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Dose Escalation Study to Investigate Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BAY85-3934 in Subjects With Chronic Kidney Disease (CKD)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01679587
First received: September 3, 2012
Last updated: April 29, 2016
Last verified: April 2016
  Purpose
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

Condition Intervention Phase
Kidney Diseases
Drug: Molidustat (BAY85-3934)
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
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)

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Number of participants with adverse events [ Time Frame: Approximately 9 weeks ] [ Designated as safety issue: Yes ]
  • Blood pressure [ Time Frame: Approximately 9 weeks ] [ Designated as safety issue: Yes ]
    Systolic, diastolic, mean blood pressure

  • Heart rate [ Time Frame: Approximately 9 weeks ] [ Designated as safety issue: Yes ]
  • Cmax [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    Maximum observed drug concentration in measured matrix after single dose administration

  • Cmax/D [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    Cmax divided by dose

  • AUC [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    Area under the concentration vs time curve from zero to infinity after single dose

  • AUC/D [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    AUC divided by dose

  • Heart rate over 1 min [ Time Frame: Pre-dose and up to 24 h post-dose ] [ Designated as safety issue: No ]
  • Standing blood pressure procedure [ Time Frame: Starting from 2 h post-dose and up to 4 h post-dose ] [ Designated as safety issue: No ]
  • Impedance cardiography [ Time Frame: Pre-dose and up tp 8 h post-dose ] [ Designated as safety issue: No ]
    Stroke volume, heart rate, cardiac index, cardiac output, and total peripheral resistance


Secondary Outcome Measures:
  • Change of hematology profile [ Time Frame: From baseline to Day 1 after single dose ] [ Designated as safety issue: No ]
    Hematology profile includes blood concentration of erythropoietin, reticulocytes, erythrocytes, hemoglobin, hematocrit, and exploratory biomarkers.

  • Cmax,norm [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    Cmax divided by dose per body weight

  • AUCnorm [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    AUC divided by dose per body weight

  • AUC(0-24) [ Time Frame: Pre-dose and up to 24 h post-dose ] [ Designated as safety issue: No ]
    AUC from 0 until 24 h after study drug administration

  • AUC(0-tlast) [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    AUC from time 0 to the last data point > lower limit of quantification

  • t½ [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    Half-life associated with the terminal slope

  • tmax [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    Time to reach Cmax (in case of two identical Cmax values, the first tmax was used)

  • MRT [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    Mean residence time

  • CL/F [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    Total body clearance of drug calculated after extravascular administration (eg, apparent oral clearance)

  • Vz/F [ Time Frame: Pre-dose and up to 48 h post-dose ] [ Designated as safety issue: No ]
    Apparent volume of distribution during terminal phase after extravascular administration

  • Geometric mean erythropoietin Cmax [ Time Frame: Pre-dose and up to 24 h post-dose ] [ Designated as safety issue: Yes ]
  • Geometric mean reticulocyte count [ Time Frame: Pre-dose and up to 24 h post-dose ] [ Designated as safety issue: Yes ]
  • Geometric mean erythrocyte count [ Time Frame: Pre-dose and up to 24 h post-dose ] [ Designated as safety issue: Yes ]
  • Geometric mean reticulocytes/erythrocytes values [ Time Frame: Pre-dose and up to 24 h post-dose ] [ Designated as safety issue: Yes ]
  • Geometric mean hemoglobin values [ Time Frame: Pre-dose and up to 24 h post-dose ] [ Designated as safety issue: Yes ]
  • Geometric mean hematocrit [ Time Frame: Pre-dose and up to 24 h post-dose ] [ Designated as safety issue: Yes ]
  • Geometric mean erythropoietin tmax [ Time Frame: Pre-dose and up to 24 h post-dose ] [ Designated as safety issue: No ]
  • Geometric mean erythropoietin AUC(0-24) [ Time Frame: Pre-dose and up to 24 h post-dose ] [ Designated as safety issue: No ]

Enrollment: 49
Study Start Date: September 2012
Study Completion Date: July 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Molidustat, 80 mg
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.
Drug: Molidustat (BAY85-3934)
20 mg molidustat as a single tablet
Drug: Placebo
Single oral dose of matching placebo will be given in each treatment arm
Experimental: Molidustat, 120 mg
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.
Drug: Molidustat (BAY85-3934)
20 mg molidustat as a single tablet
Drug: Placebo
Single oral dose of matching placebo will be given in each treatment arm
Experimental: Molidustat, 40 mg
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.
Drug: Molidustat (BAY85-3934)
20 mg molidustat as a single tablet
Drug: Placebo
Single oral dose of matching placebo will be given in each treatment arm
Experimental: Molidustat, 160 mg
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.
Drug: Molidustat (BAY85-3934)
20 mg molidustat as a single tablet
Drug: Placebo
Single oral dose of matching placebo will be given in each treatment arm

  Eligibility

Ages Eligible for Study:   18 Years to 79 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Presence of chronic kidney disease (CKD) not on dialysis assessed by medical history and eGFR (MDRD) = < 60 mL/min estimated at the pre-study visit
  • Stable renal disease, ie not expected to begin dialysis during the study
  • Systolic blood pressure =>110 mmHg and =<160 mmHg
  • Heart rate =<100 BPM
  • Hemoglobin = >9 g/dL
  • Female subjects without child-bearing potential, ie postmenopausal women with 12 months of spontaneous amenorrhea or with 6 months of spontaneous amenorrhea and serum FSH levels >30 mIU/mL, women with 6 weeks post bilateral ovariectomy, women with bilateral tubal ligation, and women with hysterectomy
  • Body mass index (BMI): = >18 and = < 35 kg/m2 at the pre-study visit

Exclusion Criteria:

  • Incompletely cured pre-existing diseases for which a relevant impairment of absorption, distribution, metabolism, elimination or effects of the study drug is assumed
  • Known hypersensitivity to the study drugs (active substances or excipients of the preparations)
  • Known severe allergies, non-allergic drug reactions, or multiple drug allergies
  • Chronic heart failure, New York Heart Association (NYHA) III-IV
  • Coronary artery disease with uncured significant stenosis
  • Angina pectoris
  • Significant stenosis of cerebral vessels
  • Significant uncorrected rhythm or conduction disturbances such as a second- or third-degree atrioventricular block without a cardiac pacemaker or episodes of sustained ventricular tachycardia
  • Subjects with impaired liver function (Child Pugh B to C based on medical history)
  • History of thrombotic or thromboembolic events (eg myocardial infarction, stroke, transient ischemic attack, deep vein thrombosis, pulmonary embolism) within the recent 6 months
  • Proliferative choroidal or retinal disease, such as neovascular age-related macular degeneration or proliferative diabetic retinopathy that required or is likely to require treatment (intraocular injections or laser photocoagulation) during the study
  • Subjects with a history of malignant disease during the last 5 years
  • Treatment with EPO-stimulating agents (ESA) or rhEPO within the last 2 weeks before first intake of study drug
  • Suspicion of drug or alcohol abuse
  • Positive results for hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibodies (anti-HCV), human immune deficiency virus antibodies (anti-HIV 1+2) at the pre-study visit
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01679587

Locations
Germany
München, Bayern, Germany, 81241
Mönchengladbach, Nordrhein-Westfalen, Germany, 41061
Kiel, Schleswig-Holstein, Germany, 24105
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01679587     History of Changes
Other Study ID Numbers: 16370  2012-002375-33 
Study First Received: September 3, 2012
Last Updated: April 29, 2016
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Kidney Diseases
Renal Insufficiency, Chronic
Urologic Diseases
Renal Insufficiency

ClinicalTrials.gov processed this record on September 29, 2016