Clinical trial NCT01332942: Combined Single / Multiple Dose Escalation Study in Patients With Renal Anemia Due to CKD (Chronic Kidney Disease)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Anemia
Keywords: Anemia
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2011-04-11
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Number of Subjects with Treatment-Emergent Adverse Events (TEAE)
timeFrame: From start of study drug administration until last follow-up visit (14 days after the last study drug administration)
measure: Mean Change in Heart Rate Within 4 hours Post-dose
timeFrame: Within 4 hours from after administration of study drug on Day 1 and Day 14
measure: Mean Change in Heart Rate Over 1 Minute for Doses 25, 50, 75 Milligrams
timeFrame: From start of study drug administration until 12 hours after the last study drug administration
measure: Mean Change in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Within 4 hours Post-dose
timeFrame: Within 4 hours post-dose at Day 1 and Day 14
measure: Number of Subjects with Clinically Relevant Abnormal Findings in the Electrocardiogram (ECG)
timeFrame: Day 1 and Day 14
measure: Number of Subjects with Clinically Relevant Laboratory Values
timeFrame: Day 1 and Day 14
measure: Maximum Observed Drug Concentration (Cmax) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat
timeFrame: Single dose: 0-48 hours post-dose
measure: Maximum Observed Drug Concentration Divided by Dose (Cmax/D) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat
timeFrame: Single dose: 0-48 hours post-dose
measure: Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat
timeFrame: Single dose: 0-48 hours post-dose
measure: 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
timeFrame: Single dose: 0-48 hours post-dose
measure: Maximum Observed Drug Concentration (Cmax,md) in Plasma of Molidustat and its Metabolite After Multiple Dose Administration of Molidustat
timeFrame: Multiple dose: 0-24 hours post dose on Day 14 (13d)
measure: Maximum Observed Drug Concentration in Plasma Divided by Dose (Cmax,md/D) of Molidustat and its Metabolite After Multiple Dose Administration of Molidustat
timeFrame: Multiple dose: 0-24 hours post dose on Day 14 (13d)
measure: 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
timeFrame: Multiple dose: 0-24 hours post dose on Day 14 (13d)
measure: 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
timeFrame: Multiple dose: 0-24 hours post dose on Day 14 (13d)
Secondary outcomes:
measure: 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
timeFrame: Single dose: 0-48 hours post-dose
measure: 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
timeFrame: Single dose: 0-48 hours post-dose
measure: 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
timeFrame: Single dose: 0-24 hours post-dose
measure: 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
timeFrame: Single dose: 0-48 hours post-dose
measure: Half Life Associated With the Terminal Slope (t1/2) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat
timeFrame: Single dose: 0-48 hours post-dose
measure: Time to Reach Maximum Drug Concentration (tmax) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat
timeFrame: Single dose: 0-48 hours post-dose
measure: Mean Residence Time (MRT) of Molidustat and its Metabolite After Single Dose of Molidustat
timeFrame: Single dose: 0-48 hours post-dose
measure: Apparent Oral Clearance (CL/F) of Molidustat and its Metabolite After Single Dose of Molidustat
timeFrame: Single dose: 0-48 hours post-dose
measure: Apparent Volume of Distribution During Terminal Phase (Vz/F) After Single Dose of Molidustat
timeFrame: Single dose: 0-48 hours post-dose
measure: Amount Excreted into Urine (Aeur) of Molidustat and its Metabolite After Single Dose of Molidustat
timeFrame: Urine collection intervals: 0d00 - 0d12h, 0d12h - 1d00
