<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/NCT03019653</url>
  </required_header>
  <id_info>
    <org_study_id>16-001847</org_study_id>
    <secondary_id>R01HL084155-06A1</secondary_id>
    <nct_id>NCT03019653</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of ANX-042 in Human Cardiorenal Syndrome</brief_title>
  <acronym>ANX-042 Aim 1</acronym>
  <official_title>A Phase Ib, Double-Blind, Placebo-Controlled, Single-site Trial to Determine the Safety and Efficacy of a Novel Renal-Specific Peptide, ANX-042, in Enhancing GFR Without Significant Hypotension in Human Cardiorenal Syndrome (CRS): ANX-042 Aim #1</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Mayo Clinic</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to look at kidney function and hormonal function in patients&#xD;
      with a history of heart failure and kidney dysfunction, and to see how the use of a new drug,&#xD;
      ANX-042, affects those functions.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Subjects will have a choice of admitting the night prior to renal clearance study day or the&#xD;
      day of. Subjects will admit (fasting) to the Clinical Research and Trials Unit, after 3 weeks&#xD;
      of diet compliance, the morning of the first renal clearance study day. They will avoid&#xD;
      taking any sulfa containing medications and Probenecid for 72 hours prior to Visit Two and&#xD;
      Visit Three. They will complete a 24-hour urine collection which will be assessed for&#xD;
      creatinine clearance, microalbumin and sodium concentration and excretion. A pregnancy test&#xD;
      will be performed, if necessary. Their first urine void after admitting will be collected for&#xD;
      protein analysis. Brief physical exam (same as at Visit 1) will be performed by a qualified&#xD;
      Study Team Member. Their usual morning dose of medications will be held until given initial&#xD;
      water load prior to start of renal clearance infusion. Echocardiogram to determine systolic,&#xD;
      diastolic function and cardiac output will be performed prior to the start of study drug&#xD;
      infusion. A bladder ultrasound will be performed after their first void. If subject is unable&#xD;
      to sufficiently empty their bladder, a urinary catheter will be placed with their permission.&#xD;
      The subjects will be placed in the supine position for 1 hour. During the first 15 minutes,&#xD;
      two standard intravenous (IV) catheters will be placed (one in each arm). One catheter will&#xD;
      be used for infusion and the other (in the contralateral arm) for blood sampling. Subjects&#xD;
      will be asked to drink 5 mL/Kg of water initially and then drink an amount equal to the urine&#xD;
      output, and blood drawn, after each clearance period to ensure sufficient urinary flow. A&#xD;
      priming dose (calculated according to body size) of iothalamate (0.06 mg/Kg) to measure&#xD;
      glomerular filtration rate (GFR) will be infused, followed by a constant rate IV sustaining&#xD;
      dose (calculated according to estimated kidney function) of iothalamate to achieve&#xD;
      steady-state plasma concentrations of 15 to 20 mg/L. The subjects will be asked to empty&#xD;
      their bladder spontaneously at the end of each clearance period.&#xD;
&#xD;
      After an equilibration period of 45 minutes, urine and blood samples will be collected at&#xD;
      30-minutes to determine the baseline GFR and urinary sodium excretion (UNaV). Blood pressure&#xD;
      will be measured at 20-minute intervals for the first 2 hours, then every 30 minutes, by&#xD;
      using automatic blood pressure cuff. Heart rate will be continuously monitored by&#xD;
      electrocardiography. Urinary samples for determination of volume, sodium, potassium, and&#xD;
      iothalamate will be obtained at the end of each clearance period. Venous blood samples for&#xD;
      iothalamate and sodium will be obtained at the middle of each clearance period. During the&#xD;
      first clearance, venous blood samples for renin, aldosterone, angiotensin II, AnxA1, Atrial&#xD;
      Natriuretic Peptide (ANP), Brain natriuretic peptide (BNP) and cGMP will be obtained and&#xD;
      urine samples for Annexin A1(AnxA1) and cyclic guanosine monophosphate (cGMP) will also be&#xD;
      obtained. Buffy coat from Ethylenediaminetetraacetic acid (EDTA) vacutainer tubes will be&#xD;
      saved for possible future DNA analysis.&#xD;
&#xD;
      After the baseline renal clearance, subjects will be randomized to receive infusion of active&#xD;
      study drug or placebo for 8 hours. The research pharmacist will prepare the study drug or&#xD;
      placebo infusion, thus both the patients and investigators will be blinded. Renal clearance&#xD;
