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)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Bayer
- 入组人数
- 49
- 主要终点
- Number of participants with adverse events
研究概览
简要总结
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 79 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Molidustat (BAY85-3934) (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Molidustat (BAY85-3934) (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Molidustat (BAY85-3934) (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Molidustat (BAY85-3934) (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of participants with adverse events
时间窗: Approximately 9 weeks
Blood pressure
时间窗: Approximately 9 weeks
Systolic, diastolic, mean blood pressure
Heart rate
时间窗: Approximately 9 weeks
Cmax
时间窗: Pre-dose and up to 48 h post-dose
Maximum observed drug concentration in measured matrix after single dose administration
Cmax/D
时间窗: Pre-dose and up to 48 h post-dose
Cmax divided by dose
AUC
时间窗: 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
时间窗: Pre-dose and up to 48 h post-dose
AUC divided by dose
Heart rate over 1 min
时间窗: Pre-dose and up to 24 h post-dose
Standing blood pressure procedure
时间窗: Starting from 2 h post-dose and up to 4 h post-dose
Impedance cardiography
时间窗: Pre-dose and up tp 8 h post-dose
Stroke volume, heart rate, cardiac index, cardiac output, and total peripheral resistance
次要结局
- Change of hematology profile(From baseline to Day 1 after single dose)
- Cmax,norm(Pre-dose and up to 48 h post-dose)
- AUCnorm(Pre-dose and up to 48 h post-dose)
- AUC(0-24)(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)
- AUC(0-tlast)(Pre-dose and up to 48 h post-dose)
- t½(Pre-dose and up to 48 h post-dose)
- tmax(Pre-dose and up to 48 h post-dose)
- MRT(Pre-dose and up to 48 h post-dose)
- CL/F(Pre-dose and up to 48 h post-dose)
- Vz/F(Pre-dose and up to 48 h post-dose)
- 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)