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Clinical Research
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A Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD

Robert Toto, Jeffrey Petersen, Jeffrey S. Berns, Eldrin Foster Lewis, Qui Tran and Matthew R. Weir
JASN February 2021, 32 (2) 469-478; DOI: https://doi.org/10.1681/ASN.2020050556
Robert Toto
1University of Texas Southwestern Medical Center, Dallas, Texas
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Jeffrey Petersen
2Amgen Inc., Thousand Oaks, California
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Jeffrey S. Berns
3Perelman School of Medicine at the University of Pennsylvania and Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
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Eldrin Foster Lewis
4Stanford University Medical School, Stanford, California
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Qui Tran
2Amgen Inc., Thousand Oaks, California
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Matthew R. Weir
5Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
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  • Figure 1.
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    Figure 1.

    Kaplan–Meier plot of time to first RBC transfusion shows similarity between FD and TD group. The hazard ratio and 95% CI estimates are obtained from the Cox proportional hazards model. Stratification factors are RBC transfusion received within 12 months before randomization, yes versus no; and site practice setting, nephrology versus non-nephrology.

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    Figure 2.

    Histogram of cumulative dose of darbepoetin during the study shows the titration-dose (TD) group receiving higher cumulative dose than the maximum seen in fixed-dose (FD) group. The cumulative dose is the sum of all darbepoetin doses received from all study visits. The median cumulative doses in the TD arm and FD arm are 740.0 and 480.0 μg, respectively. Hb, hemoglobin.

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    Figure 3.

    Hemoglobin concentration at each study visit (median and interquartile range) while receiving investigational product is numerically higher in TD group compared to FD group.

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    Table 1.

    Dosing algorithm for the hemoglobin-based TD group

    Hemoglobin (g/dl)Hemoglobin ROR (g/dl per 4 wk)
    ≤1.0>1.0 and ≤2.0>2.0
    <10.0To next higher PSDaMaintainTo next lower PSDb
    10.0–10.5MaintainTo next lower PSDbTo next lower PSDb
    >10.5–11.0To next lower PSDbTo next lower PSDbPlaceboc
    >11.0PlacebocPlacebocPlaceboc
    • PSD, protocol-specified dose.

    • ↵a Subjects receiving 300 μg who require a dose increase will continue to receive 300 μg.

    • ↵b Subjects receiving 10 μg who require a dose reduction will receive placebo.

    • ↵c Restart darbepoetin when hemoglobin <10.0 g/dl, at next lower PSD.

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    Table 2.

    Baseline demographics and characteristics

    CharacteristicTD (n=377)FD (n=379)Total (n=756)
    Age (yr), mean (SD)69.2 (13.5)69.5 (13.1)69.4 (13.3)
    Male sex, n (%)154 (40.8)161 (42.5)315 (41.7)
    Race, n (%)
     American Indian or Alaska Native1 (0.3)0 (0.0)1 (0.1)
     Asian25 (6.6)21 (5.5)46 (6.1)
     Black125 (33.2)134 (35.4)259 (34.3)
     Native Hawaiian or other Pacific Islander5 (1.3)4 (1.1)9 (1.2)
     White220 (58.4)215 (56.7)435 (57.5)
     Mixed race/other1 (0.3)5 (1.3)6 (0.8)
    Hispanic/Latino ethnicity, n (%)92 (24.4)95 (25.1)187 (24.7)
    Weight (kg), mean (SD)82.3 (23.0)81.2 (22.4)81.7 (22.7)
    Primary cause of CKD, n (%)
     Diabetes187 (49.6)187 (49.3)374 (49.5)
     Hypertension131 (34.7)139 (36.7)270 (35.7)
     GN13 (3.4)16 (4.2)29 (3.8)
     Polycystic kidney disease5 (1.3)7 (1.8)12 (1.6)
     Urologic1 (0.3)2 (0.5)3 (0.4)
     Unknown/other40 (10.6)28 (7.4)68 (9.0)
    eGFR (ml/min per 1.73 m2), mean (SD)22.0 (8.0)22.5 (8.9)22.3 (8.5)
    Hemoglobin (g/dl), mean (SD)9.0 (0.7)9.0 (0.6)9.0 (0.6)
    Ferritin (μg/L), mean (SD)294.2 (228.7)343.2 (274.7)318.8 (253.8)
    TSAT (%), mean (SD)30.7 (9.8)31.0 (11.2)30.9 (10.5)
    Medical history, n (%)a
     Endocrine/metabolic342 (90.7)340 (89.7)682 (90.2)
       Diabetes mellitus type 110 (2.7)8 (2.1)18 (2.4)
       Diabetes mellitus type 2251 (66.6)252 (66.5)503 (66.5)
       Hyperlipidemia301 (79.8)287 (75.7)588 (77.8)
     CV375 (99.5)377 (99.5)752 (99.5)
      Congestive heart failure99 (26.3)79 (20.8)178 (23.5)
      Coronary artery disease103 (27.3)123 (32.5)226 (29.9)
       Myocardial infarction31 (8.2)30 (7.9)61 (8.1)
       Coronary artery bypass graft surgery29 (7.7)41 (10.8)70 (9.3)
       Coronary artery stenting/angioplasty46 (12.2)46 (12.1)92 (12.2)
    • TSAT, transferrin saturation.

