Darbepoetin Alfa Once Monthly Dosing Schedule Maintains Hemoglobin Concentration Comparable to Every 2 Weeks Dosing Schedule in Advanced Chronic Kidney Disease Patients Not on Dialysis: A Multicenter, Phase 4 Study

Study Design and Procedures This was a prospective, open-label, multicenter, single-arm phase 4 clinical trial designed to evaluate the efficacy and safety of once-monthly subcutaneous darbepoetin alfa (DARB) compared with the established biweekly dosing schedule in Korean patients with anemia secondary to non-dialysis chronic kidney disease (ND-CKD). Study Flow Summary Screening Phase (Week -12 to 0): A total of 65 patients received DARB every 2 weeks for 12 weeks. Eligibility required stable Hb levels (≥9.5 g/dL) with \<25% dose variation during this period. Enrollment (Week 0): Forty patients who met all inclusion criteria and no exclusion criteria were enrolled into the evaluation phase and switched to once-monthly DARB dosing. Evaluation Phase (Week 1 to 12): Patients received once-monthly DARB for 12 weeks with predefined dose adjustments to maintain Hb within 10.0-11.0 g/dL. Follow-up Visits: Assessments were performed at Weeks 13, 17, 21, and 25. Dosing Schedule Initial monthly dose was based on the cumulative biweekly dose administered during the final month of the screening phase. Dose titration rules: Hb \<10.0 g/dL → increase to next higher dose Hb 10.0-11.0 g/dL → maintain current dose Hb \>11.0-12.0 g/dL → reduce to next lower dose Hb \>12.0 g/dL → temporarily withhold, reinitiate at lower dose once Hb ≤12.0 g/dL Available doses: 20, 30, 40, 60, and 120 mcg (prefilled syringes). Laboratory and Clinical Assessments Hemoglobin, serum iron, ferritin, transferrin saturation (TSAT), TIBC, creatinine, eGFR (MDRD), and blood pressure were measured at scheduled visits. Safety assessments included adverse event monitoring, physical examinations, and routine laboratory tests. Statistical Considerations Primary endpoint: Proportion of patients maintaining Hb ≥10.0 g/dL at Week 25, analyzed for non-inferiority with a prespecified margin of 0.2 g/dL. Secondary endpoints: Mean Hb, iron parameters, response frequency, total DARB dose, oral iron requirements, and safety outcomes including adverse events and blood pressure changes. Analysis sets: Full Analysis Set (FAS): All 40 enrolled patients who received ≥1 dose and had ≥1 post-baseline Hb measurement. Per-Protocol (PP) Set: Patients in the FAS without major protocol deviations who completed the study. Missing data were imputed using Next Observation Carried Backward (NOCB). Study Completion Of the 65 patients screened, 40 entered the evaluation phase and all 40 completed the study, allowing full assessment of efficacy and safety outcomes. Significance This trial demonstrates that once-monthly darbepoetin alfa is non-inferior to biweekly dosing for maintaining hemoglobin in Korean patients with ND-CKD. These findings support the feasibility of extending the dosing interval to monthly administration, potentially improving adherence and reducing treatment burden in real-world practice.