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

Kidney Diseases Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01679587
• Other study ID #: 16370
• Secondary ID: 2012-002375-33
• Status: Completed
• Phase: Phase 1
• First received: September 3, 2012
• Last updated: April 29, 2016
• Start date: September 2012
• Est. completion date: July 2013

Study information

• Verified date: April 2016
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 49
• Est. completion date: July 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 79 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject)

Related Conditions & MeSH terms

• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• Molidustat (BAY85-3934)
20 mg molidustat as a single tablet
• Placebo
Single oral dose of matching placebo will be given in each treatment arm

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with adverse events		Approximately 9 weeks	Yes
Primary	Blood pressure	Systolic, diastolic, mean blood pressure	Approximately 9 weeks	Yes
Primary	Heart rate		Approximately 9 weeks	Yes
Primary	Cmax	Maximum observed drug concentration in measured matrix after single dose administration	Pre-dose and up to 48 h post-dose	No
Primary	Cmax/D	Cmax divided by dose	Pre-dose and up to 48 h post-dose	No
Primary	AUC	Area under the concentration vs time curve from zero to infinity after single dose	Pre-dose and up to 48 h post-dose	No
Primary	AUC/D	AUC divided by dose	Pre-dose and up to 48 h post-dose	No
Primary	Heart rate over 1 min		Pre-dose and up to 24 h post-dose	No
Primary	Standing blood pressure procedure		Starting from 2 h post-dose and up to 4 h post-dose	No
Primary	Impedance cardiography	Stroke volume, heart rate, cardiac index, cardiac output, and total peripheral resistance	Pre-dose and up tp 8 h post-dose	No
Secondary	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	No
Secondary	Cmax,norm	Cmax divided by dose per body weight	Pre-dose and up to 48 h post-dose	No
Secondary	AUCnorm	AUC divided by dose per body weight	Pre-dose and up to 48 h post-dose	No
Secondary	AUC(0-24)	AUC from 0 until 24 h after study drug administration	Pre-dose and up to 24 h post-dose	No
Secondary	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	No
Secondary	t½	Half-life associated with the terminal slope	Pre-dose and up to 48 h post-dose	No
Secondary	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	No
Secondary	MRT	Mean residence time	Pre-dose and up to 48 h post-dose	No
Secondary	CL/F	Total body clearance of drug calculated after extravascular administration (eg, apparent oral clearance)	Pre-dose and up to 48 h post-dose	No
Secondary	Vz/F	Apparent volume of distribution during terminal phase after extravascular administration	Pre-dose and up to 48 h post-dose	No
Secondary	Geometric mean erythropoietin Cmax		Pre-dose and up to 24 h post-dose	Yes
Secondary	Geometric mean reticulocyte count		Pre-dose and up to 24 h post-dose	Yes
Secondary	Geometric mean erythrocyte count		Pre-dose and up to 24 h post-dose	Yes
Secondary	Geometric mean reticulocytes/erythrocytes values		Pre-dose and up to 24 h post-dose	Yes
Secondary	Geometric mean hemoglobin values		Pre-dose and up to 24 h post-dose	Yes
Secondary	Geometric mean hematocrit		Pre-dose and up to 24 h post-dose	Yes
Secondary	Geometric mean erythropoietin tmax		Pre-dose and up to 24 h post-dose	No
Secondary	Geometric mean erythropoietin AUC(0-24)		Pre-dose and up to 24 h post-dose	No

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