Randomized, Single-blind, Placebo-controlled, Combined Single / Multiple Dose Escalation, Group Comparison Study to Investigate Safety, Tolerability, Pharmacodynamic Effect and Pharmacokinetics of BAY 85-3934 in Patients With Renal Anemia Due to CKD (Stages 3 and 4)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Bayer
- 入组人数
- 44
- 主要终点
- Mean Change in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Within 4 hours Post-dose
研究概览
简要总结
The drug that is under investigation during this study is BAY85-3934 which is intended to be used as a treatment for patients suffering from renal anemia due to chronic kidney disease (stage 3 and 4).
The purpose of this study is to provide safety and tolerability information on the drug. Other objectives of the study are to investigate the effect of the drug on the body (pharmacodynamics) as well as the absorption, breakdown, metabolism, distribution and excretion (pharmacokinetics) by measuring the concentration in blood and urine.
The study will be conducted in one study center in the United Kingdom and several centers in Germany. 84 (of which 36 are optional) patients who meet the inclusion criteria will participate in the study. BAY 85-3934 will be given following a combined single / multiple dose escalation design in seven (of which three are optional) dose steps.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The informed consent must be signed before any study specific tests or procedures are done
- •Renal anemia due to CKD (stage 3 and 4) not on dialysis assessed by medical history and Creatine Clearance (CLCR) between 15 to 59 mL/min ± 10 % (ie CLCR between 13 - 65 mL/min) estimated at the pre-study visit from the creatinine concentration measured in serum (Modification of Diet in Renal Disease (MDRD) formula)
- •Stable renal disease, ie without major changes in therapy within the last 6 weeks and not expected to begin dialysis within the study.
- •Female subjects with no child-bearing potential (postmenopausal women with 12 month of spontaneous amenorrhea or with 6 month of spontaneous amenorrhea and serum FSH levels > 30 mIU/mL, women with 6 weeks post bilateral ovariectomy, woman with bilateral tubal ligation, and women with hysterectomy).
- •Male subjects who agree to use two forms of effective contraception during the study and for 12 weeks after receiving the study drug. This must include a condom with spermicide gel for 21 days after drug administration.
- •Male subjects who agree not to act as sperm donors for 12 weeks after dosing.
- •Age: ≥ 18 and ≤ 85 years at the pre-study visit
- •Body mass index (BMI): ≥ 18 and ≤ 35 kg / m2 at the pre-study visit
- •Hemoglobin (Hb) of 8.0 - 12 g/dL (male) or 8.0 - 11.5 g/dL (female) at two consecutive measurements (1 measurement performed within 12 weeks to 2 days before the pre-study visit during routine diagnostics independently of the study and 1 measurement at the pre-study visit)
- •Ability to understand and follow study-related instructions
排除标准
- •Incompletely cured pre-existing diseases for which it can be assumed that the absorption, distribution, metabolism, elimination and effects of the study drugs will not be normal
- •Known hypersensitivity to the study drugs (active substances or excipients of the preparations)
- •Known severe allergies, non-allergic drug reactions, or multiple drug allergies
- •Patients with impaired liver function (Child Pugh B and C based on medical history)
- •Patients with hemolysis/hemolytic anemia or active bleeding/blood loss
- •Major surgery or an intervention causing relevant blood loss or inflammation within the last 2 month
- •Planned intervention or surgery during the study which might impact the study objectives.
- •Febrile illness within 1 week before the first study drug administration or clinically significant infection.
- •Patients with chronic inflammatory diseases (eg systemic lupus erythematosis, rheumatoid arthritis, Crohn´s disease) that could impact erythropoiesis or with persistent inflammatory activity (eg C-reactive protein (CRP) > 20mg/L)
- •History of thrombotic or thromboembolic events (e.g. 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.
- •History of myelodysplastic syndrome, multiple myeloma, bone marrow fibrosis, or pure red cell aplasia.
- •History of hemosiderosis or hemochromatosis.
- •Patients with a history of malignant disease during the last 5 years
- •Treatment with erythropoiesis stimulating agents (ESA) within the last 4 weeks before first intake of study drug
- •Intravenous iron substitution 2 weeks before and during the treatment period with BAY 85-3934
- •RBC transfusion during previous 8 weeks
- •Use of products containing carnitine and/or anabolics
- •Use of medicines or substances which oppose the study objectives or which might influence them within 14 days before the first study drug administration
- •Significant uncorrected rhythm or conduction disturbances such as a second- or third-degree AV block without a cardiac pacemaker or episodes of sustained ventricular tachycardia
- •Systolic blood pressure below 100 or above 160 mmHg at the pre-study visit
- •Diastolic blood pressure below 50 or above 100 mmHg at the pre-study visit
- •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
- •Heart rate above 110 bpm
- •Ferritin levels ≤ 30 ng/mL at the pre-study visit
- •Transferrin-saturation < 15% at the pre-study visit
研究组 & 干预措施
Placebo
干预措施: BAY85-3934 (Drug)
Molidustat (BAY85-3934) 5 mg
干预措施: BAY85-3934 (Drug)
Molidustat (BAY85-3934) 10 mg
干预措施: BAY85-3934 (Drug)
Molidustat (BAY85-3934) 25 mg
干预措施: BAY85-3934 (Drug)
Molidustat (BAY85-3934) 50 mg
干预措施: BAY85-3934 (Drug)
Molidustat (BAY85-3934) 75 mg
干预措施: BAY85-3934 (Drug)
结局指标
主要结局
Mean Change in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Within 4 hours Post-dose
时间窗: Within 4 hours post-dose at Day 1 and Day 14
SBP, DBP was observed in all treatment groups in supine phase.
