<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/NCT01679587</url>
  </required_header>
  <id_info>
    <org_study_id>16370</org_study_id>
    <secondary_id>2012-002375-33</secondary_id>
    <nct_id>NCT01679587</nct_id>
  </id_info>
  <brief_title>Dose Escalation Study to Investigate Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BAY85-3934 in Subjects With Chronic Kidney Disease (CKD)</brief_title>
  <official_title>Multicenter, Randomized, Single-blind, Placebo-controlled, Combined 2-fold Cross-over and Group-comparison, Dose-escalation Study to Investigate Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Single Oral Doses of BAY 85-3934 in Subjects With Chronic Kidney Disease (CKD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Bayer</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary objective was to assess in subjects with CKD: Safety and tolerability of molidustat&#xD;
      (BAY 85-3934), effects of molidustat on non-invasive hemodynamics Secondary objectives were&#xD;
      to assess: Effects on pharmacodynamic parameters of erythropoiesis (erythropoietin,&#xD;
      reticulocytes, erythrocytes, hemoglobin, hematocrit), pharmacokinetics of molidustat,&#xD;
      exploratory biomarkers, ie, midregional pro-atrial natriuretic peptide, midregional&#xD;
      pro-adrenomedullin, plasma renin activity, and optionally B-type natriuretic peptide,&#xD;
      vascular endothelial growth factor, cyclic guanosine monophosphate, cyclic adenosine&#xD;
      monophosphate, and noradrenaline&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">July 2013</completion_date>
  <primary_completion_date type="Actual">February 2013</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>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with adverse events</measure>
    <time_frame>Approximately 9 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Blood pressure</measure>
    <time_frame>Approximately 9 weeks</time_frame>
    <description>Systolic, diastolic, mean blood pressure</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Heart rate</measure>
    <time_frame>Approximately 9 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>Maximum observed drug concentration in measured matrix after single dose administration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax/D</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>Cmax divided by dose</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>Area under the concentration vs time curve from zero to infinity after single dose</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC/D</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>AUC divided by dose</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Heart rate over 1 min</measure>
    <time_frame>Pre-dose and up to 24 h post-dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Standing blood pressure procedure</measure>
    <time_frame>Starting from 2 h post-dose and up to 4 h post-dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Impedance cardiography</measure>
    <time_frame>Pre-dose and up tp 8 h post-dose</time_frame>
    <description>Stroke volume, heart rate, cardiac index, cardiac output, and total peripheral resistance</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of hematology profile</measure>
    <time_frame>From baseline to Day 1 after single dose</time_frame>
    <description>Hematology profile includes blood concentration of erythropoietin, reticulocytes, erythrocytes, hemoglobin, hematocrit, and exploratory biomarkers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax,norm</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>Cmax divided by dose per body weight</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUCnorm</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>AUC divided by dose per body weight</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(0-24)</measure>
    <time_frame>Pre-dose and up to 24 h post-dose</time_frame>
    <description>AUC from 0 until 24 h after study drug administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(0-tlast)</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>AUC from time 0 to the last data point &gt; lower limit of quantification</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>t½</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>Half-life associated with the terminal slope</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tmax</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>Time to reach Cmax (in case of two identical Cmax values, the first tmax was used)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MRT</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>Mean residence time</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CL/F</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>Total body clearance of drug calculated after extravascular administration (eg, apparent oral clearance)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vz/F</measure>
    <time_frame>Pre-dose and up to 48 h post-dose</time_frame>
