The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Safety and Efficacy of Vadadustat

for Anemia in Patients Undergoing Dialysis
K.-U. Eckardt, R. Agarwal, A. Aswad, A. Awad, G.A. Block, M.R. Bacci,
Y.M.K. Farag, S. Fishbane, H. Hubert, A. Jardine, Z. Khawaja, M.J. Koury,
B.J. Maroni, K. Matsushita, P.A. McCullough, E.F. Lewis, W. Luo, P.S. Parfrey,
P. Pergola, M.J. Sarnak, B. Spinowitz, J. Tumlin, D.L. Vargo, K.A. Walters,
W.C. Winkelmayer, J. Wittes, R. Zwiech, and G.M. Chertow​​

A BS T R AC T

BACKGROUND
Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class The authors’ full names, academic
of compounds that stimulate endogenous erythropoietin production. degrees, and affiliations are listed in
­
the Appendix. Address reprint requests
METHODS to Dr. Eckardt at the Department of
Nephrology and Medical Intensive
­
We conducted two randomized, open-label, noninferiority phase 3 trials to evalu- Care, Charité–Universitätsmedizin Berlin,
ate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in Charitéplatz 1, 10117 Berlin, Germany, or
patients with anemia and incident or prevalent dialysis-dependent chronic kidney at ­nephro-intensiv@​­charite​.­de.
disease (DD-CKD). The primary safety end point, assessed in a time-to-event A list of investigators is provided in the
analysis, was the first occurrence of a major adverse cardiovascular event (MACE, Supplementary Appendix, available at
NEJM.org.
a composite of death from any cause, a nonfatal myocardial infarction, or a non-
fatal stroke), pooled across the trials (noninferiority margin, 1.25). A key second- N Engl J Med 2021;384:1601-12.
DOI: 10.1056/NEJMoa2025956
ary safety end point was the first occurrence of a MACE plus hospitalization for Copyright © 2021 Massachusetts Medical Society.
either heart failure or a thromboembolic event. The primary and key secondary
efficacy end points were the mean change in hemoglobin from baseline to weeks
24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (non­
inferiority margin, −0.75 g per deciliter).
RESULTS
A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadus-
tat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent
DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients
(18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin
alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The
mean differences between the groups in the change in hemoglobin concentration
were −0.31 g per deciliter (95% CI, −0.53 to −0.10) at weeks 24 to 36 and −0.07 g
per deciliter (95% CI, −0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD
trial and −0.17 g per deciliter (95% CI, −0.23 to −0.10) and −0.18 g per deciliter
(95% CI, −0.25 to −0.12), respectively, in the prevalent DD-CKD trial. The inci-
dence of serious adverse events in the vadadustat group was 49.7% in the incident
DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the
darbepoetin alfa group were 56.5% and 58.3%, respectively.
CONCLUSIONS
Among patients with anemia and CKD who were undergoing dialysis, vadadustat
was noninferior to darbepoetin alfa with respect to cardiovascular safety and cor-
rection and maintenance of hemoglobin concentrations. (Funded by Akebia
Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers,
NCT02865850 and NCT02892149.)

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A
nemia, a common complication of
chronic kidney disease (CKD), is associ-
ated with a reduced health-related quality
of life, an increase in red-cell transfusions, and
a heightened risk of cardiovascular events.1-3
Erythropoiesis-stimulating agents (ESAs) (i.e.,
recombinant human erythropoietin and its de-
rivatives) are standard care for the management
of anemia in patients with CKD. The use of ESAs
to target hemoglobin concentrations in the nor-
mal or near-normal range in patients with CKD
has been shown to increase the risks of stroke,
vascular access thrombosis, and death4-6; such
findings have resulted in recommendations for
caution in the use of ESAs and for only partial
correction of anemia.7
Hypoxia-inducible factor (HIF), a transcription
factor that regulates physiological responses to
hypoxia, stimulates erythropoietin production by
the liver and kidneys.8-10 HIF is regulated by oxy-
gen-dependent proteasomal degradation through
a family of prolyl hydroxylases that serve as oxy-
gen sensors.9,11 HIF prolyl hydroxylase inhibitors
comprise a recently developed class of com-
pounds that stabilize HIF, in turn stimulating
endogenous erythropoietin production and ulti-
mately erythropoiesis.10,12-15
Vadadustat, an oral HIF prolyl hydroxylase in-
hibitor, is an investigational drug that is in de-
velopment for the treatment of anemia associ-
ated with CKD. In phase 2 trials, vadadustat was
reported to increase and maintain hemoglobin
concentrations in patients with CKD and anemia
— both those who were undergoing dialysis and
those who were not undergoing dialysis.16-19 The
vadadustat phase 3 program includes four phase 3
international, randomized, controlled trials: two
trials involving patients with non–dialysis-depen-
dent CKD (the PRO2TECT trials) and two trials
involving patients with dialysis-dependent CKD
(DD-CKD) (the INNO2VATE trials). Here, we re-
port the results of the two INNO2VATE trials,
which evaluated the cardiovascular safety and
hematologic efficacy of vadadustat as compared
with the ESA darbepoetin alfa.
Me thods
Trial Design and Oversight
Details regarding the rationale, design, and Participants
methods of the two INNO2VATE trials were de- In both trials, eligible patients were at least 18
scribed previously,20 and the protocols for the years of age, had CKD and were undergoing di-
trials are available with the full text of this article
at NEJM.org. Both trials were randomized, open-
label, active-controlled, event-driven trials that
were designed to evaluate the cardiovascular
safety and hematologic efficacy of vadadustat, as
compared with darbepoetin alfa, for the treat-
ment of anemia in patients undergoing hemo-
dialysis or peritoneal dialysis. In both trials,
personnel at Akebia Therapeutics and Otsuka
Pharmaceutical were unaware of the treatment as-
signments. In the incident DD-CKD trial (correc-
tion–conversion trial; ClinicalTrials.gov number,
NCT02865850), which involved the correction
and maintenance of hemoglobin concentrations,
patients were to have initiated dialysis within 16
weeks before screening and were to have had
limited exposure to ESAs. In the prevalent
DD‑CKD trial (conversion trial; NCT02892149),
which involved the maintenance of hemoglobin
concentrations, patients were to have been under-
going maintenance dialysis for at least 12 weeks
before screening and were to have been receiving
treatment with an ESA.20
Akebia Therapeutics designed the trials and
protocols with input from an executive steering
committee, and Otsuka Pharmaceutical partici-
pated in the executive steering committee meet-
ings and provided input on trial protocol amend-
ments. An independent ethics committee approved
the informed consent forms. The trial investiga-
tors conducted the trials in collaboration with
Akebia Therapeutics. The executive steering com-
mittee supervised the conduct and progress of
the trials. The trials were monitored by an inde-
pendent data and safety monitoring committee
(lists of the members of these committees are
provided in the Supplementary Appendix, avail-
able at NEJM.org). The first and last authors
wrote the first draft of the manuscript and made
final decisions regarding the content of the sub-
mitted manuscript. All the authors had access to
the trial data, critically reviewed earlier drafts of
the manuscript, and approved the manuscript for
submission. The investigators vouch for the ac-
curacy and completeness of the data; the authors
and Akebia Therapeutics vouch for the fidelity of
the trials to the respective protocols and for the
analysis of the data.

