Strategies Using Darbepoetin Alfa to Avoid Transfusions in Chronic Kidney Disease

Phase 3

Completed

Conditions: Anemia in Chronic Kidney Disease Patients Not on Dialysis

Interventions: Biological: Darbepoetin alfa
Other: Placebo

Registration Number: NCT01652872

Lead Sponsor: Amgen

Brief 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 756

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Hb-Based Titration Group	Darbepoetin alfa	Participants received darbepoetin alfa as a subcutaneous (SC) injection once every 4 weeks (Q4W) for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb rate of rise (ROR), and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 micrograms/kilogram (mcg/kg) and the protocol specified doses ranged from 10 to 300 mcg.
Fixed Dose Group	Darbepoetin alfa	Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96 week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was \> 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to \< 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg.
Hb-Based Titration Group	Placebo	Participants received darbepoetin alfa as a subcutaneous (SC) injection once every 4 weeks (Q4W) for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb rate of rise (ROR), and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 micrograms/kilogram (mcg/kg) and the protocol specified doses ranged from 10 to 300 mcg.
Fixed Dose Group	Placebo	Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96 week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was \> 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to \< 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants in Receipt of 1 or More RBC Transfusions	From randomization until the end of study, up to week 101.	The percentage of participants receiving at least 1 RBC transfusion during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach).

Secondary Outcome Measures

Name	Time	Method
Mean Number of Units of RBC Transfused	From randomization until the end of study, up to week 101.	The total number of units of RBC transfused per participant during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). The mean total number of RBC units transfused per participant is presented.
Time to First RBC Transfusion	From randomization until the end of study, up to week 101.	Time to first RBC transfusion during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). The time to first RBC transfusion is presented using Kaplan-Meier (KM) estimates at 6, 12, 18, and 24 months.
Mean Achieved Hb Concentration While Receiving Investigational Product	From week 13 until the end of study, up to week 101.	Average achieved Hb concentration while receiving investigational product was recorded as mean Hb using the area under the curve (AUC) method for each treatment group. The AUC of Hb was calculated according to the trapezoidal method, standardized as daily AUC. Participants with available Hb values from study day 85 (week 13) to the last dose date were included in the calculation.
Geometric Mean Cumulative Dose of Darbepoetin Alfa Per 4 Weeks	From randomization until the end of study, up to week 101.	Cumulative doses of darbepoetin alfa adjusted for investigation product exposure time (e.g. mean cumulative darbepoetin alfa dose per 4 weeks) were calculated for each treatment group using the total cumulative dose during the study divided by total number of weeks dosed then multiplied by 4. The geometric mean cumulative dose is presented.