      and blood draws will be carried out every 2 hours during the infusion as described above (4&#xD;
      times), and blood draw for assays at the end of 4 and 8 hours infusion as listed above.&#xD;
      Another echocardiogram will be repeated after 4 hour of drug infusion. Subjects will be given&#xD;
      3 meals throughout the day. Dismissal will occur after one hour of post-infusion monitoring.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date>January 2017</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</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>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Glomerular Filtration Rate</measure>
    <time_frame>baseline to 3 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Sodium Excretion</measure>
    <time_frame>baseline to 3 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Urine Flow</measure>
    <time_frame>baseline to 3 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Blood Pressure</measure>
    <time_frame>baseline to 3 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Renin-angiotensin-aldosterone system (RAAS)</measure>
    <time_frame>baseline to 3 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Urine Annexin A1 (AnxA1) Protein Levels</measure>
    <time_frame>baseline to 3 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Subjects with Hypotension</measure>
    <time_frame>3 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Heart Failure</condition>
  <condition>Cardiorenal Disease</condition>
  <condition>Renal Disfunction</condition>
  <arm_group>
    <arm_group_label>ANX-042 first, then Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In the first intervention period the subjects will receive an infusion of ANX-042. There will be a 3 week washout period. In the second intervention period, the subjects will receive an infusion of placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo first, then ANX-042</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In the first intervention period the subjects will receive placebo. There will be a 3 week washout period. In the second intervention period, the subjects will receive an infusion of ANX-042.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ANX-042</intervention_name>
    <description>The first 20 subjects will receive a dose 0.003 µg/kg/min by infusion, the next 20 subjects will receive a dose of 0.006 µg/kg/min, then the next 20 subjects will receive 0.01 µg/kg/min.</description>
    <arm_group_label>ANX-042 first, then Placebo</arm_group_label>
    <arm_group_label>Placebo first, then ANX-042</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>The pharmacy created a placebo for this study is sterile Dextrose (5%) solution (D5W) 0.9% Sodium Chloride for intravenous administration to match study drug.</description>
    <arm_group_label>ANX-042 first, then Placebo</arm_group_label>
    <arm_group_label>Placebo first, then ANX-042</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Left ventricular ejection fraction of equal or less than 40% assessed by&#xD;
             echocardiography, nuclear scan, MRI or left ventriculogram within the past 48 months.&#xD;
             If assessment is greater than 12 months old, hand-held echocardiogram (ECHO)&#xD;
             determination will be performed at consent visit once enrolled.&#xD;
&#xD;
          -  Stable New York Heart Association (NYHA) class II and III symptoms as defined by: no&#xD;
             change in NYHA symptoms over the past 3 months, on stable doses of furosemide,&#xD;
             angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type 1 (AT1) blocker,&#xD;
             beta blocker, or aldosterone antagonist over the last 4 weeks and no episode of&#xD;
             decompensated Congestive Heart Failure (CHF) over the past 6 months.&#xD;
&#xD;
          -  Calculated creatinine clearance of equal or less than 89 ml/min and greater than 20&#xD;
             ml/min, using the Modification of Diet in Renal Disease (MDRD) formula assessed within&#xD;
             the past 48 months and a confirmatory calculated creatinine clearance equal or less&#xD;
             than 89 ml/min and greater than 20 ml/min at the time of enrollment.&#xD;
&#xD;
          -  Digoxin, antiarrhythmic medications and other vasodilators will be allowed; however,&#xD;
             all medications must be at stable doses 4 weeks prior to enrollment. Subjects taking&#xD;
             non-steroidal anti-inflammatory drugs (NSAIDs), except aspirin, will not be able to&#xD;
             increase their medication dose for the duration of the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior diagnosis of intrinsic renal diseases, such as glomerular nephritis or&#xD;
             polycystic kidney disease, including renal artery stenosis of &gt; 50% (unless&#xD;