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 Vadadustat for Anemia in Patients Undergoing Dialysis
alysis, had a serum ferritin concentration of at
least 100 ng per milliliter and a transferrin satu-
ration of at least 20%, and had not received a
red-cell transfusion within the previous 8 weeks.
In addition, patients had a hemoglobin concen-
tration between 8 and 11 g per deciliter (incident
DD-CKD trial) or a hemoglobin concentration
between 8 and 11 g per deciliter (patients in the
United States) or between 9 and 12 g per deci-
liter (patients in other countries) (prevalent
DD-CKD trial). Patients were excluded if they
had anemia that was considered to be due to
causes other than CKD or if they had uncon-
trolled hypertension or had had a recent cardio-
vascular event.20 All the patients provided written
informed consent.
Randomization and Trial Periods
Eligible patients were randomly assigned, in a
1:1 ratio, to receive vadadustat or darbepoetin
alfa. Randomization was stratified according to
geographic region (United States vs. Europe vs.
other regions), New York Heart Association
(NYHA) heart failure classification (class 0 or I vs.
class II or III), and hemoglobin concentration at
trial entry (incident DD-CKD trial, <9.5 vs. ≥9.5 g
per deciliter; prevalent DD-CKD trial, <10 vs. ≥10 g
per deciliter). Both trials had four defined trial
periods: a correction or conversion period (weeks
0 to 23); a maintenance period (weeks 24 to 52),
comprising the primary (weeks 24 to 36) and
secondary (weeks 40 to 52) efficacy evaluation
periods; a long-term treatment period (weeks 53
to the end of treatment); and a 4-week safety
follow-up period.20
End Points
The primary safety end point, assessed in a
time-to-event analysis, was the first occurrence
of an adjudicated major adverse cardiovascular
event (MACE) — a composite end point of death
from any cause, a nonfatal myocardial infarc-
tion, or a nonfatal stroke — pooled across the
two trials. Key secondary safety end points,
which were also pooled across the trials, were
the first occurrence of “expanded MACE” (a
MACE plus hospitalization for either heart fail-
ure or a thromboembolic event, excluding vas-
cular access failure); death from cardiovascular
causes, a nonfatal stroke, or a nonfatal myocar-
dial infarction combined; death from cardio-
vascular causes; and death from any cause.
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Adjudication of MACE was performed by an
independent clinical end-point committee whose
members were unaware of the treatment as-
signments (a list of the committee members is
provided in the Supplementary Appendix). The
primary efficacy end point was the mean
change in the hemoglobin concentration from
baseline to the average concentration during
the primary evaluation period, and the key sec-
ondary efficacy end point was the mean change
in the hemoglobin concentration from baseline
to the average concentration during the sec-
ondary evaluation period.20
Intervention
The starting dose of vadadustat was 300 mg
orally once daily, with doses of 150, 450, and
600 mg available for adjustment of the dose to
a maximum of 600 mg daily. Darbepoetin alfa
was administered subcutaneously or intrave-
nously; the initial dose was based on the previ-
ous dose or, in the case of patients who had
not received darbepoetin alfa before random-
ization, on information in the product label.
Doses of the trial medications were adjusted ac-
cording to protocol-specified dose-adjustment
algorithms to achieve target hemoglobin con-
centrations (in the United States, 10 to 11 g per
deciliter; in other countries, 10 to 12 g per
deciliter).20 We encouraged the use of iron
supplementation (intravenous, oral, or intradi-
alytic administration) to maintain a serum fer-
ritin concentration of at least 100 ng per mil-
liliter or a transferrin saturation of at least
20%. The provision of red-cell transfusions did
not necessitate discontinuation of the trial med-
ication. Starting at week 6, patients in both
treatment groups could receive ESAs as rescue
therapy if they had worsening symptoms of
anemia and a hemoglobin concentration of less
than 9.5 g per deciliter. In addition, in the dar-
bepoetin alfa group, an ESA was defined post
hoc as a rescue medication if the dose was at
least double that of the previous dose of darbe-
poetin alfa. Patients temporarily discontinued
the trial medication while receiving ESAs as
rescue therapy.
Statistical Analysis
The prespecified noninferiority margins, which
were selected in consultation with regulatory
agencies, were an upper bound of the 95% con-
1603
 The n e w e ng l a n d j o u r na l of m e dic i n e

