A Study of Efepoetin Alfa in Treating Anaemia Associated With Chronic Kidney Diseases Patient

Study Overview
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Brief Summary
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This is an open-label, randomised, multicenter, Mircera-controlled, parallel-group, Phase III study to determine whether subcutaneous administered efepoetin alfa is as effective and well tolerated as subcutaneous Mircera for anaemia correction and maintenance in erythropoiesis stimulating agent (ESA)-naïve subjects who have CKD and are not on dialysis. ESA prior users who have stopped using ESA at least 12 weeks till screening will also be eligible for this study provided they fulfil all the subject entry criteria.

Detailed Description
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The study will consist of a 20-week correction period for dosage titration and Hb correction, followed by an 8-week evaluation period for efficacy assessments of corrective treatment. Subjects who respond to efepoetin alfa (defined as an increase in Hb ≥1.0 g/dL versus baseline and Hb level within 10 - 12 g/dL range without blood transfusion during the 28 weeks after the first dose) will be eligible to continue treatment, and will be randomised to receive subcutaneous efepoetin alfa either once every 2W or every 4W for an additional 24-week extension period to assess long-term safety and maintenance effect. Mircera responders will also be allowed to continue the drug during the extension period, receiving it every 4 weeks using the dose equal to twice the previous once-every-two-week dose. The safety data collected will be part of an ongoing pooled analysis of safety data from the efepoetin alfa clinical development program.

Official Title
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Open-Label Randomised Controlled Trial of Efepoetin Alfa for Treatment of Anaemia Associated With Chronic Kidney Disease Patients Not on Dialysis (ND-CKD). A Non- Inferiority Trial Compared to Methoxy Polyethylene Glycol-Epoetin Beta (MIRCERA)

Conditions
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Anaemia Associated With Chronic Kidney Disease

Intervention / Treatment
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* Drug: efepoetin alfa
* Drug: Mircera


