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

doi:10.1681/ASN.2020050556

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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)
Hemoglobin (g/dl)	≤1.0	>1.0 and ≤2.0	>2.0
<10.0	To next higher PSD^a	Maintain	To next lower PSD^b
10.0–10.5	Maintain	To next lower PSD^b	To next lower PSD^b
>10.5–11.0	To next lower PSD^b	To next lower PSD^b	Placebo^c
>11.0	Placebo^c	Placebo^c	Placebo^c

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

Characteristic	TD (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 Native	1 (0.3)	0 (0.0)	1 (0.1)
Asian	25 (6.6)	21 (5.5)	46 (6.1)
Black	125 (33.2)	134 (35.4)	259 (34.3)
Native Hawaiian or other Pacific Islander	5 (1.3)	4 (1.1)	9 (1.2)
White	220 (58.4)	215 (56.7)	435 (57.5)
Mixed race/other	1 (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 (%)
Diabetes	187 (49.6)	187 (49.3)	374 (49.5)
Hypertension	131 (34.7)	139 (36.7)	270 (35.7)
GN	13 (3.4)	16 (4.2)	29 (3.8)
Polycystic kidney disease	5 (1.3)	7 (1.8)	12 (1.6)
Urologic	1 (0.3)	2 (0.5)	3 (0.4)
Unknown/other	40 (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/metabolic	342 (90.7)	340 (89.7)	682 (90.2)
Diabetes mellitus type 1	10 (2.7)	8 (2.1)	18 (2.4)
Diabetes mellitus type 2	251 (66.6)	252 (66.5)	503 (66.5)
Hyperlipidemia	301 (79.8)	287 (75.7)	588 (77.8)
CV	375 (99.5)	377 (99.5)	752 (99.5)
Congestive heart failure	99 (26.3)	79 (20.8)	178 (23.5)
Coronary artery disease	103 (27.3)	123 (32.5)	226 (29.9)
Myocardial infarction	31 (8.2)	30 (7.9)	61 (8.1)
Coronary artery bypass graft surgery	29 (7.7)	41 (10.8)	70 (9.3)
Coronary artery stenting/angioplasty	46 (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 Point	TD (N=377)	FD (N=377)	Treatment Effect
Total number of units of RBC transfused per subject, n (%)
0	285 (75.6)	286 (75.9)
1	19 (5.0)	20 (5.3)
2	42 (11.1)	33 (8.8)
3–5	22 (5.8)	20 (5.3)
6–10	6 (1.6)	14 (3.7)
>10	3 (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
6	0.115	0.136
12	0.192	0.204
18	0.261	0.246
24	0.297	0.289	Hazard 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

Context	TD (n=377)	FD (n=377)
No. of transfusion events, N₁	127	141
Hemoglobin at time of first transfusion within an event (g/dl)
n	124	130
Mean (SD)	7.4 (0.86)	7.3 (0.88)
Median	7.4	7.4
Min, max	4.2, 10.5	4.5, 11.1
Primary reason, n (%)^a
Acute bleeding	21 (16.5)	19 (13.5)
Acute trauma	4 (3.1)	1 (0.7)
Planned or recent nontrauma surgery	8 (6.3)	14 (9.9)
Critical illness	2 (1.6)	5 (3.5)
Worsening symptoms	66 (52.5)	75 (53.2)
Worsening anemia	26 (20.5)	26 (18.4)
Unknown	0 (0.0)	1 (0.7)
Clinical situation, n (%)^a^,^b
Bleeding	28 (22.0)	27 (19.1)
Trauma	3 (2.4)	0 (0.0)
Surgery/procedure	9 (7.1)	14 (9.9)
GI hemorrhage	15 (11.8)	9 (6.4)
Other	3 (2.4)	3 (2.1)
Symptom	77 (60.6)	89 (63.1)
Chest pain	10 (7.9)	2 (1.4)
Dyspnea	35 (27.6)	49 (34.8)
Constitutional	50 (39.4)	57 (40.4)
Other	13 (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 Term	Darbepoetin
System Organ Class Preferred Term	TD (n=377), n (%)	FD (n=377), n (%)
Number of subjects reporting treatment-related treatment emergent adverse events	37 (9.8)	26 (6.9)
Blood and lymphatic system disorders	4 (1.1)	6 (1.6)
Anemia	4 (1.1)	3 (0.8)
Anemia of chronic disease	0 (0.0)	1 (0.3)
Iron deficiency anemia	0 (0.0)	2 (0.5)
General disorders and administration site conditions	4 (1.1)	2 (0.5)
Chest pain	1 (0.3)	0 (0.0)
Fatigue	0 (0.0)	1 (0.3)
Injection-site edema	1 (0.3)	0 (0.0)
Injection-site pain	1 (0.3)	1 (0.3)
Pyrexia	1 (0.3)	0 (0.0)
Investigations	13 (3.4)	9 (2.4)
BP diastolic	0 (0.0)	1 (0.3)
BP diastolic increased	0 (0.0)	1 (0.3)
BP increased	13 (3.4)	7 (1.9)
BP systolic increased	0 (0.0)	2 (0.5)
Nervous system disorders	5 (1.3)	1 (0.3)
Cerebrovascular accident	1 (0.3)	0 (0.0)
Dizziness	2 (0.5)	1 (0.3)
Headache	2 (0.5)	0 (0.0)
Hypoesthesia	0 (0.0)	1 (0.3)
Vascular disorders	10 (2.7)	5 (1.3)
Deep vein thrombosis	0 (0.0)	1 (0.3)
Hypertension	9 (2.4)	4 (1.1)
Thrombophlebitis superficial	1 (0.3)	0 (0.0)

N, number of subjects in full analysis set.
Percentages are based on N.
Coded using MedDRA version 20.1

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Table 6.

Time to major clinical events

Safety End Point (time to first event), d	TD (N=377)	FD (N=377)	Hazard Ratio (95% CI)^a
Composite: all-cause mortality, stroke, MI, decompensated HF			0.85 (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 mortality			0.96 (0.56 to 1.64)
n (%)	28 (7.4)	26 (6.9)
Mean (SEM)	553.8 (5.1)	653.5 (6.1)
CV mortality			0.89 (0.45 to 1.75)
n (%)	18 (4.8)	16 (4.2)
Mean (SEM)	563.2 (4.1)	663.0 (4.7)
Stroke			4.79 (0.56 to 40.97)
n (%)	1 (0.3)	5 (1.3)
Mean (SEM)	368.0 (NE)	669.8 (2.5)
MI			0.75 (0.36 to 1.59)
n (%)	16 (4.2)	12 (3.2)
Mean (SEM)	677.9 (5.5)	674.4 (4.8)
Decompensated HF			0.70 (0.43 to 1.14)
n (%)	40 (10.6)	28 (7.4)
Mean (SEM)	640.6 (8.0)	601.6 (7.0)
Thromboembolic events			0.49 (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.