The present study was designed to determine whether or not darbepoetin alfa is non-inferior to recombinant human erythropoietin in the treatment of anemia in children with chronic kidney disease stage 3-5 (on or not on dialysis).

PRIMARY OBJECTIVE:

To demonstrate that Darbepoetin alpha is non-inferior to erythropoietin for the treatment of anemia in subjects with chronic kidney disease (CKD) stage 3-5 (on or not on dialysis).

SECONDARY OBJECTIVE:

To determine the safety and tolerability of Darbepoetin alpha in the treatment of anemia in the pediatric population with CKD stage 3-5.

STUDY DESIGN:

An open-label, randomized, non-inferiority study of darbepoetin alpha (DA) and recombinant human erythropoietin(rHuEpo) for the treatment of anemia in children with chronic kidney disease stages 3 to 5 (on or not on dialysis)

DURATION OF STUDY:

The study was conducted over a period of 1 year (from 1st February 2018 to 31st January 2019).

STUDY SETTING:

This study was conducted in the Division of Pediatric Nephrology, Department of Paediatrics, Institute of Child Health, Sir Ganga Ram Hospital, New Delhi, India.

CONSENT:

A prior written informed consent was obtained from parents/ legal guardians of eligible children for participation in the study.

SAMPLE SIZE CALCULATION:

The primary objective of the study is to assess the non-inferiority of darbepoetin alfa compared with rHuEpo. Using a previous study with similar protocol [1], considering darbepoetin alfa and rHuEpo as equipotent, we accepted a type I error of 0.05 and a type II error of 0.80 for detecting a true difference. A 1.0 or greater difference in mean change in Hb variable between two groups was considered clinically significant. An estimate of standard deviation in dependent variables was assumed as 1.5. As a result, we have calculated that minimum of 28 patients are needed in each group (total-56) in order to obtain 5% type 1 error and a 80% power of detecting a difference of 1.0 or more. However, due to time constraints a sample of minimum 15 subjects in each group was planned.

Note: Sample size estimation was done by powerandsamplesize.com.

METHODOLOGY:

The study was conducted in the following phases:

1. Screening Phase (Visit 1, Day -14 to Day -1) The potential subjects were screened as per the inclusion and exclusion criteria only after obtaining written informed consent from the parent/subject.

2. Enrollment and Randomization Phase (Visit 2, Day 0)

   Subjects were randomized in two groups in a 1:1 ratio by computer generated mechanism (graphpad.com) as follows:

   1. Treatment arm 1: Erythropoietin
   2. Treatment arm 2: Darbepoetin alfa

3. Treatment Phase (Visit 3, Day 1 to Visit 8, Day 168) Patients received respective treatments for 24 week period and they were followed up every 4 weeks. Both rHuEpo and darbepoetin alfa were titrated over the first 23 weeks of the study to maintain the subjects' Hb levels between 11 to 12 g/dl without adjusting the dosing frequency. Route of administration was subcutaneous. Efficacy was determined between weeks 24 and 28.

ETHICS APPROVAL The study was approved by the Institutional Ethics Committee of Sir Ganga Ram Hospital, New Delhi.

Inclusion Criteria:

1. Age 1-18 years.
2. CKD patients stages 3 to 5 (on or not on dialysis).
3. Baseline hemoglobin 9 - 12 g/dL.
4. Subject should have adequate transferrin saturation (≥20%) and serum ferritin (≥100 ng/mL).
5. Stable erythropoietin therapy for 8 weeks ( defined as a ≤25% change in prescribed dose, no change in the route of administration and no more than one missed or withheld dose).

Exclusion Criteria:

1. Subject scheduled for a living-related kidney transplant.
2. Subject with uncontrolled hypertension.
3. HIV positive patient.
4. The patient with known hematologic disease or cause of anemia other than renal disease.
5. Patient with a history of seizure disorder or received antiepileptic medication for a seizure disorder within 6 months prior to enrolment.
6. Hyperparathyroidism (Intact parathyroid hormone more than 1500 pg/ml or biopsy proven marrow fibrosis).
7. Major surgery within 12 weeks.
8. Active inflammatory disease within 8 weeks of randomization requiring immunosuppressive therapy.
9. Clinical evidence of malignancy.
10. Blood transfusion within 8 weeks prior to initiation of therapy.

The IPD might be shared if requested from the sponsor-investigator.