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

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)

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

Study Overview

• Status: Completed
• Conditions: Kidney Diseases
• Intervention / Treatment: Drug: Molidustat (BAY85-3934); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Bayern
    • München, Bayern, Germany, 81241
  • Nordrhein-Westfalen
    • Mönchengladbach, Nordrhein-Westfalen, Germany, 41061
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events		Approximately 9 weeks
Blood pressure	Systolic, diastolic, mean blood pressure	Approximately 9 weeks
Heart rate		Approximately 9 weeks
Cmax	Maximum observed drug concentration in measured matrix after single dose administration	Pre-dose and up to 48 h post-dose
Cmax/D	Cmax divided by dose	Pre-dose and up to 48 h post-dose
AUC	Area under the concentration vs time curve from zero to infinity after single dose	Pre-dose and up to 48 h post-dose
AUC/D	AUC divided by dose	Pre-dose and up to 48 h post-dose
Heart rate over 1 min		Pre-dose and up to 24 h post-dose
Standing blood pressure procedure		Starting from 2 h post-dose and up to 4 h post-dose
Impedance cardiography	Stroke volume, heart rate, cardiac index, cardiac output, and total peripheral resistance	Pre-dose and up tp 8 h post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of hematology profile	Hematology profile includes blood concentration of erythropoietin, reticulocytes, erythrocytes, hemoglobin, hematocrit, and exploratory biomarkers.	From baseline to Day 1 after single dose
Cmax,norm	Cmax divided by dose per body weight	Pre-dose and up to 48 h post-dose
AUCnorm	AUC divided by dose per body weight	Pre-dose and up to 48 h post-dose
AUC(0-24)	AUC from 0 until 24 h after study drug administration	Pre-dose and up to 24 h post-dose
AUC(0-tlast)	AUC from time 0 to the last data point > lower limit of quantification	Pre-dose and up to 48 h post-dose
t½	Half-life associated with the terminal slope	Pre-dose and up to 48 h post-dose
tmax	Time to reach Cmax (in case of two identical Cmax values, the first tmax was used)	Pre-dose and up to 48 h post-dose
MRT	Mean residence time	Pre-dose and up to 48 h post-dose
CL/F	Total body clearance of drug calculated after extravascular administration (eg, apparent oral clearance)	Pre-dose and up to 48 h post-dose
Vz/F	Apparent volume of distribution during terminal phase after extravascular administration	Pre-dose and up to 48 h post-dose
Geometric mean erythropoietin Cmax		Pre-dose and up to 24 h post-dose
Geometric mean reticulocyte count		Pre-dose and up to 24 h post-dose
Geometric mean erythrocyte count		Pre-dose and up to 24 h post-dose
Geometric mean reticulocytes/erythrocytes values		Pre-dose and up to 24 h post-dose
Geometric mean hemoglobin values		Pre-dose and up to 24 h post-dose
Geometric mean hematocrit		Pre-dose and up to 24 h post-dose
Geometric mean erythropoietin tmax		Pre-dose and up to 24 h post-dose
Geometric mean erythropoietin AUC(0-24)		Pre-dose and up to 24 h post-dose

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: September 3, 2012
• First Submitted That Met QC Criteria: September 3, 2012
• First Posted (Estimate): September 6, 2012

Study Record Updates

• Last Update Posted (Estimate): May 2, 2016
• Last Update Submitted That Met QC Criteria: April 29, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic
• Other Study ID Numbers: 16370; 2012-002375-33 (EudraCT Number)