fidence interval of 1.25 for the primary safety
end point and a lower bound of −0.75 g per
deciliter for the primary efficacy end point.20 To
evaluate the primary and key secondary efficacy
end points, an analysis of covariance with mul-
tiple imputation for missing data was used, with
baseline hemoglobin concentration, geographic
region, and NYHA class as covariates. The analy-
sis of the time to a first occurrence of a MACE
was performed with the use of a Cox regression
model stratified according to trial. The model
included the following covariates: baseline hemo-
globin concentration, geographic region (United
States vs. Europe vs. other regions), NYHA class
(0 or I vs. II or III), sex, age (≤65 years vs. >65
years), race (White vs. non-White), cardiovascu-
lar disease (yes vs. no), and diabetes mellitus
(yes vs. no). Subgroup analyses were performed
with the use of the same Cox model as that used
in the primary analysis.
R e sult s
Patients
Across the two trials, 3923 patients underwent
randomization: 369 in the incident DD-CKD
trial and 3554 in the prevalent DD-CKD trial
(Fig. S1 in the Supplementary Appendix). The
median duration of follow-up was 1.2 years (in-
terquartile range [25th to 75th percentile], 0.8 to
1.7) in the incident DD-CKD trial and 1.7 years
(interquartile range, 1.2 to 2.2) in the prevalent
DD-CKD trial.
The baseline characteristics at randomization
have been described previously.20 The demo-
graphic, clinical, and laboratory characteristics
of the two treatment groups were generally well
balanced in both trials (Table 1 and Table S1),
except that in the incident DD-CKD trial, the
percentage of patients with diabetes mellitus
was higher among the patients randomly as-
signed to receive vadadustat than among those
randomly assigned to receive darbepoetin alfa Primary, Key Secondary, and Other Efficacy
(58.0% vs. 51.1%).
Primary and Key Secondary Safety End Points
Analyses of the safety end points were based on
the pooled safety population, which included
1947 patients in the vadadustat group and 1955
patients in the darbepoetin alfa group. Figure 1A
shows the cumulative probability of a first
MACE. A first MACE occurred in 355 of the 1947
patients (18.2%) in the vadadustat group and in
377 of the 1955 patients (19.3%) in the darbepo-
etin alfa group (hazard ratio, 0.96; 95% confi-
dence interval [CI], 0.83 to 1.11). The numbers
and percentages of patients in whom the first
MACE was death from any cause, a nonfatal
myocardial infarction, or a nonfatal stroke were
253 (13.0%), 76 (3.9%), and 26 (1.3%), respec-
tively, in the vadadustat group and 253 (12.9%),
87 (4.5%), and 37 (1.9%), respectively, in the
darbepoetin alfa group (Table S2). The results
within each trial were qualitatively consistent
with the pooled analysis, but the confidence in-
terval in the incident DD-CKD trial, which was
a much smaller trial than the prevalent DD-CKD
trial, was wide (incident DD-CKD trial: hazard
ratio of a first MACE, 0.97; 95% CI, 0.54 to 1.76;
prevalent DD-CKD trial: hazard ratio, 0.96; 95%
CI, 0.83 to 1.12) (Table S3).
Figure 1B shows the cumulative probability of
a first expanded MACE, which occurred in 420
of the 1947 patients (21.6%) in the vadadustat
group and in 449 of the 1955 patients (23.0%) in
the darbepoetin alfa group (hazard ratio, 0.96;
95% CI, 0.84 to 1.10). Figures 1C and 1D show
the pooled cumulative probability of death from
cardiovascular causes (hazard ratio, 0.96; 95% CI,
0.77 to 1.20) and the cumulative probability of
death from any cause (hazard ratio, 0.95; 95% CI,
0.81 to 1.12), respectively. Figure S2 shows the
cumulative probability of a composite of death
from cardiovascular causes, a nonfatal myocar-
dial infarction, or a nonfatal stroke (hazard ra-
tio, 0.95; 95% CI, 0.80 to 1.14). Table S2 shows
similar incidences of MACE, expanded MACE,
and their components in the two treatment
groups across both trials. The results of pre-
specified subgroup analyses of a first occurrence
of a MACE and a first occurrence of an expand-
ed MACE were consistent across subgroups, as
shown in Figure 2 and Figure S3, respectively.
End Points
Incident DD-CKD Trial
The median doses of vadadustat and darbepoetin
alfa over the course of the trial are shown in
Figure S5. Figure 3A shows the mean changes
in hemoglobin concentrations in the two treat-
ment groups over time. The least-squares mean
(±SE) change in hemoglobin concentration from
baseline to the average of the values during

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 Vadadustat for Anemia in Patients Undergoing Dialysis

Table 1. Selected Demographic, Clinical, and Laboratory Characteristics of the Patients at Baseline in the Randomized
Populations.*

