Kidney Diseases
Conditions
Brief 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
Interventions
20 mg molidustat as a single tablet
DRUGPlacebo
Single oral dose of matching placebo will be given in each treatment arm
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with adverse events | Approximately 9 weeks | — |
| Blood pressure | Approximately 9 weeks | Systolic, diastolic, mean blood pressure |
| Heart rate | Approximately 9 weeks | — |
| Cmax | Pre-dose and up to 48 h post-dose | Maximum observed drug concentration in measured matrix after single dose administration |
| Cmax/D | Pre-dose and up to 48 h post-dose | Cmax divided by dose |
| AUC | Pre-dose and up to 48 h post-dose | Area under the concentration vs time curve from zero to infinity after single dose |
| AUC/D | Pre-dose and up to 48 h post-dose | AUC divided by 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 | Pre-dose and up tp 8 h post-dose | Stroke volume, heart rate, cardiac index, cardiac output, and total peripheral resistance |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| AUCnorm | Pre-dose and up to 48 h post-dose | AUC divided by dose per body weight |
| 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 | — |
| Geometric mean hemoglobin values | Pre-dose and up to 24 h post-dose | — |
| Change of hematology profile | From baseline to Day 1 after single dose | Hematology profile includes blood concentration of erythropoietin, reticulocytes, erythrocytes, hemoglobin, hematocrit, and exploratory biomarkers. |
| Cmax,norm | Pre-dose and up to 48 h post-dose | Cmax divided by dose per body weight |
| AUC(0-24) | Pre-dose and up to 24 h post-dose | AUC from 0 until 24 h after study drug administration |
| AUC(0-tlast) | Pre-dose and up to 48 h post-dose | AUC from time 0 to the last data point \> lower limit of quantification |
| t½ | Pre-dose and up to 48 h post-dose | Half-life associated with the terminal slope |
| tmax | Pre-dose and up to 48 h post-dose | Time to reach Cmax (in case of two identical Cmax values, the first tmax was used) |
| MRT | Pre-dose and up to 48 h post-dose | Mean residence time |
| CL/F | Pre-dose and up to 48 h post-dose | Total body clearance of drug calculated after extravascular administration (eg, apparent oral clearance) |
| Vz/F | Pre-dose and up to 48 h post-dose | Apparent volume of distribution during terminal phase after extravascular administration |
Countries
Germany
Outcome results
None listed