Number of Subjects with Clinically Relevant Abnormal Findings in the Electrocardiogram (ECG)
时间窗: Day 1 and Day 14
Electrocardiograms were recorded and analyzed by an electronic ECG reading system.
Number of Subjects with Clinically Relevant Laboratory Values
时间窗: Day 1 and Day 14
Laboratory parameters include hematology, coagulation, serum chemistry, urinalysis.
Maximum Observed Drug Concentration (Cmax) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat
时间窗: Single dose: 0-48 hours post-dose
Cmax refers to the highest measured drug concentration after a single dose which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Maximum Observed Drug Concentration Divided by Dose (Cmax/D) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat
时间窗: Single dose: 0-48 hours post-dose
Cmax/D is defined as maximum observed drug concentration divided by dose. Cmax refers to the highest measured drug concentration after single dose which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat
时间窗: Single dose: 0-48 hours post-dose
AUC is a measure of systemic drug exposure after single dose, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC is defined as area under concentration versus time curve from time 0 (pre-dose) to extrapolated infinite time. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Number of Subjects with Treatment-Emergent Adverse Events (TEAE)
时间窗: From start of study drug administration until last follow-up visit (14 days after the last study drug administration)
An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important serious event. TEAEs were defined as AEs/SAEs that started or worsened after the study drug treatment.
Mean Change in Heart Rate Within 4 hours Post-dose
时间窗: Within 4 hours from after administration of study drug on Day 1 and Day 14
Heart rate was observed in all treatment groups in supine position.
Mean Change in Heart Rate Over 1 Minute for Doses 25, 50, 75 Milligrams
时间窗: From start of study drug administration until 12 hours after the last study drug administration
Heart rate was assessed over 1 minute from the Electrocardiogram (ECG) recording.
Maximum Observed Drug Concentration in Plasma Divided by Dose (Cmax,md/D) of Molidustat and its Metabolite After Multiple Dose Administration of Molidustat
时间窗: Multiple dose: 0-24 hours post dose on Day 14 (13d)
Cmax,md/D is defined as maximum observed drug concentration divided by dose after multiple dose administration. Cmax,md refers to the highest measured drug concentration within the dosing interval which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Area Under the Concentration Versus Time Curve From 0 to 24 hour (AUC[0-24]md) in Plasma During any Dose Interval of Molidustat and its Metabolite After Multiple Dose of Molidustat
时间窗: Multiple dose: 0-24 hours post dose on Day 14 (13d)
AUC(0-24)md is defined as area under the concentration versus time curve from 0 to 24 hour after multiple dose. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Area Under the Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat
时间窗: Single dose: 0-48 hours post-dose
AUC is a measure of systemic drug exposure after single dose, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. AUC is defined as area under concentration versus time curve from time 0 (pre-dose) to extrapolated infinite time. AUC/D is defined as area under the concentration versus time curve from zero to infinity divided by dose. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Maximum Observed Drug Concentration (Cmax,md) in Plasma of Molidustat and its Metabolite After Multiple Dose Administration of Molidustat
时间窗: Multiple dose: 0-24 hours post dose on Day 14 (13d)
Cmax,md defined as maximum observed drug concentration after multiple dose. Cmax,md refers to the highest measured drug concentration in the dosing interval which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
Area Under the Concentration Versus Time Curve From 0 to 24 hour Divided by Dose (AUC[0-24] md/D) in Plasma During any Dose Interval of Molidustat and its Metabolite After Multiple Dose of Molidustat
时间窗: Multiple dose: 0-24 hours post dose on Day 14 (13d)
AUC(0-24)md/D is defined as area under the concentration versus time curve from 0 to 24 hour divided by dose after multiple dose. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
次要结局
- Maximum Observed Drug Concentration in Plasma Divided by Dose per Kilogram Body Weight (Cmax,norm) of Molidustat and its Metabolite After Single Dose of Molidustat(Single dose: 0-48 hours post-dose)