Characteristic Incident DD-CKD Trial Prevalent DD-CKD Trial

Vadadustat Darbepoetin Alfa Vadadustat Darbepoetin Alfa
(N = 181) (N = 188) (N = 1777) (N = 1777)
Age — yr 56.5±14.8 55.6±14.6 57.9±13.9 58.4±13.8
Male sex — no. (%) 107 (59.1) 113 (60.1) 990 (55.7) 1004 (56.5)
Racial or ethnic group — no. (%)†
White 129 (71.3) 143 (76.1) 1135 (63.9) 1096 (61.7)
Black 38 (21.0) 35 (18.6) 432 (24.3) 444 (25.0)
Asian 12 (6.6) 8 (4.3) 76 (4.3) 99 (5.6)
American Indian 1 (0.6) 0 19 (1.1) 30 (1.7)
Native Hawaiian 0 0 13 (0.7) 6 (0.3)
Other group 0 1 (0.5) 42 (2.4) 45 (2.5)
Multiple groups 1 (0.6) 0 8 (0.5) 5 (0.3)
Not reported 0 1 (0.5) 52 (2.9) 52 (2.9)
Hispanic ethnic group — no. (%)†
Hispanic 71 (39.2) 66 (35.1) 682 (38.4) 674 (37.9)
Non-Hispanic 104 (57.5) 118 (62.8) 1043 (58.7) 1040 (58.5)
Not reported 5 (2.8) 3 (1.6) 36 (2.0) 47 (2.6)
Unknown 1 (0.6) 1 (0.5) 16 (0.9) 16 (0.9)
Time since dialysis initiated — yr 0.14±0.09 0.15±0.28 4.00±4.02 3.94±4.01
Type of dialysis — no. (%)‡
In-center hemodialysis 158 (87.3) 169 (90.9) 1652 (93.0) 1633 (91.9)
Peritoneal dialysis 22 (12.2) 16 (8.6) 137 (7.7) 143 (8.0)
Unknown or combination 3 (1.7) 1 (0.5) 17 (1.0) 18 (1.0)
Disease history — no. (%)
Diabetes mellitus 105 (58.0) 96 (51.1) 971 (54.6) 998 (56.2)
Cardiovascular disease 69 (38.1) 73 (38.8) 868 (48.8) 932 (52.4)
Hemoglobin concentration — g/dl 9.4±1.1 9.2±1.1 10.6±0.9 10.2±0.8

* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. DD-CKD denotes dialysis-
dependent chronic kidney disease.
† Racial and ethnic groups were reported by the patient.
‡ This analysis was performed in the safety population in both trials. Patients could have been included in more than one
category.

weeks 24 to 36 was 1.26±0.11 g per deciliter in
the vadadustat group and 1.58±0.11 g per deci-
liter in the darbepoetin alfa group. The corre-
sponding changes from baseline to the average
of the values during weeks 40 to 52 were
1.42±0.13 g per deciliter and 1.50±0.14 g per
deciliter, respectively. The mean (±SE) differ-
ences between the groups in the change in hemo-
globin concentration were −0.31±0.11 g per deci-
liter (95% CI, −0.53 to −0.10) at weeks 24 to 36
and −0.07±0.13 g per deciliter (95% CI, −0.34 to
0.19) at weeks 40 to 52.
The percentages of patients who had an aver-
age hemoglobin concentration within their
country-specific target range during weeks 24 to
36 were 43.6% in the vadadustat group and
56.9% in the darbepoetin alfa group. During
weeks 40 to 52, the percentages were 39.8% and
41.0%, respectively (Table S5).
The percentages of patients who received red-
cell transfusions during weeks 24 to 36 were
1.3% in the vadadustat group and 1.8% in the
darbepoetin alfa group. During weeks 40 to 52,
the percentages were 2.4% and 0.7%, respectively.

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 1606
A MACE B Expanded MACE
1.0 1.0
Hazard ratio, 0.96 (95% CI, 0.83–1.11) Hazard ratio, 0.96 (95% CI, 0.84–1.10)
0.9 P=0.5 by log-rank test stratified according to trial 0.9 P=0.4 by log-rank test stratified according to trial
0.8 0.8

0.7 0.7

0.6 0.6

0.5 0.5
Darbepoetin alfa
0.4 0.4

0.3 0.3
Darbepoetin alfa
0.2 0.2

Cumulative Probability of Event

Cumulative Probability of Event
Vadadustat
0.1 Vadadustat 0.1

0.0 0.0
The

0 4 8 12 16 20 24 28 32 36 40 44 0 4 8 12 16 20 24 28 32 36 40 44
Months since Randomization Months since Randomization
No. at Risk No. at Risk
Vadadustat 1947 1881 1801 1615 1372 1040 711 491 262 89 6 0 Vadadustat 1947 1856 1756 1561 1316 987 670 463 244 83 6 0
Darbepoetin alfa 1955 1893 1807 1628 1393 1053 718 491 265 94 13 1 Darbepoetin alfa 1955 1877 1776 1587 1339 1007 672 459 246 87 11 1

C Death from Cardiovascular Causes D Death from Any Cause

1.0 1.0
Hazard ratio, 0.96 (95% CI, 0.77–1.20) Hazard ratio, 0.95 (95% CI, 0.81–1.12)
0.9 P=0.6 by Gray's test stratified according to trial 0.9 P=0.5 by log-rank test stratified according to trial
0.8 0.8
n e w e ng l a n d j o u r na l

0.7 0.7

The New England Journal of Medicine

of

0.6 0.6

0.5 0.5

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0.4 0.4 Darbepoetin alfa

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

0.3 0.3
m e dic i n e

0.2 0.2

Cumulative Probability of Event

Cumulative Probability of Event

Darbepoetin alfa
0.1 0.1 Vadadustat
Vadadustat
0.0 0.0
0 4 8 12 16 20 24 28 32 36 40 44 0 4 8 12 16 20 24 28 32 36 40 44