    <description>Apparent volume of distribution during terminal phase after extravascular administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric mean erythropoietin Cmax</measure>
    <time_frame>Pre-dose and up to 24 h post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric mean reticulocyte count</measure>
    <time_frame>Pre-dose and up to 24 h post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric mean erythrocyte count</measure>
    <time_frame>Pre-dose and up to 24 h post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric mean reticulocytes/erythrocytes values</measure>
    <time_frame>Pre-dose and up to 24 h post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric mean hemoglobin values</measure>
    <time_frame>Pre-dose and up to 24 h post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric mean hematocrit</measure>
    <time_frame>Pre-dose and up to 24 h post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric mean erythropoietin tmax</measure>
    <time_frame>Pre-dose and up to 24 h post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Geometric mean erythropoietin AUC(0-24)</measure>
    <time_frame>Pre-dose and up to 24 h post-dose</time_frame>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">49</enrollment>
  <condition>Kidney Diseases</condition>
  <arm_group>
    <arm_group_label>Molidustat, 80 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects received a single oral dose of 80 mg BAY 85-3934 in the first period and placebo in the second period, separated by a wash-out period of at least 1 week.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Molidustat, 120 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects received a single oral dose of 120 mg BAY 85-3934 in the first period and placebo in the second period, separated by a wash-out period of at least 1 week.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Molidustat, 40 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects received a single oral dose of 40 mg BAY 85-3934 in the first period and placebo in the second period, separated by a wash-out period of at least 1 week. This is an optional dose escalation step.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Molidustat, 160 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects received a single oral dose of 160 mg BAY 85-3934 in the first period and placebo in the second period, separated by a wash-out period of at least 1 week. This is an optional dose escalation step.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Molidustat (BAY85-3934)</intervention_name>
    <description>20 mg molidustat as a single tablet</description>
    <arm_group_label>Molidustat, 120 mg</arm_group_label>
    <arm_group_label>Molidustat, 160 mg</arm_group_label>
    <arm_group_label>Molidustat, 40 mg</arm_group_label>
    <arm_group_label>Molidustat, 80 mg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Single oral dose of matching placebo will be given in each treatment arm</description>
    <arm_group_label>Molidustat, 120 mg</arm_group_label>
    <arm_group_label>Molidustat, 160 mg</arm_group_label>
    <arm_group_label>Molidustat, 40 mg</arm_group_label>
    <arm_group_label>Molidustat, 80 mg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Presence of chronic kidney disease (CKD) not on dialysis assessed by medical history&#xD;
             and eGFR (MDRD) = &lt; 60 mL/min estimated at the pre-study visit&#xD;
&#xD;
          -  Stable renal disease, ie not expected to begin dialysis during the study&#xD;
&#xD;
          -  Systolic blood pressure =&gt;110 mmHg and =&lt;160 mmHg&#xD;
&#xD;
          -  Heart rate =&lt;100 BPM&#xD;
&#xD;
          -  Hemoglobin = &gt;9 g/dL&#xD;
&#xD;
          -  Female subjects without child-bearing potential, ie postmenopausal women with 12&#xD;
             months of spontaneous amenorrhea or with 6 months of spontaneous amenorrhea and serum&#xD;
             FSH levels &gt;30 mIU/mL, women with 6 weeks post bilateral ovariectomy, women with&#xD;
             bilateral tubal ligation, and women with hysterectomy&#xD;
&#xD;
          -  Body mass index (BMI): = &gt;18 and = &lt; 35 kg/m2 at the pre-study visit&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Incompletely cured pre-existing diseases for which a relevant impairment of&#xD;
             absorption, distribution, metabolism, elimination or effects of the study drug is&#xD;
             assumed&#xD;
&#xD;
          -  Known hypersensitivity to the study drugs (active substances or excipients of the&#xD;
             preparations)&#xD;
&#xD;
          -  Known severe allergies, non-allergic drug reactions, or multiple drug allergies&#xD;
&#xD;
          -  Chronic heart failure, New York Heart Association (NYHA) III-IV&#xD;
&#xD;
          -  Coronary artery disease with uncured significant stenosis&#xD;
&#xD;
          -  Angina pectoris&#xD;
&#xD;
          -  Significant stenosis of cerebral vessels&#xD;
&#xD;
          -  Significant uncorrected rhythm or conduction disturbances such as a second- or&#xD;
             third-degree atrioventricular block without a cardiac pacemaker or episodes of&#xD;
             sustained ventricular tachycardia&#xD;
&#xD;
          -  Subjects with impaired liver function (Child Pugh B to C based on medical history)&#xD;
&#xD;
          -  History of thrombotic or thromboembolic events (eg myocardial infarction, stroke,&#xD;
             transient ischemic attack, deep vein thrombosis, pulmonary embolism) within the recent&#xD;
             6 months&#xD;
&#xD;
          -  Proliferative choroidal or retinal disease, such as neovascular age-related macular&#xD;
             degeneration or proliferative diabetic retinopathy that required or is likely to&#xD;
             require treatment (intraocular injections or laser photocoagulation) during the study&#xD;
&#xD;
          -  Subjects with a history of malignant disease during the last 5 years&#xD;
&#xD;
          -  Treatment with EPO-stimulating agents (ESA) or rhEPO within the last 2 weeks before&#xD;
             first intake of study drug&#xD;
&#xD;
          -  Suspicion of drug or alcohol abuse&#xD;
&#xD;
          -  Positive results for hepatitis B virus surface antigen (HBsAg), hepatitis C virus&#xD;
             antibodies (anti-HCV), human immune deficiency virus antibodies (anti-HIV 1+2) at the&#xD;
             pre-study visit&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>79 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bayer Study Director</last_name>
    <role>Study Director</role>
    <affiliation>Bayer</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>München</city>
        <state>Bayern</state>
        <zip>81241</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Mönchengladbach</city>
        <state>Nordrhein-Westfalen</state>
        <zip>41061</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Kiel</city>
        <state>Schleswig-Holstein</state>
        <zip>24105</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <link>
    <url>http://www.clinicaltrialsregister.eu/</url>
    <description>Click here to find information about studies related to Bayer Healthcare products conducted in Europe.</description>
  </link>
  <verification_date>April 2016</verification_date>
  <study_first_submitted>September 3, 2012</study_first_submitted>
  <study_first_submitted_qc>September 3, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 6, 2012</study_first_posted>
  <last_update_submitted>April 29, 2016</last_update_submitted>
  <last_update_submitted_qc>April 29, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 2, 2016</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>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</mesh_term>
  </condition_browse>
  <!-- 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/NCT01679587
org study id: 16370
secondary id: 2012-002375-33
nct id: NCT01679587
lead sponsor: 
has dmc: No
Primary objective was to assess in subjects with CKD: Safety and tolerability of molidustat
      (BAY 85-3934), effects of molidustat on non-invasive hemodynamics Secondary objectives were
      to assess: Effects on pharmacodynamic parameters of erythropoiesis (erythropoietin,
      reticulocytes, erythrocytes, hemoglobin, hematocrit), pharmacokinetics of molidustat,
      exploratory biomarkers, ie, midregional pro-atrial natriuretic peptide, midregional
      pro-adrenomedullin, plasma renin activity, and optionally B-type natriuretic peptide,
      vascular endothelial growth factor, cyclic guanosine monophosphate, cyclic adenosine
      monophosphate, and noradrenaline
allocation: Randomized
intervention model: Crossover Assignment
masking: Single (Participant)
measure: Number of participants with adverse events
time frame: Approximately 9 weeks
measure: Blood pressure
time frame: Approximately 9 weeks
description: Systolic, diastolic, mean blood pressure
measure: Heart rate
time frame: Approximately 9 weeks
measure: Cmax
time frame: Pre-dose and up to 48 h post-dose
description: Maximum observed drug concentration in measured matrix after single dose administration
measure: Cmax/D
time frame: Pre-dose and up to 48 h post-dose
description: Cmax divided by dose
measure: AUC
time frame: Pre-dose and up to 48 h post-dose
description: Area under the concentration vs time curve from zero to infinity after single dose
measure: AUC/D
time frame: Pre-dose and up to 48 h post-dose
description: AUC divided by dose
measure: Heart rate over 1 min
time frame: Pre-dose and up to 24 h post-dose
measure: Standing blood pressure procedure
time frame: Starting from 2 h post-dose and up to 4 h post-dose
measure: Impedance cardiography
time frame: Pre-dose and up tp 8 h post-dose
description: Stroke volume, heart rate, cardiac index, cardiac output, and total peripheral resistance
measure: Change of hematology profile
time frame: From baseline to Day 1 after single dose
description: Hematology profile includes blood concentration of erythropoietin, reticulocytes, erythrocytes, hemoglobin, hematocrit, and exploratory biomarkers.
