Dose Escalation Study to Investigate Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BAY85-3934 in Subjects With Chronic Kidney Disease (CKD)
- Registration Number
- NCT01679587
- Lead Sponsor
- Bayer
- 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
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 49
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Molidustat, 120 mg Molidustat (BAY85-3934) 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. Molidustat, 40 mg Molidustat (BAY85-3934) 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. Molidustat, 160 mg Molidustat (BAY85-3934) 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. Molidustat, 80 mg Placebo 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. Molidustat, 120 mg Placebo 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. Molidustat, 40 mg Placebo 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. Molidustat, 160 mg Placebo 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. Molidustat, 80 mg Molidustat (BAY85-3934) 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.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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
AUCnorm Pre-dose and up to 48 h post-dose AUC 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
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 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
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 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