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Months since Randomization Months since Randomization
No. at Risk No. at Risk
Vadadustat 1947 1901 1835 1657 1418 1078 750 524 282 97 7 0 Vadadustat 1947 1901 1835 1657 1418 1078 750 524 282 97 7 0
Darbepoetin alfa 1955 1907 1840 1666 1436 1092 747 521 281 100 14 2 Darbepoetin alfa 1955 1907 1840 1666 1436 1092 747 521 281 100 14 2
 Vadadustat for Anemia in Patients Undergoing Dialysis

Figure 1 (facing page). MACE, Expanded MACE, Death from Cardiovascular Causes, and Death from Any Cause
in the Pooled Safety Population of the Two Trials.
Shown are the cumulative probability of a first adjudicated major adverse cardiovascular event (MACE; a composite of
death from any cause, a non­fatal myocardial infarction, or a nonfatal stroke) (Panel A), a first adjudicated expanded
MACE (a MACE plus hospitalization for either heart failure or a thromboembolic event, excluding vascular access
failure) (Panel B), death from cardiovascular causes (Panel C), and death from any cause (Panel D). CI denotes con-
fidence interval.

Prevalent DD-CKD Trial Measures of Iron Metabolism

The median doses of vadadustat and darbepoet-
in alfa over the course of the trial are shown in
Figure S5. Figure 3B shows the mean changes in
hemoglobin concentrations in the two treatment
groups over time. The least-squares mean (±SE)
change in hemoglobin concentration from base-
line to the average of the values during weeks 24
to 36 was 0.19±0.03 g per deciliter in the vada-
dustat group and 0.36±0.03 g per deciliter in the
darbepoetin alfa group. The corresponding chang-
es from baseline to the average of the values
during weeks 40 to 52 were 0.23±0.04 g per deci-
liter and 0.41±0.03 g per deciliter, respectively.
The mean (±SE) differences between the groups
in the change in hemoglobin concentration were
−0.17±0.03 g per deciliter (95% CI, −0.23 to
−0.10) at weeks 24 to 36 and −0.18±0.04 g per
deciliter (95% CI, −0.25 to −0.12) at weeks 40 to
52. In addition, Table S4 shows the differences
between the two groups in the change in hemo-
globin concentration according to the length of
time that patients had been undergoing dialysis.
The percentages of patients whose average
hemoglobin concentration was within their
country-specific target range during weeks 24 to
36 were 49.2% in the vadadustat group and
53.2% in the darbepoetin alfa group. During
weeks 40 to 52, the percentages were 44.3% and
50.9%, respectively (Table S5).
The percentages of patients who received red-
cell transfusions during weeks 24 to 36 were
2.0% in the vadadustat group and 1.3% in the
darbepoetin alfa group. During weeks 40 to 52,
the percentages were 2.0% and 1.9%, respec-
tively.
Blood Pressure
The mean systolic and diastolic blood pressures
over time in each trial are shown in Figure S4.
The values in the vadadustat and darbepoetin
alfa groups were similar over the course of the
trials.
In both trials, the mean serum concentrations of
hepcidin and ferritin and the mean transferrin
saturation were similar in the vadadustat and
darbepoetin alfa groups during weeks 24 to 36
and weeks 40 to 52 (Table S6).
Rescue Therapy with an ESA
In the incident DD-CKD trial, 35 patients (20.4%)
in the vadadustat group and 29 patients (16.0%) in
the darbepoetin alfa group received an ESA as
rescue medication during weeks 0 to 23. In the
prevalent DD-CKD trial, 466 patients (27.6%) in
the vadadustat group and 525 patients (30.2%)
in the darbepoetin alfa group received such ther-
apy during weeks 0 to 23 (Table S7).
Adverse Events
In the incident DD-CKD trial, 83.8% of the pa-
tients in the vadadustat group and 85.5% of the
patients in the darbepoetin alfa group had at
least one adverse event after the start of treat-
ment (Table 2). The incidence of serious adverse
events was 49.7% in the vadadustat group and
56.5% in the darbepoetin alfa group.
In the prevalent DD-CKD trial, 88.3% of the
patients in the vadadustat group and 89.3% of
the patients in the darbepoetin alfa group had at
least one adverse event after the start of treat-
ment (Table 2). The incidence of serious adverse
events was 55.0% and 58.3%, respectively.
Discussion
These two international phase 3 clinical trials
(the INNO2VATE trials) evaluated the safety and
efficacy of once-daily oral vadadustat, as com-
pared with parenteral darbepoetin alfa, for the
maintenance treatment of anemia associated
with DD-CKD. The trials met the prespecified
noninferiority margins for cardiovascular safety,
pooled across the two trials, and hematologic
efficacy, assessed separately for each trial. The

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Subgroup No. of Patients/Total No. (%) Hazard Ratio (95% CI)