measure: Renal Body Clearance of Drug (CLR) of Molidustat and its Metabolite After Single Dose of Molidustat
timeFrame: Urine collection interval: 0d00 - 1d00
measure: Maximum Observed Concentration Divided by Dose per Kilogram Body Weight (Cmax,md,norm) in Plasma After Multiple Dose Administration During a Dosage Interval
timeFrame: Multiple dose: 0-24 hours post dose on Day 14 (13d)
measure: 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
timeFrame: Multiple dose: 0-24 hours post dose on Day 14 (13d)
measure: Half Life Associated With the Terminal Slope (t1/2,md) in Plasma of Molidustat and its Metabolite After Multiple Dose of Molidustat
timeFrame: Multiple dose: 0-24 hours post dose on Day 14 (13d)
measure: Time to Reach Maximum Drug Concentration (tmax,md) in Plasma of Molidustat and its Metabolite After Multiple Dose of Molidustat
timeFrame: Multiple dose: 0-24 hours post dose on Day 14 (13d)
measure: Amount Excreted into Urine (Aeur,md)of Molidustat and its Metabolite After Multiple Dose of Molidustat
timeFrame: Urine collection interval: 13d00 - 14d00
measure: Renal Body Clearance (CLR,md) of Molidustat and its Metabolite After Multiple Dose of Molidustat
timeFrame: Urine collection interval: 13d00 - 14d00
measure: Accumulation Ratio of AUC in the Dosing Interval (RAAUC) of Molidustat
timeFrame: All samples from 0-24h on 0d and from 0-24h on 13d
measure: Accumulation Ratio of Cmax (RACmax) of Molidustat
timeFrame: All samples from 0-24h on 0d and from 0-24h on 13d
measure: Linearity Factor of Pharmacokinetics After Repeated Administration of Identical Doses (RLin) of Molidustat
timeFrame: All samples from 0-24h on 0d and from 0-24h on 13d
measure: Erythropoietin Concentration: Area Under the Concentration Versus Time Curve From 0 to 24 hour (AUC[0-24]) Post-dose on Day 1 (0d)
timeFrame: Single dose: Pre-dose and 4, 8, 12 and 24 hours post-dose
measure: 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)
timeFrame: Multiple dose: Pre-dose and 4, 8, 12 and 24 hours post-dose on 13day
measure: Erythropoietin Concentration: Maximum Observed Drug Concentration in Plasma (Cmax[0-24]) After Single Dose of Molidustat on Day 1 (0d)
timeFrame: Single dose: Pre-dose and 4, 8, 12, 24 hours post-dose
measure: Erythropoietin Concentration: Maximum Observed Drug Concentration in Plasma (Cmax [0-24]md) Within 0-24 hours Post Dose on Day 14 (13d)
timeFrame: Multiple dose: Pre-dose and 4, 8, 12 and 24 hours post-dose on 13day
measure: Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Reticulocytes (Absolute) Within Day 1 (0d) - Day 14 (13d)
timeFrame: Day 1 to Day 14
measure: Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Reticulocytes ( Ratio-to-Baseline-Adjusted) Within Day 1(0d) - Day 14 (13d)
timeFrame: Day 1 to Day 14
measure: Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Hemoglobin (Absolute) Within Day 1 (0d) - Day 14 (13d)
timeFrame: Day 1 to Day 14
measure: Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Hemoglobin ( Ratio-to-Baseline-Adjusted) Within Day 1 (0d) - Day
timeFrame: Day 1 to Day 14
measure: Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Hematocrit (Absolute) Within Day 1 (0d) - Day 14(13d)
timeFrame: Day 1 to Day 14
measure: Pharmacodynamic Parameter: Maximum Observed Drug Concentration in Plasma (Cmax) of Hematocrit (Ratio-to-Baseline-Adjusted) Within Day 1( 0d) - Day 14 (13d)
timeFrame: Day 1 to Day 14
Other outcomes:
Locations:
city: München
country: Germany
state: Bayern
city: Hannover
country: Germany
state: Niedersachsen
city: Hannover
country: Germany
state: Niedersachsen
city: Düsseldorf
country: Germany
state: Nordrhein-Westfalen
city: Köln
country: Germany
state: Nordrhein-Westfalen
city: Kiel
country: Germany
state: Schleswig-Holstein
city: Berlin
country: Germany
city: Berlin
country: Germany
city: Hamburg
country: Germany
city: Wuppertal
country: Germany
city: London
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References: