Combined Single / Multiple Dose Escalation Study in Patients With Renal Anemia Due to CKD (Chronic Kidney Disease)

NCT01332942 | Completed Phase 1

• 2 other identifiers: 146272010-023585-50
• Study Type: interventional
• Target: 44
• Locations: 2 countries
• Sites: 11

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.

Conditions

Anemia

Keywords

Anemia

Outcome Measures

Primary Outcomes (14)

• Number of Subjects with Treatment-Emergent Adverse Events (TEAE)

  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.

  From start of study drug administration until last follow-up visit (14 days after the last study drug administration)

• Mean Change in Heart Rate Within 4 hours Post-dose

  Heart rate was observed in all treatment groups in supine position.

  Within 4 hours from after administration of study drug on Day 1 and Day 14

• Mean Change in Heart Rate Over 1 Minute for Doses 25, 50, 75 Milligrams

  Heart rate was assessed over 1 minute from the Electrocardiogram (ECG) recording.

  From start of study drug administration until 12 hours after the last study drug administration

• Mean Change in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Within 4 hours Post-dose

  SBP, DBP was observed in all treatment groups in supine phase.

  Within 4 hours post-dose at Day 1 and Day 14

• Number of Subjects with Clinically Relevant Abnormal Findings in the Electrocardiogram (ECG)

  Electrocardiograms were recorded and analyzed by an electronic ECG reading system.

  Day 1 and Day 14

• Number of Subjects with Clinically Relevant Laboratory Values

  Laboratory parameters include hematology, coagulation, serum chemistry, urinalysis.

  Day 1 and Day 14

• Maximum Observed Drug Concentration (Cmax) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat

  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.

  Single dose: 0-48 hours post-dose

• Maximum Observed Drug Concentration Divided by Dose (Cmax/D) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat

  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.

  Single dose: 0-48 hours post-dose

• Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) in Plasma of Molidustat and its Metabolite After Single Dose of Molidustat

  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.

  Single dose: 0-48 hours post-dose

• 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

  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.

  Single dose: 0-48 hours post-dose

• Maximum Observed Drug Concentration (Cmax,md) in Plasma of Molidustat and its Metabolite After Multiple Dose Administration of Molidustat

  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.

  Multiple dose: 0-24 hours post dose on Day 14 (13d)

• Maximum Observed Drug Concentration in Plasma Divided by Dose (Cmax,md/D) of Molidustat and its Metabolite After Multiple Dose Administration of Molidustat

  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.

  Multiple dose: 0-24 hours post dose on Day 14 (13d)

• 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

  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.

  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 (AUC[0-24] md/D) in Plasma During any Dose Interval of Molidustat and its Metabolite After Multiple Dose of Molidustat

  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.

  Multiple dose: 0-24 hours post dose on Day 14 (13d)

Secondary Outcomes (30)

• 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

• 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

Study Arms (6)

Placebo

PLACEBO COMPARATOR

Drug: BAY85-3934

Molidustat (BAY85-3934) 5 mg

EXPERIMENTAL

Drug: BAY85-3934

Molidustat (BAY85-3934) 10 mg

EXPERIMENTAL

Drug: BAY85-3934

Molidustat (BAY85-3934) 25 mg

EXPERIMENTAL

Drug: BAY85-3934

Molidustat (BAY85-3934) 50 mg

EXPERIMENTAL

Drug: BAY85-3934

Molidustat (BAY85-3934) 75 mg

EXPERIMENTAL

Drug: BAY85-3934

Interventions

BAY85-3934 DRUG

Subjects received an oral single dose of placebo tablet matched to the molidustat dose (BAY85-3934) on Day 1 followed by a washout day and once daily multipledose over 12 days (from Day 3 to Day 14).

Placebo

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Bayer: lead

Study Sites (11)

Unknown Facility

München, Bavaria, 81241, Germany

Location

Unknown Facility

Hamburg, Hamburg, 20253, Germany

Location

Unknown Facility

Hanover, Lower Saxony, 30159, Germany

Location

Unknown Facility

Hanover, Lower Saxony, 30625, Germany

Location

Unknown Facility

Cologne, North Rhine-Westphalia, 50931, Germany

Location

Unknown Facility

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Unknown Facility

Kiel, Schleswig-Holstein, 24105, Germany

Location

Unknown Facility

Berlin, State of Berlin, 10117, Germany

Location

Unknown Facility

Berlin, State of Berlin, 13125, Germany

Location

Unknown Facility

Wuppertal, 42283, Germany

Location

Unknown Facility

London, London, SE5 9RS, United Kingdom

Location

Related Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

MeSH Terms

Conditions

Anemia

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2011
• First Posted: April 11, 2011
• Study Start: April 1, 2011
• Primary Completion: May 1, 2013
• Study Completion: December 1, 2013
• Last Updated: July 14, 2015

Record last verified: 2015-07

Locations

DE (10); GB (1)