             revascularized)&#xD;
&#xD;
          -  Peritoneal or hemodialysis within 90 days or anticipation that dialysis or&#xD;
             ultrafiltration of any form will be required during the study period&#xD;
&#xD;
          -  Hospitalization for decompensated CHF during the past 6 months&#xD;
&#xD;
          -  Myocardial infarction within 6 months of screening&#xD;
&#xD;
          -  Unstable angina within 6 months of screening, or any evidence of acute myocardial&#xD;
             ischemia&#xD;
&#xD;
          -  Significant valvular stenosis (greater than moderate in severity) , hypertrophic,&#xD;
             restrictive or obstructive cardiomyopathy, constrictive pericarditis, primary&#xD;
             pulmonary hypertension, or biopsy proven active myocarditis&#xD;
&#xD;
          -  Severe congenital heart diseases&#xD;
&#xD;
          -  Sustained ventricular tachycardia or ventricular fibrillation within 14 days of&#xD;
             screening&#xD;
&#xD;
          -  Second or third degree heart block without a permanent cardiac pacemaker&#xD;
&#xD;
          -  Stroke within 3 months of screening, or other evidence of significantly compromised&#xD;
             central nervous system (CNS) perfusion&#xD;
&#xD;
          -  Alanine transaminase (ALT) &gt;2 times the upper limit of normal&#xD;
&#xD;
          -  Serum sodium of &lt; 125 milliequivalent/dL (mEq/dL) or &gt; 160 mEq/dL&#xD;
&#xD;
          -  Serum potassium of &lt; 3.0 mEq/dL or &gt; 5.7 mEq/dL&#xD;
&#xD;
          -  Hemoglobin &lt; 8.5 gm/dl&#xD;
&#xD;
          -  Other acute or chronic medical conditions or laboratory abnormality which may increase&#xD;
             the risks associated with study participation or may interfere with interpretation of&#xD;
             the data&#xD;
&#xD;
          -  Have received an investigational drug within 1 month prior to dosing&#xD;
&#xD;
          -  Patients with an allergy to iodine&#xD;
&#xD;
          -  Female subject who is pregnant or breastfeeding&#xD;
&#xD;
          -  In the opinion of the investigator, is unlikely to comply with the study protocol or&#xD;
             is unsuitable for any reasons&#xD;
&#xD;
          -  Documented systolic blood pressure less than 90 mmHg at consent visit&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paul M McKie, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic in Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.mayo.edu/research/clinical-trials</url>
    <description>Mayo Clinic Clinical Trials</description>
  </link>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 11, 2017</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 12, 2017</study_first_posted>
  <last_update_submitted>March 7, 2023</last_update_submitted>
  <last_update_submitted_qc>March 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Mayo Clinic</investigator_affiliation>
    <investigator_full_name>Paul M. McKie, M.D.</investigator_full_name>
    <investigator_title>PI</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Renal Insufficiency</mesh_term>
    <mesh_term>Cardio-Renal Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03019653
org study id: 16-001847
secondary id: R01HL084155-06A1
nct id: NCT03019653
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
The purpose of this study is to look at kidney function and hormonal function in patients
      with a history of heart failure and kidney dysfunction, and to see how the use of a new drug,
      ANX-042, affects those functions.
Subjects will have a choice of admitting the night prior to renal clearance study day or the
      day of. Subjects will admit (fasting) to the Clinical Research and Trials Unit, after 3 weeks
      of diet compliance, the morning of the first renal clearance study day. They will avoid
      taking any sulfa containing medications and Probenecid for 72 hours prior to Visit Two and
      Visit Three. They will complete a 24-hour urine collection which will be assessed for
      creatinine clearance, microalbumin and sodium concentration and excretion. A pregnancy test
      will be performed, if necessary. Their first urine void after admitting will be collected for
      protein analysis. Brief physical exam (same as at Visit 1) will be performed by a qualified
      Study Team Member. Their usual morning dose of medications will be held until given initial
      water load prior to start of renal clearance infusion. Echocardiogram to determine systolic,
      diastolic function and cardiac output will be performed prior to the start of study drug
      infusion. A bladder ultrasound will be performed after their first void. If subject is unable
      to sufficiently empty their bladder, a urinary catheter will be placed with their permission.