    • ↵a Each subject may have more than one condition.

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    Table 3.

    Results for secondary end points

    Secondary End PointTD (N=377)FD (N=377)Treatment Effect
    Total number of units of RBC transfused per subject, n (%)
     0285 (75.6)286 (75.9)
     119 (5.0)20 (5.3)
     242 (11.1)33 (8.8)
     3–522 (5.8)20 (5.3)
     6–106 (1.6)14 (3.7)
     >103 (0.8)4 (1.1)
     Mean (95% CI)0.71 (0.53 to 0.89)0.87 (0.65 to 1.10)LSM ratio, 1.28 (95% CI, 0.81 to 2.05)a
    Time to first RBC transfusion, KM estimates at mo
     60.1150.136
     120.1920.204
     180.2610.246
     240.2970.289Hazard ratio, 1.01 (95% CI, 0.76 to 1.35)
    Average achieved hemoglobin concentration while receiving investigational product (g/dl), median (Q1, Q3)9.9 (9.4, 10.2)9.4 (8.9, 10.0)Difference, −0.34 (95% CI, −0.46 to −0.22)b
    Average cumulative dose of darbepoetin per 4 wk (µg), median (Q1, Q3)53.6 (31.1, 89.9)30.9 (21.8, 40.0)Difference, −22.1 (95% CI, −26.1 to −18.1)b
    During the study (µg), median (Q1, Q3)740.0 (280.0, 1640.0)480.0 (220.0, 720.0)Difference, −285.0 (95% CI, −380.0 to −190.0)b
    • LSM and hazard ratio are FD relative to TD. Differences are FD−TD. N, number of subjects randomized receiving at least one dose of investigational product; LSM, least square mean; KM, Kaplan-Meier.

    • ↵a The treatment effect and 95% CI are obtained using a negative binomial regression model, which includes the stratification factors and accounts for subject exposure time.

    • ↵b Hodges–Lehmann estimate and 95%CI from Wilcoxon rank-sum statistic.

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    Table 4.

    Clinical context around RBC transfusions

    ContextTD (n=377)FD (n=377)
    No. of transfusion events, N1127141
    Hemoglobin at time of first transfusion within an event (g/dl)
     n124130
     Mean (SD)7.4 (0.86)7.3 (0.88)
     Median7.47.4
     Min, max4.2, 10.54.5, 11.1
    Primary reason, n (%)a
     Acute bleeding21 (16.5)19 (13.5)
     Acute trauma4 (3.1)1 (0.7)
     Planned or recent nontrauma surgery8 (6.3)14 (9.9)
     Critical illness2 (1.6)5 (3.5)
     Worsening symptoms66 (52.5)75 (53.2)
     Worsening anemia26 (20.5)26 (18.4)
     Unknown0 (0.0)1 (0.7)
    Clinical situation, n (%)a,b
     Bleeding28 (22.0)27 (19.1)
      Trauma3 (2.4)0 (0.0)
      Surgery/procedure9 (7.1)14 (9.9)
      GI hemorrhage15 (11.8)9 (6.4)
      Other3 (2.4)3 (2.1)
     Symptom77 (60.6)89 (63.1)
      Chest pain10 (7.9)2 (1.4)
      Dyspnea35 (27.6)49 (34.8)
      Constitutional50 (39.4)57 (40.4)
      Other13 (10.2)16 (11.3)
    • Min, minimum; max, maximum; GI, gastrointestinal.

    • ↵a Transfusion event incidence. Percentages are based on N1, number of transfusion events.

    • ↵b Clinical situation categories are not mutually exclusive. Subjects may have multiple types of clinical events instigating transfusions.

