Clinical trial NCT01679587: Dose Escalation Study to Investigate Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BAY85-3934 in Subjects With Chronic Kidney Disease (CKD)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Kidney Diseases
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2012-09-06
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER

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


Eligibility 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

Primary outcomes:
measure: Number of participants with adverse events
timeFrame: Approximately 9 weeks
measure: Blood pressure
timeFrame: Approximately 9 weeks
measure: Heart rate
timeFrame: Approximately 9 weeks
measure: Cmax
timeFrame: Pre-dose and up to 48 h post-dose
measure: Cmax/D
timeFrame: Pre-dose and up to 48 h post-dose
measure: AUC
timeFrame: Pre-dose and up to 48 h post-dose
measure: AUC/D
timeFrame: Pre-dose and up to 48 h post-dose
measure: Heart rate over 1 min
timeFrame: Pre-dose and up to 24 h post-dose
measure: Standing blood pressure procedure
timeFrame: Starting from 2 h post-dose and up to 4 h post-dose
measure: Impedance cardiography
timeFrame: Pre-dose and up tp 8 h post-dose
Secondary outcomes:
measure: Change of hematology profile
timeFrame: From baseline to Day 1 after single dose
measure: Cmax,norm
timeFrame: Pre-dose and up to 48 h post-dose
measure: AUCnorm
timeFrame: Pre-dose and up to 48 h post-dose
measure: AUC(0-24)
timeFrame: Pre-dose and up to 24 h post-dose
measure: AUC(0-tlast)
timeFrame: Pre-dose and up to 48 h post-dose
measure: t½
timeFrame: Pre-dose and up to 48 h post-dose
measure: tmax
timeFrame: Pre-dose and up to 48 h post-dose
measure: MRT
timeFrame: Pre-dose and up to 48 h post-dose
measure: CL/F
timeFrame: Pre-dose and up to 48 h post-dose
measure: Vz/F
timeFrame: Pre-dose and up to 48 h post-dose
measure: Geometric mean erythropoietin Cmax
timeFrame: Pre-dose and up to 24 h post-dose
measure: Geometric mean reticulocyte count
timeFrame: Pre-dose and up to 24 h post-dose
measure: Geometric mean erythrocyte count
timeFrame: Pre-dose and up to 24 h post-dose
measure: Geometric mean reticulocytes/erythrocytes values
timeFrame: Pre-dose and up to 24 h post-dose
measure: Geometric mean hemoglobin values
timeFrame: Pre-dose and up to 24 h post-dose
measure: Geometric mean hematocrit
timeFrame: Pre-dose and up to 24 h post-dose
measure: Geometric mean erythropoietin tmax
timeFrame: Pre-dose and up to 24 h post-dose
measure: Geometric mean erythropoietin AUC(0-24)
timeFrame: Pre-dose and up to 24 h post-dose
Other outcomes:
Locations:
city: München
country: Germany
state: Bayern
city: Mönchengladbach
country: Germany
state: Nordrhein-Westfalen
city: Kiel
country: Germany
state: Schleswig-Holstein
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.