All patients 3902/3902 (100.0) 0.96 (0.83–1.11)
Baseline hemoglobin concentration
Low 1422/3902 (36.4) 1.04 (0.82–1.31)
High 2480/3902 (63.6) 0.91 (0.76–1.10)
Region
United States 2361/3902 (60.5) 1.00 (0.84–1.18)
Europe 572/3902 (14.7) 0.89 (0.57–1.39)
Other 969/3902 (24.8) 0.87 (0.60–1.26)
NYHA heart failure class
0 or I 3398/3902 (87.1) 0.94 (0.80–1.11)
II or III 504/3902 (12.9) 1.05 (0.76–1.46)
Target hemoglobin concentration
10–11 g/dl 2361/3902 (60.5) 1.00 (0.84–1.18)
10–12 g/dl 1541/3902 (39.5) 0.86 (0.65–1.14)
Age
<65 yr 2572/3902 (65.9) 1.00 (0.81–1.23)
≥65 yr 1330/3902 (34.1) 0.92 (0.75–1.13)
Sex
Male 2199/3902 (56.4) 1.03 (0.85–1.24)
Female 1703/3902 (43.6) 0.87 (0.69–1.09)
Ethnic group
Hispanic 1485/3902 (38.1) 0.97 (0.77–1.23)
Non-Hispanic 2293/3902 (58.8) 0.98 (0.81–1.18)
Race
White 2486/3902 (63.7) 0.84 (0.70–1.01)
Black 948/3902 (24.3) 1.17 (0.88–1.56)
Other 468/3902 (12.0) 1.21 (0.76–1.91)
Diabetes mellitus
No 1744/3902 (44.7) 1.02 (0.79–1.32)
Yes 2158/3902 (55.3) 0.94 (0.79–1.12)
History of cardiovascular disease
No 1967/3902 (50.4) 1.00 (0.77–1.30)
Yes 1935/3902 (49.6) 0.95 (0.80–1.13)
Type of dialysis
Hemodialysis 3590/3902 (92.0) 0.95 (0.82–1.10)
Peritoneal 309/3902 (7.9) 1.10 (0.62–1.93)
C-reactive protein
≤0.6 mg/dl 2422/3902 (62.1) 0.94 (0.76–1.15)
>0.6 mg/dl 1423/3902 (36.5) 1.02 (0.83–1.25)
Baseline transferrin saturation
<Median 1919/3902 (49.2) 1.04 (0.85–1.27)
≥Median 1980/3902 (50.7) 0.86 (0.69–1.07)
Baseline ferritin concentration
<Median 1952/3902 (50.0) 0.97 (0.78–1.21)
≥Median 1949/3902 (49.9) 0.96 (0.79–1.16)
0.25 0.50 0.75 1.00 1.25 1.75 2.50

Vadadustat Better Darbepoetin Alfa Better

Figure 2. Subgroup Analyses of a First Occurrence of a MACE in the Pooled Safety Population of the Two Trials.
A baseline hemoglobin concentration was categorized as low if the concentration was less than 9.5 g per deciliter in the incident dialysis-
dependent chronic kidney disease (DD-CKD) trial and less than 10.0 g per deciliter in the prevalent DD-CKD trial. A baseline hemoglo-
bin concentration was categorized as high if the concentration was 9.5 g or higher per deciliter in the incident DD-CKD trial and 10.0 g
or higher per deciliter in the prevalent DD-CKD trial. Race and ethnic group were reported by the patient. In the analysis of baseline
transferrin saturation, the median saturation was 34.5%, and in the analysis of baseline serum ferritin concentration, the median con-
centration was 709 ng per milliliter. NYHA denotes New York Heart Association.

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 Vadadustat for Anemia in Patients Undergoing Dialysis

Vadadustat Darbepoetin alfa

A Incident DD-CKD Trial

Change in Hemoglobin Concentration 4

2
(g/dl)

−1
0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 64 76 88 104 116
Weeks since Randomization
No. at Risk
Vadadustat 181 165 165 162 162 156 163 160 156 151 147 145 139 127 113 101 92 82 55 43 26 21
Darbepoetin alfa 188 180 170 174 169 167 167 166 169 165 162 157 151 139 112 106 100 82 67 46 24 19

B Prevalent DD-CKD Trial

2
Change in Hemoglobin Concentration

1
(g/dl)

−1

−2
0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 64 76 88 104 116
Weeks since Randomization
No. at Risk
Vadadustat 1777 1663 1625 1609 1590 1582 1585 1590 1548 1510 1483 1457 1434 1391 1325 1253 1232 1066 881 628 422 286
Darbepoetin alfa 1777 1658 1668 1654 1619 1603 1605 1625 1604 1557 1514 1511 1485 1456 1395 1323 1294 1184 1002 714 510 352

Figure 3. Mean Change from Baseline in Hemoglobin Concentrations in the Randomized Populations of the Two Trials.
Shown are the mean changes in hemoglobin concentrations in the incident DD-CKD trial (Panel A) and in the prevalent DD-CKD trial
(Panel B). Means ±SD (denoted by I bars) are presented here to show the extent of variability, which might have been less apparent if
means ±SE were presented, given the large sample size.

safety profile of vadadustat was similar to that tat was also noninferior to darbepoetin alfa in
of darbepoetin alfa with respect to three com- maintaining hemoglobin concentrations in a tar-
bined cardiovascular end points and the constitu- get range during the primary (weeks 24 to 36)
ents of these end points, as well as investigator- and secondary (weeks 40 to 52) evaluation peri-
reported adverse events. In these trials involving ods. These findings were consistent across all
patients who either were new to dialysis or had the prespecified subgroups.
been undergoing maintenance dialysis, vadadus- In this issue of the Journal, Chertow et al.21 re-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Adverse Events in the Safety Populations.*

