Strategies Using Darbepoetin Alfa to Avoid Transfusions in Chronic Kidney Disease

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