Study to Assess Darbepoetin Alfa Dosing for the Correction of Anemia in Pediatric Patients With Chronic Kidney Disease

Study Overview
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Brief Summary
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The primary objectives of this study are the following: To test if the proportion of participants achieving a hemoglobin value greater than or equal to 10.0 g/dL at any time point after the first dose during the study is greater than 0.8 when administered de novo darbepoetin alfa once a week (QW) for treatment of anemia in pediatric patients with chronic kidney disease receiving and not receiving dialysis, and To test if the proportion of participants achieving a hemoglobin value greater than or equal to 10.0 g/dL at any time point after the first dose during the study is greater than 0.8 when administered de novo darbepoetin alfa every 2 weeks (Q2W) for treatment of anemia in pediatric patients with chronic kidney disease receiving and not receiving dialysis.

Official Title
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A Multi-Center, Double-Blind, Randomized Study Evaluating De Novo Weekly and Once Every Two Week Darbepoetin Alfa Dosing for the Correction of Anemia in Pediatric Subjects With Chronic Kidney Disease Receiving and Not Receiving Dialysis

Conditions
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Anemia, Chronic Kidney Disease, Kidney Disease

Intervention / Treatment
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* Drug: Darbepoetin Alfa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Current diagnosis of Chronic Kidney Disease, either receiving or not receiving dialysis Anemic, with two consecutive screening hemoglobin values drawn at least 7 days apart < 11.0 g/dL Transferrin saturation (Tsat) greater than or equal to 20% Exclusion Criteria: Any erythropoiesis stimulating agent (ESA) use within 12 weeks prior to randomization other hematologic disorders upper or lower gastrointenstinal bleeding within 6 months prior to randomization uncontrolled hypertension prior history (within 12 weeks prior to randomization) of acute myocardial ischemia, hospitalization for congestive heart failure, myocardial infarction, stroke or transient ischemic attack prior history (within 6 months prior to randomization) of thromboembolism