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    Table 5.

    Treatment-related adverse events system organ class with >1% incidence in any treatment group

    System Organ Class Preferred TermDarbepoetin
    TD (n=377), n (%)FD (n=377), n (%)
    Number of subjects reporting treatment-related treatment emergent adverse events37 (9.8)26 (6.9)
    Blood and lymphatic system disorders4 (1.1)6 (1.6)
     Anemia4 (1.1)3 (0.8)
     Anemia of chronic disease0 (0.0)1 (0.3)
     Iron deficiency anemia0 (0.0)2 (0.5)
    General disorders and administration site conditions4 (1.1)2 (0.5)
     Chest pain1 (0.3)0 (0.0)
     Fatigue0 (0.0)1 (0.3)
     Injection-site edema1 (0.3)0 (0.0)
     Injection-site pain1 (0.3)1 (0.3)
     Pyrexia1 (0.3)0 (0.0)
    Investigations13 (3.4)9 (2.4)
     BP diastolic0 (0.0)1 (0.3)
     BP diastolic increased0 (0.0)1 (0.3)
     BP increased13 (3.4)7 (1.9)
     BP systolic increased0 (0.0)2 (0.5)
    Nervous system disorders5 (1.3)1 (0.3)
     Cerebrovascular accident1 (0.3)0 (0.0)
     Dizziness2 (0.5)1 (0.3)
     Headache2 (0.5)0 (0.0)
     Hypoesthesia0 (0.0)1 (0.3)
    Vascular disorders10 (2.7)5 (1.3)
     Deep vein thrombosis0 (0.0)1 (0.3)
     Hypertension9 (2.4)4 (1.1)
     Thrombophlebitis superficial1 (0.3)0 (0.0)
    • N, number of subjects in full analysis set.

    • Percentages are based on N.

    • Coded using MedDRA version 20.1

    • View popup
    Table 6.

    Time to major clinical events

    Safety End Point (time to first event), dTD (N=377)FD (N=377)Hazard Ratio (95% CI)a
    Composite: all-cause mortality, stroke, MI, decompensated HF0.85 (0.60 to 1.21)
     n (%)68 (18.0)57 (15.1)
     Mean (SEM)612.5 (10.1)617.2 (9.6)
    Composite: all-cause mortality, stroke, MI (MACE)0.85 (0.55 to 1.33)
     n (%)43 (11.4)36 (9.5)
     Mean (SEM)643.7 (8.3)648.4 (7.3)
    All-cause mortality0.96 (0.56 to 1.64)
     n (%)28 (7.4)26 (6.9)
     Mean (SEM)553.8 (5.1)653.5 (6.1)
    CV mortality0.89 (0.45 to 1.75)
     n (%)18 (4.8)16 (4.2)
     Mean (SEM)563.2 (4.1)663.0 (4.7)
    Stroke4.79 (0.56 to 40.97)
     n (%)1 (0.3)5 (1.3)
     Mean (SEM)368.0 (NE)669.8 (2.5)
    MI0.75 (0.36 to 1.59)
     n (%)16 (4.2)12 (3.2)
     Mean (SEM)677.9 (5.5)674.4 (4.8)
    Decompensated HF0.70 (0.43 to 1.14)
     n (%)40 (10.6)28 (7.4)
     Mean (SEM)640.6 (8.0)601.6 (7.0)
    Thromboembolic events0.49 (0.09 to 2.68)
     n (%)4 (1.1)2 (0.5)
     Mean (SEM)191.3 (0.6)592.6 (2.0)
    • N, number of subjects randomized receiving at least one dose of investigational product; MI, myocardial infarction; HF, heart failure; MACE, major adverse CV events; NE, not estimable.

    • ↵a Hazard ratio is FD relative to TD.

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February 2021
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A Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD
Robert Toto, Jeffrey Petersen, Jeffrey S. Berns, Eldrin Foster Lewis, Qui Tran, Matthew R. Weir
JASN Feb 2021, 32 (2) 469-478; DOI: 10.1681/ASN.2020050556

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A Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD
Robert Toto, Jeffrey Petersen, Jeffrey S. Berns, Eldrin Foster Lewis, Qui Tran, Matthew R. Weir
JASN Feb 2021, 32 (2) 469-478; DOI: 10.1681/ASN.2020050556
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Keywords

  • chronic kidney disease
  • darbepoetin
  • dosing strategy
  • blood transfusion

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