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age should be greater than or equal to the minimum age of consent in the applicable country Stage 3 or 4 CKD (eGFR ≥ 15 and < 60 mL/min/1.73 m2) ESA-naive (no prior ESA use) subjects whose Hb at baseline is ≥ 8 g/dL and < 10 g/dL, or ESA prior users whose Hb at baseline is ≥ 8 g/dL and < 10 g/dL and who have stopped using ESA at least 12 weeks till the screening Ferritin ≥ 100 ng/mL and transferrin saturation (TSAT) ≥ 20% Subject must be willing to complete all study-related activities and follow-up visits Evidence of a signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. Exclusion Criteria: Need for dialysis therapy expected in the next 12 months or rapid progression of CKD (e.g., eGFR decrease of >20% within 12 weeks) Received a blood transfusion (including RBC transfusion) within the 12 weeks prior to screening, or blood transfusion is anticipated during the study period Have a history of overt gastrointestinal bleeding or any other bleeding episode associated with a fall in Hb of ≥ 1 g/dL, within the last 8 weeks prior to screening Have an unstable Hb for any reason, in the investigator's opinion Have non-renal anaemia (any anaemia where the investigator considers the anaemia is predominantly due to a non-renal cause. Non-renal causes include, but are not limited to vitamin B12 or folic acid deficiency, homozygous sickle-cell disease, thalassemia of all types, other non-renal cause of anaemia such as myelodysplasia or haematological malignancies) Platelet count of ≤ 50 x109/L Vitamin B12 deficiency defined as total serum levels of < 181 pmol/L (246 pg/ml) 10 Folic acid deficiency defined as total serum levels < 7.63 nmol/L (3.37 ng/mL) 10 Pure red cell aplasia, or a history of pure red cell aplasia Poorly controlled hypertension defined as a sitting SBP ≥170 mmHg and/or DBP ≥100 mm Hg Chronic congestive heart failure (New York Heart Association class IV) or are otherwise at high risk for early withdrawal or interruption of the study (due to myocardial infarction, severe or unstable coronary artery disease, stroke, or severe liver disease) within the 12 weeks before screening or during screening Active or not active malignancy (except non-melanoma skin cancer) within five years before screening Planned live kidney transplantation scheduled within 52 weeks after the screening visit Uncontrolled hyperparathyroidism, in the investigator's opinion Uncontrolled hypothyroidism determined by the investigator that they cannot participate in the study Active acute or chronic infection, or uncontrolled or symptomatic inflammatory disease (e.g., rheumatoid arthritis, systemic lupus erythematosus), or a C-reactive protein level > 15 mg/L. (Routinely screening for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infection is not required in this protocol. By history or current clinical evidence, patients with active acute HBV or HCV infection should be excluded. Chronic HBV/HCV infection with LFTs > 3 times of normal are excluded. Known HIV positive patients are excluded) Immunosuppressive therapy (other than corticosteroids for a chronic condition, or tacrolimus/cyclosporine) within 12 weeks prior to baseline Life expectancy of less than 52 weeks Planned surgery during the study period (excluding minor skin excisions) Have received investigational drug(s) other than those of this study within 4 weeks prior to screening, or will receive investigational drug(s) other than those of this study during the study period History or clinical evidence of cardiovascular, haematologic or hepatic (ALT, AST, bilirubin values above three times the upper limit of normal [ULN] at screening) or any physical conditions that, in the opinion of the investigator, would compromise participation in the study With a cognitive or psychiatric condition rendering the subject unable to be cooperative with and complete study requirements Hypersensitivity to any one of the investigational drugs Subjects are, in the judgement of the investigator, otherwise inappropriate for entry into the study Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are KGBio or CRO employees directly involved in the conduct of the trial Participation in other studies involving same investigational drug(s) (Phases 1-4) of this study within 12 weeks before screening Females of childbearing potential or males who are unable/unwilling to take adequate contraceptive precautions defined by the protocol for the duration of the study and for at least 28 days after last dose of investigational product. Females have a positive pregnancy test result within 24 hours prior to study entry, is otherwise known to be pregnant, plans to become pregnant in the next 12 months or is currently breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: efepoetin alfa<br>Route of administration: Subcutaneous Injection. The administration interval and initial dosage for subjects who are randomly assigned to subcutaneous efepoetin alfa will be starting from 4 μg/kg BW once per 2 weeks, then titrated based on Hb level during study period. | Drug: efepoetin alfa<br>* The administration interval and initial dosage for subjects who are randomly assigned to subcutaneous efepoetin alfa will be starting from 4 μg/kg BW once per 2 weeks, then titrated based on Hb level during study period.<br>|
| Placebo Comparator: Mircera<br>Route of administration: Subcutaneous Injection. The starting dosage of Mircera arm will be 0.6 μg/kg BW per 2 weeks based on prior data in similar study populations with subsequent titration to achieve targeted Hb range. During the correction treatment period, the dosage of study drug will be adjusted to achieve a Hb level range within 10 - 12 g/dL and an increase ≥1.0 g/dL versus the individual patient's baseline Hb level. During the extension period, Hb levels should be maintained between 10 and 12 g/dL. | Drug: Mircera<br>* The starting dosage of Mircera arm will be 0.6 μg/kg BW per 2 weeks based on prior data in similar study populations with subsequent titration to achieve targeted Hb range. During the correction treatment period, the dosage of study drug will be adjusted to achieve a Hb level range within 10 - 12 g/dL and an increase ≥1.0 g/dL versus the individual patient's baseline Hb level. During the extension period, Hb levels should be maintained between 10 and 12 g/dL.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the efficacy of efepoetin alfa in the treatment of anaemia associated with CKD as measured by haemoglobin (Hb) response rate at the end of correction treatment evaluation period | Measurement is done by an increase in Hb more than or equal to 1 g/dL compared with baseline and a Hb concentration within range of 10 - 12 g/dL inclusive without transfusion during evaluation period | Measurement from the date of Randomization till the End of the Corrective Treatment period, assessed up to 20 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterise safety and tolerability of subcutaneous efepoetin alfa is being measured by based on the frequency of adverse events and on the number of out of range laboratory values. | Safety endpoints parameters including Serious Adverse Events (SAE) specified below Composite outcome of cardiovascular death or a nonfatal myocardial infarction or stroke All-cause mortality Cardiovascular mortality Acute myocardial infarction Heart failure Acute kidney injury defined according to Acute Kidney Injury Network (AKIN) criteria Abnormal clinical laboratory tests (haematology, biochemistry including serum ferritin and TSAT) Anti-efepoetin alfa or anti-Mircera antibody titres Clinically meaningful abnormal findings of vital signs Development of clinically meaningful electrocardiogram abnormalities Hospitalisations (excluding those for logistic reasons) It is a composite outcome. Any abnormal test findings during the study will be helpful in reviewing the outcome. | Measurement from the time the subject provides informed consent through and including 28 calendar days after the last study drug administration. |