      The subjects will be placed in the supine position for 1 hour. During the first 15 minutes,
      two standard intravenous (IV) catheters will be placed (one in each arm). One catheter will
      be used for infusion and the other (in the contralateral arm) for blood sampling. Subjects
      will be asked to drink 5 mL/Kg of water initially and then drink an amount equal to the urine
      output, and blood drawn, after each clearance period to ensure sufficient urinary flow. A
      priming dose (calculated according to body size) of iothalamate (0.06 mg/Kg) to measure
      glomerular filtration rate (GFR) will be infused, followed by a constant rate IV sustaining
      dose (calculated according to estimated kidney function) of iothalamate to achieve
      steady-state plasma concentrations of 15 to 20 mg/L. The subjects will be asked to empty
      their bladder spontaneously at the end of each clearance period.

      After an equilibration period of 45 minutes, urine and blood samples will be collected at
      30-minutes to determine the baseline GFR and urinary sodium excretion (UNaV). Blood pressure
      will be measured at 20-minute intervals for the first 2 hours, then every 30 minutes, by
      using automatic blood pressure cuff. Heart rate will be continuously monitored by
      electrocardiography. Urinary samples for determination of volume, sodium, potassium, and
      iothalamate will be obtained at the end of each clearance period. Venous blood samples for
      iothalamate and sodium will be obtained at the middle of each clearance period. During the
      first clearance, venous blood samples for renin, aldosterone, angiotensin II, AnxA1, Atrial
      Natriuretic Peptide (ANP), Brain natriuretic peptide (BNP) and cGMP will be obtained and
      urine samples for Annexin A1(AnxA1) and cyclic guanosine monophosphate (cGMP) will also be
      obtained. Buffy coat from Ethylenediaminetetraacetic acid (EDTA) vacutainer tubes will be
      saved for possible future DNA analysis.

      After the baseline renal clearance, subjects will be randomized to receive infusion of active
      study drug or placebo for 8 hours. The research pharmacist will prepare the study drug or
      placebo infusion, thus both the patients and investigators will be blinded. Renal clearance
      and blood draws will be carried out every 2 hours during the infusion as described above (4
      times), and blood draw for assays at the end of 4 and 8 hours infusion as listed above.
      Another echocardiogram will be repeated after 4 hour of drug infusion. Subjects will be given
      3 meals throughout the day. Dismissal will occur after one hour of post-infusion monitoring.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
measure: Change in Glomerular Filtration Rate
time frame: baseline to 3 weeks
measure: Change in Sodium Excretion
time frame: baseline to 3 weeks
measure: Change in Urine Flow
time frame: baseline to 3 weeks
measure: Change in Blood Pressure
time frame: baseline to 3 weeks
measure: Change in Renin-angiotensin-aldosterone system (RAAS)
time frame: baseline to 3 weeks
measure: Change in Urine Annexin A1 (AnxA1) Protein Levels
time frame: baseline to 3 weeks
measure: Number of Subjects with Hypotension
time frame: 3 weeks
arm group label: ANX-042 first, then Placebo
arm group type: Active Comparator
description: In the first intervention period the subjects will receive an infusion of ANX-042. There will be a 3 week washout period. In the second intervention period, the subjects will receive an infusion of placebo
arm group label: Placebo first, then ANX-042
arm group type: Active Comparator
description: In the first intervention period the subjects will receive placebo. There will be a 3 week washout period. In the second intervention period, the subjects will receive an infusion of ANX-042.
intervention type: Drug
intervention name: ANX-042
description: The first 20 subjects will receive a dose 0.003 µg/kg/min by infusion, the next 20 subjects will receive a dose of 0.006 µg/kg/min, then the next 20 subjects will receive 0.01 µg/kg/min.
arm group label: ANX-042 first, then Placebo
arm group label: Placebo first, then ANX-042
intervention type: Drug
intervention name: Placebo
description: The pharmacy created a placebo for this study is sterile Dextrose (5%) solution (D5W) 0.9% Sodium Chloride for intravenous administration to match study drug.
arm group label: ANX-042 first, then Placebo
arm group label: Placebo first, then ANX-042
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Paul M McKie, MD
role: Principal Investigator
affiliation: Mayo Clinic
facility: 
country: United States
url: https://www.mayo.edu/research/clinical-trials
description: Mayo Clinic Clinical Trials
responsible party type: Principal Investigator
investigator affiliation: Mayo Clinic
investigator full name: Paul M. McKie, M.D.
investigator title: PI
mesh term: Renal Insufficiency
mesh term: Cardio-Renal Syndrome
sharing ipd: No