dose escalation study to investigate safety, tolerability, pharmacodynamics, and pharmacokinetics of bay85-3934 in subjects with chronic kidney disease (ckd)

Conditions: Kidney Diseases

Summary: 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


Eligibility 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