Event Incident DD-CKD Trial Prevalent DD-CKD Trial

Vadadustat Darbepoetin Alfa Vadadustat Darbepoetin Alfa
(N = 179) (N = 186) (N = 1768) (N = 1769)
number of patients (percent)
Any adverse event 150 (83.8) 159 (85.5) 1562 (88.3) 1580 (89.3)
Any drug-related adverse event 7 (3.9) 5 (2.7) 169 (9.6) 68 (3.8)
Any serious adverse event 89 (49.7) 105 (56.5) 973 (55.0) 1032 (58.3)
Any serious adverse event that resulted 15 (8.4) 18 (9.7) 266 (15.0) 276 (15.6)
in death†
Any drug-related serious adverse event 1 (0.6) 4 (2.2) 29 (1.6) 27 (1.5)
Any adverse event that resulted in dis- 5 (2.8) 2 (1.1) 91 (5.1) 20 (1.1)
continuation of treatment
Any drug-related adverse event that 2 (1.1) 0 42 (2.4) 5 (0.3)
resulted in discontinuation
of treatment
Common adverse events‡
Hypertension 29 (16.2) 24 (12.9) 187 (10.6) 244 (13.8)
Diarrhea 18 (10.1) 18 (9.7) 230 (13.0) 178 (10.1)
Pneumonia 13 (7.3) 15 (8.1) 195 (11.0) 172 (9.7)
Hyperkalemia 8 (4.5) 10 (5.4) 160 (9.0) 191 (10.8)
Fluid overload 13 (7.3) 6 (3.2) 156 (8.8) 173 (9.8)
Fall 11 (6.1) 9 (4.8) 150 (8.5) 159 (9.0)
Headache 8 (4.5) 11 (5.9) 160 (9.0) 135 (7.6)
Hypotension 7 (3.9) 16 (8.6) 146 (8.3) 141 (8.0)
Nausea 14 (7.8) 13 (7.0) 149 (8.4) 134 (7.6)
Vomiting 13 (7.3) 10 (5.4) 120 (6.8) 124 (7.0)
Urinary tract infection 11 (6.1) 16 (8.6) 110 (6.2) 117 (6.6)
Dialysis-related complication 8 (4.5) 11 (5.9) 99 (5.6) 122 (6.9)
Cough 11 (6.1) 5 (2.7) 99 (5.6) 121 (6.8)
Arteriovenous fistula site compli- 8 (4.5) 9 (4.8) 94 (5.3) 120 (6.8)
cation
Dyspnea 13 (7.3) 10 (5.4) 92 (5.2) 119 (6.7)
Upper respiratory tract infection 5 (2.8) 9 (4.8) 99 (5.6) 112 (6.3)
Pain in extremity 8 (4.5) 6 (3.2) 91 (5.1) 117 (6.6)
Sepsis 6 (3.4) 9 (4.8) 89 (5.0) 101 (5.7)
Arteriovenous fistula thrombosis 6 (3.4) 10 (5.4) 106 (6.0) 78 (4.4)
Nasopharyngitis 10 (5.6) 8 (4.3) 92 (5.2) 84 (4.7)
Back pain 7 (3.9) 4 (2.2) 76 (4.3) 99 (5.6)
Hypoglycemia 5 (2.8) 9 (4.8) 92 (5.2) 78 (4.4)
Atrial fibrillation 5 (2.8) 6 (3.2) 69 (3.9) 95 (5.4)
Bronchitis 5 (2.8) 7 (3.8) 67 (3.8) 95 (5.4)
Procedural hypotension 11 (6.1) 12 (6.5) 69 (3.9) 74 (4.2)

* Shown are the numbers of adverse events and serious adverse events that occurred after the start of treatment in each
trial. The safety populations included all patients who received at least one dose of the trial treatment.
† In the incident DD-CKD trial, there were 15 deaths (8.4% of the patients) in the vadadustat group and 20 deaths (10.8%)
in the darbepoetin alfa group. In the prevalent DD-CKD trial, there were 276 deaths (15.6%) and 290 deaths (16.4%),
respectively.
‡ Common adverse events were events that occurred in at least 5% of patients in either treatment group in each trial.

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 Vadadustat for Anemia in Patients Undergoing Dialysis
port the pooled results of two trials (the PRO2TECT
trials) in which vadadustat was compared with
darbepoetin alfa in patients with non–dialysis-
dependent CKD. In those trials, vadadustat, as
compared with darbepoetin alfa, met the pre-
specified noninferiority criterion for hematologic
efficacy but not the prespecified noninferiority
criterion for cardiovascular safety.
Darbepoetin alfa is an injectable recombinant
erythropoietin molecule that was developed for
sustained activation of the erythropoietin recep-
tor,22 whereas vadadustat is an orally active,
small-molecule HIF prolyl hydroxylase inhibitor
that is being developed to stabilize HIF and
thereby mimic a state of cellular hypoxia.16 The
success of ESAs in the treatment of anemia as-
sociated with CKD has provided strong evidence
that inadequate production of endogenous eryth-
ropoietin is a major cause of anemia associated
with CKD.1 Although the mechanisms repress-
ing endogenous erythropoietin production in
CKD are not fully understood, the current trials
show that derepression by stabilization of HIF is
effective for sustained management of anemia in
patients with CKD who are undergoing dialysis.
These findings extend the results of previous
phase 2 trials of vadadustat and other HIF prolyl
hydroxylase inhibitors.10,13-19 The effects of vada-
dustat on hemoglobin concentrations seen in the
current trials are consistent with the recently
published findings of a phase 3 trial of the HIF
prolyl hydroxylase inhibitor roxadustat involving
305 patients in China with CKD who were under-
going dialysis.23
In the prevalent DD-CKD trial, we observed
an initial transient decline in hemoglobin con-
centrations as well as a less rapid increase in
hemoglobin concentrations among patients ran-
domly assigned to receive vadadustat than among
those randomly assigned to receive darbepoetin
alfa. We interpret these findings as a conse-
quence of the design of the trial. All the patients
randomly assigned to vadadustat received the
same initial dose of vadadustat (i.e., 300 mg per
day). In contrast, those randomly assigned to
darbepoetin alfa either continued treatment with
darbepoetin alfa at a dose that had previously
been adjusted to individual needs or switched
from another ESA with the use of accepted con-
version factors for their previously established
dose of the other ESA. The virtual overlay of hemo-
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globin-concentration curves beyond 24 weeks
showed not only the efficacy of vadadustat but
also the ability to achieve a target hemoglobin
range without overshooting the target during
dose adjustment of vadadustat. The mean main-
tenance doses for vadadustat during the primary
and secondary efficacy evaluation periods sug-
gest that dose requirements in many patients are
above the starting dose used in these trials.
Strengths of our two trials include the large
sample size and diverse patient population (with
respect to age, sex, race or ethnic group, and
geographic region), broad inclusion criteria,
and differences in underlying causes of CKD. We
included patients who were new to dialysis and
patients who had been undergoing maintenance
dialysis, as well as patients who were undergo-
ing peritoneal dialysis and hemodialysis, so that
we could assess safety and efficacy across a
broad range of patients and dialysis experience.
Our protocols followed regional clinical practice
guidelines for target hemoglobin ranges. Only a
few patients were lost to follow-up, and we adju-
dicated all MACE safety end points.
The trials have several limitations. First, inves-
tigators were aware of the treatment assignments,
which precluded a meaningful evaluation of pa-
tient-reported physical function and fatigue. The
inability to mask the treatment assignments
probably led to a proclivity to administer rescue
therapy with an ESA in the vadadustat groups.
Second, we did not measure residual kidney
function; however, results were uniform among
patients with incident and prevalent DD-CKD
and among those with prevalent DD-CKD who
had undergone dialysis for varying lengths of
time. Third, we used darbepoetin alfa as the
control in both trials and cannot conclude non-
inferiority to other ESAs. Finally, although the
sample size was large and the median follow-up
was more than 1.5 years, many patients with
DD-CKD receive treatment for anemia for many
years, and some for decades; real-world data from
longer-term clinical practice will be informative.
In these two trials, we found that vadadustat
was noninferior to darbepoetin alfa with respect
to cardiovascular safety and correction and main-
tenance of hemoglobin concentrations in pa-
tients with CKD who were undergoing dialysis.
Supported by Akebia Therapeutics and Otsuka Pharmaceu­
tical.
1611
 Vadadustat for Anemia in Patients Undergoing Dialysis

