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Journal of the Formosan Medical Association xxx (xxxx) xxx

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.jfma-online.com

Original Article

Roxadustat treatment for anemia in

peritoneal dialysis patients: A randomized
controlled trial
Yan-Pei Hou a, Xin-Yue Mao a,b, Chang Wang a,b, Zhi-Hui Xu a,
Zhi-Hua Bu a, Meng Xu a, Bing Li a,b,*

a
Department of Nephrology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
b
Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical
University, Haikou, China

Received 9 February 2021; received in revised form 4 May 2021; accepted 7 June 2021

KEYWORDS Background/purpose: Roxadustat, a first-in-class hypoxia-inducible factor prolyl hydroxylase

Anemia; inhibitor, promotes erythropoiesis and regulates iron metabolism. This study investigated
Chronic kidney the efficacy and safety of roxadustat in Chinese patients with anemia on peritoneal dialysis
disease; (PD).
Clinical trial; Methods: One hundred and twenty-nine patients were randomized and treated with roxadu-
Peritoneal dialysis; stat (n Z 86) or erythropoiesis-stimulating agents (ESAs) (n Z 43) for 24 weeks. The primary
Roxadustat end points were the mean hemoglobin (Hb) level at week 24, the change in average Hb levels
from baseline to week 24, and the cumulative response rate throughout the treatment period.
The secondary end points included changes in hepcidin and iron indices and serum lipid levels.
Subgroup analysis examined the effect of inflammatory status on the efficacy of Hb. Safety was
assessed as the occurrence of emergent adverse events after treatment.
Results: The mean average Hb levels at week 24 and average change in Hb levels from baseline
to week 24 were 11.5 g/dL and 2.5 g/dL in the roxadustat group and 11.2 g/dL and 2.2 g/dL in
the ESAs group, respectively. The cumulative response rate was 96% in the roxadustat group
and 92% in the ESAs group at week 24. Roxadustat decreased hepcidin levels and increased to-
tal iron-binding capacity. The decreases in total cholesterol and low-density lipoprotein
cholesterol were greater with roxadustat than with ESAs. Roxadustat-induced Hb increases
were independent of baseline C-reactive protein levels. Common adverse events included hy-
perkalemia, hypertension, and insomnia.

* Corresponding author. Department of Nephrology, 2nd Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District,
Harbin, 150086, China.
E-mail address: icecreamlee@hotmail.com (B. Li).