- Area Under the Concentration Versus Time Curve From Zero to Infinity in Plasma Divided by Dose per Kilogram Body Weight (AUCnorm) of Molidustat and its Metabolite After Single Dose of Molidustat(Single dose: 0-48 hours post-dose)
- Area Under the Concentration Versus Time Curve From Zero to 24 hour (AUC[0-24]) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat(Single dose: 0-24 hours post-dose)
- Area Under the Concentration Versus Time Curve From Zero to the Last Data Point Above the Lower Limit of Quantification (AUC[0-tlast]) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat(Single dose: 0-48 hours post-dose)
- Time to Reach Maximum Drug Concentration (tmax) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat(Single dose: 0-48 hours post-dose)
- Mean Residence Time (MRT) of Molidustat and its Metabolite After Single Dose of Molidustat(Single dose: 0-48 hours post-dose)
- Apparent Oral Clearance (CL/F) of Molidustat and its Metabolite After Single Dose of Molidustat(Single dose: 0-48 hours post-dose)
- Apparent Volume of Distribution During Terminal Phase (Vz/F) After Single Dose of Molidustat(Single dose: 0-48 hours post-dose)
- Amount Excreted into Urine (Aeur) of Molidustat and its Metabolite After Single Dose of Molidustat(Urine collection intervals: 0d00 - 0d12h, 0d12h - 1d00)
- Renal Body Clearance of Drug (CLR) of Molidustat and its Metabolite After Single Dose of Molidustat(Urine collection interval: 0d00 - 1d00)
- Maximum Observed Concentration Divided by Dose per Kilogram Body Weight (Cmax,md,norm) in Plasma After Multiple Dose Administration During a Dosage Interval(Multiple dose: 0-24 hours post dose on Day 14 (13d))
- Area Under the Concentration Versus Time Curve From 0 to 24 hour Divided by Dose per Kilogram Body Weight (AUC[0-24]md,norm) in Plasma After Multiple Dose Administration During a Dosage Interval(Multiple dose: 0-24 hours post dose on Day 14 (13d))
- Half Life Associated With the Terminal Slope (t1/2) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat(Single dose: 0-48 hours post-dose)
- Accumulation Ratio of AUC in the Dosing Interval (RAAUC) of Molidustat(All samples from 0-24h on 0d and from 0-24h on 13d)
- Accumulation Ratio of Cmax (RACmax) of Molidustat(All samples from 0-24h on 0d and from 0-24h on 13d)
- Linearity Factor of Pharmacokinetics After Repeated Administration of Identical Doses (RLin) of Molidustat(All samples from 0-24h on 0d and from 0-24h on 13d)
- Erythropoietin Concentration: Area Under the Concentration Versus Time Curve From 0 to 24 hour (AUC[0-24]) Post-dose on Day 1 (0d)(Single dose: Pre-dose and 4, 8, 12 and 24 hours post-dose)
- Half Life Associated With the Terminal Slope (t1/2,md) in Plasma of Molidustat and its Metabolite After Multiple Dose of Molidustat(Multiple dose: 0-24 hours post dose on Day 14 (13d))
- Time to Reach Maximum Drug Concentration (tmax,md) in Plasma of Molidustat and its Metabolite After Multiple Dose of Molidustat(Multiple dose: 0-24 hours post dose on Day 14 (13d))
- Amount Excreted into Urine (Aeur,md)of Molidustat and its Metabolite After Multiple Dose of Molidustat(Urine collection interval: 13d00 - 14d00)
- Renal Body Clearance (CLR,md) of Molidustat and its Metabolite After Multiple Dose of Molidustat(Urine collection interval: 13d00 - 14d00)
- Erythropoietin Concentration: Area Under the Concentration Versus Time Curve From 0 to 24 hour (AUC[0-24]md) in Plasma After Multiple Dose on Day 14 (13d)(Multiple dose: Pre-dose and 4, 8, 12 and 24 hours post-dose on 13day)
- Erythropoietin Concentration: Maximum Observed Drug Concentration in Plasma (Cmax[0-24]) After Single Dose of Molidustat on Day 1 (0d)(Single dose: Pre-dose and 4, 8, 12, 24 hours post-dose)
- Erythropoietin Concentration: Maximum Observed Drug Concentration in Plasma (Cmax [0-24]md) Within 0-24 hours Post Dose on Day 14 (13d)(Multiple dose: Pre-dose and 4, 8, 12 and 24 hours post-dose on 13day)
- Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Reticulocytes (Absolute) Within Day 1 (0d) - Day 14 (13d)(Day 1 to Day 14)
- Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Reticulocytes ( Ratio-to-Baseline-Adjusted) Within Day 1(0d) - Day 14 (13d)(Day 1 to Day 14)
- Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Hemoglobin (Absolute) Within Day 1 (0d) - Day 14 (13d)(Day 1 to Day 14)
- Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Hemoglobin ( Ratio-to-Baseline-Adjusted) Within Day 1 (0d) - Day(Day 1 to Day 14)
- Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Hematocrit (Absolute) Within Day 1 (0d) - Day 14(13d)(Day 1 to Day 14)
- Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Hematocrit (Ratio-to-Baseline-Adjusted) Within Day 1( 0d) - Day 14 (13d)(Day 1 to Day 14)