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

Bayer

Status and phase: Completed; Phase 1

Conditions: Kidney Diseases

Treatments: Drug: Placebo; Drug: Molidustat (BAY85-3934)

Study type: Interventional

Funder types: Industry

Identifiers

NCT01679587

2012-002375-33 (EudraCT Number)

16370

Details and patient eligibility

About

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

Enrollment: 49 patients

Sex: All

Ages: 18 to 79 years old

Volunteers: No Healthy Volunteers

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

Trial design

49 participants in 4 patient groups

Molidustat, 80 mg

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Molidustat (BAY85-3934)

Molidustat, 120 mg

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Molidustat (BAY85-3934)

Molidustat, 40 mg

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Molidustat (BAY85-3934)

Molidustat, 160 mg

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Drug: Molidustat (BAY85-3934)