Dose Escalation Study to Investigate Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BAY85-3934 in Subjects With Chronic Kidney Disease (CKD)
Study Details
Study Description
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| 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
|
Outcome Measures
Primary Outcome Measures
- 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
- 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
- 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 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]
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | München | Bayern | Germany | 81241 | |
| 2 | Mönchengladbach | Nordrhein-Westfalen | Germany | 41061 | |
| 3 | Kiel | Schleswig-Holstein | Germany | 24105 |
Sponsors and Collaborators
- Bayer
Investigators
- Study Director: Bayer Study Director, Bayer
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 16370
- 2012-002375-33