measure: Cmax,norm
time frame: Pre-dose and up to 48 h post-dose
description: Cmax divided by dose per body weight
measure: AUCnorm
time frame: Pre-dose and up to 48 h post-dose
description: AUC divided by dose per body weight
measure: AUC(0-24)
time frame: Pre-dose and up to 24 h post-dose
description: AUC from 0 until 24 h after study drug administration
measure: AUC(0-tlast)
time frame: Pre-dose and up to 48 h post-dose
description: AUC from time 0 to the last data point > lower limit of quantification
measure: t½
time frame: Pre-dose and up to 48 h post-dose
description: Half-life associated with the terminal slope
measure: tmax
time frame: Pre-dose and up to 48 h post-dose
description: Time to reach Cmax (in case of two identical Cmax values, the first tmax was used)
measure: MRT
time frame: Pre-dose and up to 48 h post-dose
description: Mean residence time
measure: CL/F
time frame: Pre-dose and up to 48 h post-dose
description: Total body clearance of drug calculated after extravascular administration (eg, apparent oral clearance)
measure: Vz/F
time frame: Pre-dose and up to 48 h post-dose
description: Apparent volume of distribution during terminal phase after extravascular administration
measure: Geometric mean erythropoietin Cmax
time frame: Pre-dose and up to 24 h post-dose
measure: Geometric mean reticulocyte count
time frame: Pre-dose and up to 24 h post-dose
measure: Geometric mean erythrocyte count
time frame: Pre-dose and up to 24 h post-dose
measure: Geometric mean reticulocytes/erythrocytes values
time frame: Pre-dose and up to 24 h post-dose
measure: Geometric mean hemoglobin values
time frame: Pre-dose and up to 24 h post-dose
measure: Geometric mean hematocrit
time frame: Pre-dose and up to 24 h post-dose
measure: Geometric mean erythropoietin tmax
time frame: Pre-dose and up to 24 h post-dose
measure: Geometric mean erythropoietin AUC(0-24)
time frame: Pre-dose and up to 24 h post-dose
arm group label: Molidustat, 80 mg
arm group type: Experimental
description: Subjects received a single oral dose of 80 mg BAY 85-3934 in the first period and placebo in the second period, separated by a wash-out period of at least 1 week.
arm group label: Molidustat, 120 mg
arm group type: Experimental
description: Subjects received a single oral dose of 120 mg BAY 85-3934 in the first period and placebo in the second period, separated by a wash-out period of at least 1 week.
arm group label: Molidustat, 40 mg
arm group type: Experimental
description: Subjects received a single oral dose of 40 mg BAY 85-3934 in the first period and placebo in the second period, separated by a wash-out period of at least 1 week. This is an optional dose escalation step.
arm group label: Molidustat, 160 mg
arm group type: Experimental
description: Subjects received a single oral dose of 160 mg BAY 85-3934 in the first period and placebo in the second period, separated by a wash-out period of at least 1 week. This is an optional dose escalation step.
intervention type: Drug
intervention name: Molidustat (BAY85-3934)
description: 20 mg molidustat as a single tablet
arm group label: Molidustat, 120 mg
arm group label: Molidustat, 160 mg
arm group label: Molidustat, 40 mg
arm group label: Molidustat, 80 mg
intervention type: Drug
intervention name: Placebo
description: Single oral dose of matching placebo will be given in each treatment arm
arm group label: Molidustat, 120 mg
arm group label: Molidustat, 160 mg
arm group label: Molidustat, 40 mg
arm group label: Molidustat, 80 mg
criteria: 
gender: All
minimum age: 18 Years
maximum age: 79 Years
healthy volunteers: No
last name: Bayer Study Director
role: Study Director
affiliation: Bayer
facility: 
facility: 
facility: 
country: Germany
url: http://www.clinicaltrialsregister.eu/
description: Click here to find information about studies related to Bayer Healthcare products conducted in Europe.
responsible party type: Sponsor
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic