After a washout period of 4 weeks, they then received VAS203 (6 hours Infusion of 10 mg/kg VAS203).</description>
        </group>
        <group group_id="B2">
          <title>VAS203, Then Placebo</title>
          <description>Participants first received VAS203 (6 hours Infusion of 10 mg/kg VAS203). After a washout period of 4 weeks, they then received Placebo (6 hours Infusion of Saline).</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="8"/>
            <count group_id="B2" value="8"/>
            <count group_id="B3" value="16"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</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>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</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>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="31.2" spread="7.9"/>
                    <measurement group_id="B2" value="31.2" spread="7.9"/>
                    <measurement group_id="B3" value="31.2" spread="7.9"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="16"/>
                  </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>Germany</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Renal Plasma Flow</title>
        <description>Renal plasma flow measurement by para-Amino-Hippuric-Acid Clearance Method</description>
        <time_frame>0, 2h, 4h, 6h and 8 h after start of infusion</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Infusion (6 hours) of Saline&#xD;
Saline: Infusion of saline</description>
          </group>
          <group group_id="O2">
            <title>VAS203</title>
            <description>Infusion (6 hours) of VAS203 (10 mg/kg)&#xD;
VAS203: Infusion of NO-Synthase inhibitor VAS203</description>
          </group>
        </group_list>
        <measure>
          <title>Renal Plasma Flow</title>
          <description>Renal plasma flow measurement by para-Amino-Hippuric-Acid Clearance Method</description>
          <units>mL/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="541" spread="85"/>
                    <measurement group_id="O2" value="663" spread="125"/>
                  </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>&lt; 0.0001</p_value>
            <method>Mixed Models Analysis</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Glomerular Filtration Rate</title>
        <description>by para-Amino-Hippuric Acid Clearance Method</description>
        <time_frame>0, 2h, 4h, 6h and 8 h after start of infusion</time_frame>
        <group_list>
          <group group_id="O1">
            <title>VAS203</title>
            <description>Six hours infusion of 10 mg/kg VAS203.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Six hours Infusion of Saline</description>
          </group>
        </group_list>
        <measure>
          <title>Glomerular Filtration Rate</title>
          <description>by para-Amino-Hippuric Acid Clearance Method</description>
          <units>mL/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="135" spread="15"/>
                    <measurement group_id="O2" value="153.5" spread="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Serum Creatinine Concentration</title>
        <time_frame>0, 2h, 4h, 6h, 8h, 10h, 24h and 48h after start of infusion</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Infusion (6 hours) of Saline&#xD;
Saline: Infusion of saline</description>
          </group>
          <group group_id="O2">
            <title>VAS203</title>
            <description>Infusion (6 hours) of VAS203 (10 mg/kg)&#xD;
VAS203: Infusion of NO-Synthase inhibitor VAS203</description>
          </group>
        </group_list>
        <measure>
          <title>Serum Creatinine Concentration</title>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.91" spread="0.1"/>
                    <measurement group_id="O2" value="0.94" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Infusion (6 hours) of Saline&#xD;
Saline: Infusion of saline</description>
        </group>
        <group group_id="E2">
          <title>VAS203</title>
          <description>Infusion (6 hours) of VAS203 (10 mg/kg)&#xD;
VAS203: Infusion of NO-Synthase inhibitor VAS203</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="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_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="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" events="7" subjects_affected="5" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Prof Dr Rroland Schmieder</name_or_title>
      <organization>Nephrology University Erlangen Germany</organization>
      <phone>+49 9131 8536207</phone>
      <email>roland.schmieder@uk-erlangen.de</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/NCT02992236
org study id: VAS203/I/3/05
nct id: NCT02992236
lead sponsor: 
collaborator: 
has dmc: No
Analysis of the effect of the NO-Synthase inhibitor VAS203 (6 hours infusion of 10 mg/kg) on
      renal function and perfusion in 16 healthy subjects.
Analysis of the effect of i.v. VAS203 on renal function and perfusion in healthy subjects.

      Primary objective:

      Possible adverse effect of VAS203 on the Renal Plasma Flow (RPF) and the Glomerular
      Filtration Rate (GFR) during and after 6 hours of constant-rate iv. infusion of 10 mg/kg
      VAS203.

      Secondary objective:

      To analyse the effects of VAS203 on

        -  filtration fraction

        -  hemodynamics (afferent and efferent resistance, intraglomerular pressure)

        -  markers of kidney injury and renal function

        -  systolic, mean and diastolic brachial blood pressure

        -  Plasma Pharmacokinetic of VAS203 and its first metabolite.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Renal Plasma Flow
time frame: 0, 2h, 4h, 6h and 8 h after start of infusion
description: Renal plasma flow measurement by para-Amino-Hippuric-Acid Clearance Method
measure: Glomerular Filtration Rate
time frame: 0, 2h, 4h, 6h and 8 h after start of infusion
description: by para-Amino-Hippuric Acid Clearance Method
measure: Serum Creatinine Concentration
time frame: 0, 2h, 4h, 6h, 8h, 10h, 24h and 48h after start of infusion
arm group label: Placebo
arm group type: Placebo Comparator
description: Infusion (6 hours) of Saline
arm group label: VAS203
arm group type: Active Comparator
description: Infusion (6 hours) of VAS203 (10 mg/kg)
intervention type: Drug
intervention name: VAS203
description: Infusion of NO-Synthase inhibitor VAS203
arm group label: VAS203
other name: Ronopterin
intervention type: Drug
intervention name: Saline
description: Infusion of saline
arm group label: Placebo
other name: 0.9% sodium chloride
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Roland E Schmieder, Prof. Dr.
role: Principal Investigator
affiliation: Universitätsklinik Erlangen
facility: 
country: Germany
responsible party type: Sponsor
sharing ipd: Undecided
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 