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darbepoetin Alfa QW<br>Participants received darbepoetin alfa once a week (QW) for 24 weeks. The initial dose was 0.45 μg/kg; thereafter, active doses were administered to achieve and then maintain hemoglobin levels within a target range of 10.0 to 12.0 g/dL. Participants not on dialysis or who were receiving peritoneal dialysis were administered darbepoetin alfa subcutaneously; participants receiving hemodialysis were administered darbepoetin alfa intravenously. | Drug: Darbepoetin Alfa<br>* Administered by subcutaneous or intravenous injection<br>* Other names: Aranesp®;|
| Experimental: Darbepoetin Alfa Q2W<br>Participants received darbepoetin alfa every 2 weeks (Q2W) and a placebo every other 2 weeks to maintain the blind for 24 weeks. The initial dose was 0.75 μg/kg; thereafter, active doses were administered to achieve and then maintain hemoglobin levels within a target range of 10.0 to 12.0 g/dL. Participants not on dialysis or who were receiving peritoneal dialysis were administered darbepoetin alfa subcutaneously; participants receiving hemodialysis were administered darbepoetin alfa intravenously. | Drug: Darbepoetin Alfa<br>* Administered by subcutaneous or intravenous injection<br>* Other names: Aranesp®;Drug: Placebo<br>* Matching placebo solution for subcutaneous or intravenous injection to maintain the blind in the Q2W arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Achieving Hemoglobin ≥ 10.0 g/dL | The proportion of participants achieving hemoglobin ≥ 10.0 g/dL (the correction proportion) was calculated as the number of participants achieving a hemoglobin ≥ 10.0 g/dL at any time point during the study when administered de novo darbepoetin alfa without receiving any red blood cell transfusion after randomization and within 90 days before the achievement, divided by the number of participants in the efficacy analysis set. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Hemoglobin Value ≥ 10.0 g/dL | The time from study Day 1 to the day a participant first achieved hemoglobin ≥ 10.0 g/dL for participants who achieved hemoglobin ≥ 10.0 g/dL. | 24 weeks | 
| Hemoglobin Concentration Over Time |  | Baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25. | 
| Weight-adjusted Darbepoetin Alfa Dose at Time of Achieving First Hemoglobin ≥ 10.0 g/dL | The darbepoetin alfa dose at the time a participant achieved a first hemoglobin level ≥ 10.0 g/dL, divided by the participant's weight measured at the closest study week prior to the dosing, post dialysis. | 24 weeks | 
| Darbepoetin Alfa Weight-Adjusted Dose Over Time | Arithmetic means are provided; Withheld doses are counted as 0 μg. | Day 1 (initial dose) and Weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25. | 
| Change From Baseline at Week 13 and Week 25 in Parent-reported Pediatric Quality of Life Inventory (PedsQL) Scores | The PedsQL is a health-related quality of life (HRQOL) questionnaire that can be used to measure quality of life in children ≥ 2 years old. The 23-item PedsQL 4.0 includes physical functioning (8 items), emotional functioning (5 items), social functioning (5 items), and school functioning (5 items). Separate questionnaires for ages 2 to 4 (toddler), 5-7, 8-12, and 13-18 years are used for parent proxy-reporting, which assesses parents' perceptions of their child's HRQOL. The instructions ask how much of a problem each item has been during the past 1 month; each item is answered on a 5-point scale: 0 = never a problem; 1 = almost never a problem; 2 = sometimes a problem; 3 = often a problem; 4 = almost always a problem. Scores from the 4 subscales, the total score, and the psychosocial composite score were generated using standard algorithms. Each item's score in the questionnaire was converted to a 0 to 100 scale (with higher scores indicating better HRQOL). | Baseline, Week 13 and Week 25 (or end of study visit if earlier than Week 25) | 
| Change From Baseline at Week 13 and Week 25 in Child Self-reported Pediatric Quality of Life Inventory (PedsQL) Scores | The PedsQL child self-reported questionnaire was used in children > 5 years old. The 23-item PedsQL 4.0 includes physical functioning (8 items), emotional functioning (5 items), social functioning (5 items), and school functioning (5 items). Separate questionnaires for ages 5-7, 8-12, and 13-18 years was used for child self-reporting. The instructions asked how much of a problem each item has been during the past 1 month; each item is answered on a 5-point scale for ages 8 to 18 (0 = never a problem; 1 = almost never a problem; 2 = sometimes a problem; 3 = often a problem; 4 = almost always a problem), or simplified to a 3-point scale for ages 5 to 7 (0 = not at all a problem; 2 = sometimes a problem; 4 = a lot of a problem). Scores from the 4 subscales, the total score, and the psychosocial composite score were generated using standard algorithms. Each item's score in the questionnaire was converted to a 0 to 100 scale (with higher scores indicating better HRQOL). | Baseline, Week 13 and Week 25 (or end of study visit if earlier than Week 25) | 
| Number of Participants With Treatment-emergent Adverse Events | A serious adverse event (SAE) is defined as an adverse event that meets at least one of the following serious criteria: • is fatal, • is life threatening, • requires in-patient hospitalization or prolongation of existing hospitalization, • results in persistent or significant disability/incapacity, • is a congenital anomaly/birth defect, and/or • other significant medical hazard. The investigator assessed whether the adverse event was related to the investigational product (IP). Events of interest included hypertension, ischemic heart disease, cardiac failure, cerebrovascular disorders, convulsions, embolic and thrombotic events, embolic and thrombotic events: venous, embolic and thrombotic events: arterial, embolic and thrombotic events: vessel type unspecified and mixed arterial and venous, dialysis vascular access thrombosis, antibody-mediated pure red cell aplasia, hypersensitivity, lack of efficacy-effect, and malignancies. | 25 weeks | 
| Hemoglobin Serial Rate of Change (ROC) Over Time | Calculated using the serial method as the change in hemoglobin from the previous non-missing hemoglobin level divided by number of days in between, and then multiplied by 7. | Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25. | 
| Number of Participants With Hemoglobin > 12.0, > 13.0, and > 14.0 g/dL During the Study |  | 25 weeks | 
| Maximum Increase in Hemoglobin Over Any 2 Week Period | The maximum increase between any 2 non-missing hemoglobin measurements over any 2-week period from Day 1. | 25 weeks | 
| Change From Baseline in Systolic Blood Pressure Over Time |  | Baseline and Weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25. | 
| Change From Baseline in Diastolic Blood Pressure Over Time |  | Baseline and Weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25. | 
| Number of Participants Who Developed Anti-erythropoiesis Antibodies | Participants who were negative for anti-erythropoiesis antibodies at Baseline (pre-dose) and who developed anti-erythropoiesis antibodies during the study. Serum samples were tested using Amgen's Surface Plasmon Resonance Immunoassay (SPRIA) method. | 25 weeks | 
| Darbepoetin Alfa Serum Concentrations for Participants Less Than 6 Years of Age | Serum concentrations of darbepoetin alfa were measured by an enzyme-linked immunosorbent assay (ELISA). | Weeks 1, 2, and 3 before the investigational product dose and 2 days after the first investigational product dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Kidney Disease, Dialysis, Anemia, Nephrology, Pediatric, Hemodialysis, Peritoneal Dialysis, Chronic Renal Insufficiency