E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Anaemia of Chronic Kidney Disease |
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E.1.1.1 | Medical condition in easily understood language |
A decrease in the number of red blood cells as a result of chronic kidney disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058123 |
E.1.2 | Term | Renal anaemia |
E.1.2 | System Organ Class | 100000004851 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy for up to 16 weeks of fixed dose treatment with BAY 85-3934 versus placebo as measured by haemoglobin (Hb) levels. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of BAY 85-3934 when administered as a fixed dose for up to 16 weeks versus placebo.
To evaluate the pharmacodynamics (PD) of BAY 85-3934 when administered as a fixed dose for up to 16 weeks.
To evaluate the pharmacokinetics (PK) of BAY 85-3934 and optionally, its metabolite M-1, when administered as a fixed dose for up to 16 weeks.
To investigate selected parameters of kidney function and chronic kidney disease (CKD) progression as well as parameters of iron metabolism and patient reported outcomes (PRO).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Women without childbearing potential
• Male or female subjects ≥ 18 years of age with anemia of CKD at screening
• Estimated glomerular filtration rate of < 60 mL/min/1.73 m2 (Modification of Diet in Renal Disease [MDRD] or the formula according to Matsuo, et al)
• Not on dialysis and not expected to begin dialysis during the treatment period of the study (at least 16 weeks from randomization)
• Not treated with any ESA within 8 weeks before randomization
• Mean screening Hb concentration ≤ 10.5 g/dL (mean of all local laboratory Hb measurements [at least 2 measurements must be taken ≥ 2 days apart] during the 4 week screening period with the last screening
Hb measurement within 10 days prior to randomization, AND all measurements come from the same local laboratory for any given subject, AND the difference between the lowest value and the highest value is ≤ 1.2 g/dL). Re screening of subjects who fail the Hb inclusion criterion is allowed only once after the initial screen.
Note: The intention is that Hb measurements will be taken 5 to 7 days apart, but 2 days apart is the minimum. At least 1 measurement should be within 10 days prior to randomization.
• Serum ferritin levels ≥ 100 μg/L and < 1000 μg/L OR transferrin saturation ≥ 20% at screening. Re-screening of subjects is allowed only once. Iron supplementation is allowed. (See Section 6.9 for details about iron treatment during the study.)
• Folate and Vitamin B12 values above the lower limit of normal. Supplementation is allowed; re-screening of subjects who fail the folate and vitamin B12 inclusion criterion is allowed only once after the initial screen
• Body weight of 45 kg to 125 kg, inclusive, at screening |
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E.4 | Principal exclusion criteria |
• Subjects with significant acute or chronic bleeding, such as overt gastrointestinal bleeding
• Active hemolysis or diagnosis of hemolytic syndrome
• History of myelodysplastic syndrome, multiple myeloma, marrow fibrosis, or PRCA
• History of hemosiderosis or hemochromatosis
• Hereditary hemoglobinopathies (including, but not limited to, sickle cell disease, beta thalassemia, and thalassemia major) which may be the primary cause of anemia
• Aplastic anemia
• Chronic lymphoproliferative diseases
• Proliferative choroidal or retinal disease, such as neovascular agerelated macular degeneration or proliferative diabetic retinopathy requiring invasive treatment (e.g., intraocular injections or laser photocoagulation)
• Chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosis, rheumatoid arthritis, celiac disease)
• Known hypersensitivity to the study drugs (active substances or excipients of the preparations)
• Uncontrolled and symptomatic hyperparathyroidism
• Uncontrolled active infection
• Previous or concurrent cancer except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, and T1) or any cancer curatively treated > 3 years prior to randomization
• Any allograft (including renal allograft) in place and on immunosuppressive therapy or a scheduled kidney transplant within the next 16 weeks (being on a waiting list does not exclude the subject)
• Subjects treated with any ESA within the 8 weeks before randomization
- Subjects known to be hyporesponsive (e.g., Hb levels < 10.0 g/dL and weekly epoetin beta doses ≥ 9,000 IU) to ESA therapy should not be included in the study. Prior dose of ESA, if used in the past, should be recorded in concomitant medication eCRF
• BAY 85 3934 is eliminated via uridinediphosphoglucuronosyltransferase 1 family, polypeptide A1
(UGT1A1), therefore the following UGT1A1 inhibitors have to be excluded within 7 days prior to randomization:
- Anti-retroviral drugs, e.g., ritonavir, saquinavir, atazanavir, indinavir, lopinavir, nefinavir
- Tyrosine kinase inhibitors, e.g., erlotinib, pazopanib, nilotinib, sorafenib, regorafenib
- Other drugs, e.g., tranilast, paracetamol / acetaminophen (single oral doses allowed; prescribed continuous dosing is not allowed) , probenecid, phenobarbital
• Red blood cell (RBC) containing transfusion within the 8 weeks before randomization
• History of cardio- (cerebro-) vascular events (e.g., unstable angina, myocardial infarction, stroke, transient ischemic attack, deep vein thrombosis, pulmonary embolism) within the last 6 months from initial screening visit
• New York Heart Association Class III or IV congestive heart failure
• Sustained, poorly controlled arterial hypertension or hypotension at screening, defined as BP ≥ 180/110 mmHg or systolic blood pressure < 95 mmHg, respectively
• Severe rhythm or conduction disorders (e.g., HR < 50 or > 110 bpm, atrial flutter , prolonged QT > 500 msec, third degree atrioventricular [AV] block if not treated with a pacemaker
• Women of childbearing potential or pregnant or breast feeding women |
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E.5 End points |
E.5.1 | Primary end point(s) |
1) Change in local laboratory haemoglobin level from baseline to the average during the last 4 weeks treatment period |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Baseline and week 12 to 16 |
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E.5.2 | Secondary end point(s) |
1) Change in local laboratory haemoglobin level from baseline
2) Speed of change in haemoglobin level per unit time
3) Treatment exposure (Duration)
4) Number of participants with adjudicated serious adverse events SAEs): death, and SAEs of the following events: severe arrhythmias; thromboembolic events (excluding hemodialysis vascular access events: arteriovenous shunt / fistula and arteriovenous graft events); syncope; symptomatic hypotension; and heart failure
5) Pharmacodynamics characterized by erythropoietin concentration
6) Pharmacodynamics characterized by reticulocyte count |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Baseline up to 12 weeks
2) Up to 16 weeks
3) Up to 16 weeks
4) Up to 16 weeks
5) Several time points up to 16 weeks
6) Several time points up to 16 weeks |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 6 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Bulgaria |
Germany |
Hungary |
Italy |
Japan |
Korea, Republic of |
Poland |
Romania |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 2 |