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

Study Overview
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Brief Summary
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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

Official Title
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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)

Conditions
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Kidney Diseases

Intervention / Treatment
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* Drug: Molidustat (BAY85-3934)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Molidustat, 80 mg<br>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)<br>* 20 mg molidustat as a single tablet<br>Drug: Placebo<br>* Single oral dose of matching placebo will be given in each treatment arm<br>|
| Experimental: Molidustat, 120 mg<br>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)<br>* 20 mg molidustat as a single tablet<br>Drug: Placebo<br>* Single oral dose of matching placebo will be given in each treatment arm<br>|
| Experimental: Molidustat, 40 mg<br>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)<br>* 20 mg molidustat as a single tablet<br>Drug: Placebo<br>* Single oral dose of matching placebo will be given in each treatment arm<br>|
| Experimental: Molidustat, 160 mg<br>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)<br>* 20 mg molidustat as a single tablet<br>Drug: Placebo<br>* Single oral dose of matching placebo will be given in each treatment arm<br>|

What is the study measuring?
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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 |