Disclosure forms provided by the authors are available with A data sharing statement provided by the authors is available
the full text of this article at NEJM.org. with the full text of this article at NEJM.org.

Appendix
The authors’ full names and academic degrees are as follows: Kai‑Uwe Eckardt, M.D., Rajiv Agarwal, M.D., Ahmad Aswad, M.D.,
Ahmed Awad, M.D., Geoffrey A. Block, M.D., Marcelo R. Bacci, M.D., Youssef M.K. Farag, M.D., Ph.D., M.P.H., Steven Fishbane, M.D.,
Harold Hubert, M.D., Alan Jardine, M.B., Ch.B., M.D., Zeeshan Khawaja, M.D., Mark J. Koury, M.D., Bradley J. Maroni, M.D., Kunihiro
Matsushita, M.D., Ph.D., Peter A. McCullough, M.D., M.P.H., Eldrin F. Lewis, M.D., M.P.H., Wenli Luo, Ph.D., Patrick S. Parfrey, M.B.,
B.Ch., Pablo Pergola, M.D., Ph.D., Mark J. Sarnak, M.D., Bruce Spinowitz, M.D., James Tumlin, M.D., Dennis L. Vargo, M.D., Kimberly A.
Walters, Ph.D., Wolfgang C. Winkelmayer, M.D., Janet Wittes, Ph.D., Rafal Zwiech, M.D., and Glenn M. Chertow, M.D., M.P.H.
The authors’ affiliations are as follows: the Department of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin
Berlin, Berlin (K.-U.E.); the Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis
(R.A.); Gonzalez M.D. and Aswad M.D. Health Care Services, Miami (A. Aswad); Clinical Research Consultants, Kansas City, MO (A.
Awad); U.S. Renal Care, Plano (G.A.B.), Baylor University Medical Center, Baylor Heart and Vascular Hospital, Baylor Heart and Vascu-
lar Institute, Dallas (P.A.M.), Renal Associates, Division of Nephrology, University of Texas Health Science Center at San Antonio, San
Antonio (P.P.), and the Section of Nephrology, Baylor College of Medicine, Houston (W.C.W.) — all in Texas; Praxis Medical Research,
and the Department of Medicine, Division of General Practice, Faculdade de Medicina do ABC, São Paulo (M.R.B.); Akebia Therapeutics,
Cambridge (Y.M.K.F., Z.K., B.J.M., W.L., D.L.V.), and the Division of Nephrology, Tufts Medical Center, Tufts University School of
Medicine, Boston (M.J.S.) — both in Massachusetts; the Division of Nephrology, Department of Medicine, Hofstra Northwell School of
Medicine, Great Neck (S.F.), and the Division of Nephrology, New York Presbyterian, Queens (B.S.) — both in New York; Nephrology
Associates, Augusta (H.H.), and Emory University School of Medicine, Atlanta (J.T.) — both in Georgia; the Institute of Cardiovascular
and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.J.); the Department of Medicine, Vanderbilt University
Medical Center, Nashville (M.J.K.); the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore
(K.M.); Stanford University School of Medicine, Palo Alto, CA (E.F.L., G.M.C.); the Department of Medicine, Memorial University, St.
John’s, NL, Canada (P.S.P.); Statistics Collaborative, Washington, DC (K.A.W., J.W.); and the Department of Kidney Transplantation–
Dialysis Department, Barlicki Memorial Teaching Hospital No. 1, Medical University of Lodz, Lodz, Poland (R.Z.).

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