Strategies Using Darbepoetin Alfa to Avoid Transfusions in Chronic Kidney Disease

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.

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