strategies using darbepoetin alfa to avoid transfusions in chronic kidney disease

Conditions: Anemia in Chronic Kidney Disease Patients Not on Dialysis

Summary: a phase 3, multicenter, randomized, double-blind, parallel group study. anemic subjects with chronic kidney disease (ckd) and not on dialysis will be randomized 1:1 to 1 of 2 dosing strategies to evaluate the proportion of subjects receiving at least one red blood cell (rbc) transfusion. in the haemoglobin (hb)-based titration group, darbepoetin alfa doses will be titrated to maintain hb ≥ 10.0 grams/deciliter (g/dl). in the fixed dose group, subjects will receive a fixed dose of darbepoetin alfa. treatment group, darbepoetin alfa doses, and protocol specified hb concentrations will be blinded. subjects will be followed for approximately 2 years from the date of randomization.

the study is a phase 3, multicenter, randomized, double-blind, parallel group study designed to describe the benefits and potential risks of a new treatment strategy using a fixed dose of darbepoetin alfa in subjects with ckd and not on dialysis. anemic subjects without recent use of an erythropoiesis stimulating agent (esa) will be randomly allocated 1:1 to treatment with a fixed dose of darbepoetin alfa or to treatment with darbepoetin alfa using a hb-based titration strategy, which has been the conventional dosing strategy. in the hb-based titration group, darbepoetin alfa doses will be titrated to maintain hb ≥ 10.0 g/dl. this study aims to estimate the incidence of rbc transfusions (administered as deemed clinically necessary) in each group and the difference in incidence of rbc transfusions between the 2 groups. in addition, multiple aspects, such as cumulative darbepoetin alfa dose, total number of units of transfusions, hb concentration, hb-related parameters (eg, hb variability, excursions, rate of change), and adverse (eg, cardiovascular) events, will also be considered in order to determine a preferred dosing regimen. treatment group, darbepoetin alfa doses, and protocol specified hb concentrations will be blinded to the investigator, subjects and study team. subjects will be followed for approximately 2 years from the date of randomization.

Eligibility criteria:
key inclusion criteria: * clinical history of advanced ckd not on dialysis with at least 1 historic estimated glomerular filtration rate (egfr) \< 45.0 ml/mi)/1.73 m2 at least 12 weeks prior to screening * not currently receiving dialysis with an egfr \< 45.0 ml/min/1.73m2, per the central laboratory during screening * chronic anemia due to renal failure * two hb concentrations \< 10.0 g/dl, at least 2 weeks apart during screening using the modified hb point of care (poc) device * iron replete, defined as a transferrin saturation (tsat) ≥ 20% and a ferritin ≥ 100 ng/ml, per the central laboratory during screening * vitamin b12 and folate replete, defined as a vitamin b12 level \> 180 pg/ml and a folate concentration \> 7 nmol/l, per the central laboratory during screening * clinically stable in the opinion of the investigator * subject has provided written informed consent key exclusion criteria: * systemic hematologic disease (eg, sickle cell anemia, myelodysplastic syndrome, hematologic malignancy) * current or prior malignancy within 5 years of screening, with the exception of non-melanoma skin cancers and cervical intraepithelial neoplasia * treatment for any malignancy (eg, radiation, chemotherapy, hormone therapy, or biologics) within 5 years of screening, with the exception of locally excised non-melanoma skin cancer or cervical intraepithelial neoplasia * female subject not willing to use highly effective methods of birth control during treatment and for 4 weeks after the end of treatment * subject is pregnant or breast feeding, or might become pregnant during the study or within 4 weeks after the end of treatment * currently receiving intravenous (iv) antibiotics for treatment of an active infection * known human immunodeficiency virus (hiv) positive * currently receiving systemic immunosuppressive therapy with the exception of prednis(ol)one ≤ 10 mg per day (or the steroid equivalent) * history of any organ transplant * currently enrolled in another interventional study (eg, studies which require medical device use or drug therapy or with protocol required procedures), or less than 4 weeks since ending another interventional study(s) or receiving investigational agent(s) * known neutralizing anti-erythropoietic protein antibodies * known sensitivity to any of the products to be administered during dosing * previously enrolled in this study * not expected to be available for protocol required study visits or procedures to the best of the subject and investigator's knowledge * subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or comply with all required study procedures * occurrence of stroke or myocardial infarction (mi) within 24 weeks of screening * receipt of rbc transfusion within 8 weeks of screening * occurrence of seizure, clinically relevant active bleeding (eg, gastrointestinal \[gi\] bleed) or any hospitalization within 8 weeks of screening * receipt of any iv iron therapy within 4 weeks of screening * changes in oral iron therapy within 4 weeks of screening * receipt of esa therapy within 4 weeks of screening * diagnosis or treatment of malignancy, with the exception of non-melanoma skin cancers and cervical intraepithelial neoplasia during screening * receipt of esa therapy, rbc transfusions, iv iron therapy during screening * changes in oral iron therapy during screening * occurrence of stroke, mi, seizure, clinically relevant active bleeding (eg, gi bleed), any hospitalization or outpatient surgery during screening * uncontrolled hypertension during screening. defined in this study, as a mean systolic blood pressure \> 140 mmhg at both screening visits, or a mean systolic blood pressure \>/= 160 mmhg at any screening visit, or a mean diastolic blood pressure \>/= 90 mmhg at any screening visit. * expected or scheduled change in oral iron therapy or receipt of iv iron therapy within 4 weeks after randomization * expected or scheduled receipt of a rbc transfusion within 8 weeks after randomization * expected or scheduled organ transplant within 24 weeks after randomization * expected or scheduled initiation of dialysis within 24 weeks after randomization

Keywords: anemia chronic kidney disease kidney disease renal failure