https://doi.org/10.1016/j.jfma.2021.06.004
0929-6646/Copyright ª 2021, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: Y.-P. Hou, X.-Y. Mao, C. Wang et al., Roxadustat treatment for anemia in peritoneal dialysis patients: A
randomized controlled trial, Journal of the Formosan Medical Association, https://doi.org/10.1016/j.jfma.2021.06.004
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Y.-P. Hou, X.-Y. Mao, C. Wang et al.
Conclusion: Roxadustat effectively corrected and maintained target Hb levels in Chinese PD
patients.
This trial was registered in the Chinese Clinical Trial Register (ChiCTR2000035054).
Copyright ª 2021, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Introduction
The prevalence of chronic kidney disease (CKD) has become
a major problem threatening public health.1 The overall
prevalence of CKD in China was 10.8%, estimated to be
approximately 119.5 million people.2 Renal anemia is a
common complication in patients with CKD, and it is a
dangerous factor for morbidity, mortality, cardiovascular
events and CKD progression.3 Peritoneal dialysis (PD), ac-
counting for approximately 11% of the global dialysis pop-
ulation,4 is a home-based, residual renal function protected
and cost-effective form of renal replacement therapy.
Current treatments for renal anemia in PD patients are
erythropoiesis-stimulating agents (ESAs), iron supplements
and others.5 A study of 3603 PD patients from six countries
found that approximately 45.2% of patients had hemoglobin
(Hb) < 11.0 g/dL.6 The improvement of renal anemia is not
optimistic according to the above data. In addition, ESAs
treatment has many limitations. First, it will increase the
risk of death and cardiovascular disease, such as worsening
hypertension, stroke and dialysis access clotting.7 Second,
the remaining 5e10% of patients have either a blunted or
absent response to ESAs.8 Third, injection of ESAs will cause
injection pain and induce lower treatment compliance,9
especially in predialysis and PD patients. Fourth, the ab-
sorption and utilization of iron cannot be improved.10
Roxadustat is a first-in-class novel oral hypoxia-inducible
factor prolyl hydroxylase inhibitor (HIFePHI) that stimu-
lates erythropoiesis by suppressing hypoxia-inducible factor
(HIF) prolyl hydroxylase enzymes, creating a transient
“pseudohypoxic” state that increases HIF accumulation and
activates several target genes for early reactions, including
erythropoietin (EPO), EPO receptor, iron transport and
heme synthesis.11 Hepcidin, a peptide associated with iron
absorption and mobilization, is stimulated by inflammation
and downregulated by HIF stabilization.12 The level of
hepcidin is elevated due to chronic inflammation and iron
overload in CKD patients.13
Roxadustat is a promising therapeutic approach against
anemia in CKD patients and has recently been approved in
China.14 Recently, a 26-week phase III study of roxadustat
in China reported that roxadustat was as effective as ESAs
for correcting and maintaining Hb levels in patients un-
dergoing dialysis.12 To date, however, data in PD, the
main modality of home dialysis, are definitely scarce with
subgroup evidence being provided in two randomized
controlled trials, the first by Besarab et al. that included
only 12 patients incident to PD15 and the second by Chen
et al. that included 22 PD patients treated with roxadu-
stat.12 Therefore, the efficacy and safety of roxadustat in
PD patients with anemia is worthy of further study.
2
Patients and methods
Patients
According to the literature report, the standard deviation
(SD) of the roxadustat group was 1.1 g/dL, and the SD of the
control group was 1.0 g/dL. The mean difference in DHb
between the two groups was 0.2 g/dL, the noninferiority
margin was 0.4 g/dL, a Z 0.025, power Z 0.8, and PASS
software (Version 15) was used to calculate the sample size.
Considering potential dropouts, at least 86 patients were
included in the roxadustat group and 43 in the ESAs group. A
total of 151 patients recruited from the Second Affiliated
Hospital of Harbin Medical University in China were included
in our open-label randomized controlled trial from 1
September 2019 to 15 June 2020 (ChiCTR2000035054). The
study was conducted in accordance with the Declaration of
Helsinki. The Ethics Committee of Harbin Medical University
approved the research project; informed consent was
signed by all participating patients. Patients diagnosed with
CKD and renal anemia who received PD were included.
Moreover, their Hb values during the screening period had to
be < 12 g/dL. Patients who were undergoing hemodialysis
or were intended to change dialysis modality at the time of
the study were excluded. A list of inclusion and exclusion
criteria is described in Supplemental Table S1.
Study design
The study comprised a 2-week screening period, a 24-week
treatment period and a 2-week posttreatment follow-up
period. Patients who completed the above three stages
were considered to have completed the trial. Eligible pa-
tients were randomized (2:1) and treated with oral rox-
adustat or subcutaneous ESAs for up to 24 weeks. The
roxadustat group was divided into ESA-Converted group
(patients previously receiving ESA) and ESA-Naı̈ve group
(patients not previously receiving ESA). The initial dose of
roxadustat was given according to weight: 100 mg for pa-
tients weighing 45 to <60 kg and 120 mg for patients
weighing 60 kg according to a previous study.12 Patients
assigned to the ESAs group continued their prerandomiza-
tion doses. Phosphate binders were given at least 1 h before
or after roxadustat. According to the patients’ current Hb
levels and change in Hb over the previous four weeks, the
dose was adjusted to maintain Hb levels at 10e12 g/dL as
described by a previous study.12 The use of oral iron ther-
apy was allowed; intravenous iron therapy was prohibited
except as rescue therapy. In enrolled subjects, rescue
(intravenous iron therapy and/or blood transfusion) was
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Journal of the Formosan Medical Association xxx (xxxx) xxx

available if sudden bleeding or Hb decreased from the ESAs group) and the safety population (86 in the rox-
baseline  1.5 g/dL. adustat group and 43 in the ESAs group). The roxadustat
group was divided into ESA-Converted group (n Z 67) and
Efficacy and safety assessments ESA-Naı̈ve group (n Z 19). The overall discontinuation rate
was 14% in the roxadustat group and 12% in the ESAs group.
In total, 74 patients in the roxadustat group and 38 patients
The primary efficacy end points for the trial included the
in the ESAs group completed treatment (shown in Fig. 1).
mean Hb at week 24, the change in average Hb levels from
The patient demographics and baseline variables were
baseline to week 24, and the cumulative response rate (Hb
similar in the roxadustat group and the ESAs group (shown in
level 10.0 g/dL and change in Hb from baseline 1.0 g/dL)
Table 1). The mean baseline Hb level was 9.0  1.4 g/dL in
during the whole study period. Secondary end points included
the roxadustat group and 9.0  1.2 g/dL in the ESAs group,
the following: changes in hepcidin, ferritin, transferrin satu-
which was not significantly different. In addition, the iron-
ration (TSAT), serum iron, and total iron-binding capacity
related parameters of the two groups were also not signifi-
(TIBC); changes in total cholesterol levels, triglycerides, high-
cantly different. Forty-four percent of the patients in the
density lipoprotein (HDL) cholesterol, and low-density lipo-
roxadustat group had a CRP level above the upper limit of
protein (LDL) cholesterol; and safety and tolerability of rox-
normal (ULN), which was similar to that in the ESAs group. For
adustat. To evaluate the role of roxadustat in patients with
roxadustat-treated subjects, the mean baseline Hb level was
inflammation, we performed a subgroup analysis of the
9.1  1.5 g/dL in the ESA-Converted group and 8.8  0.8 g/dL
average Hb level using C-reactive protein (CRP) levels as a
in the ESA-Naı̈ve group. Table 1 shows that chronic glomer-
factor. Exploratory analyses of white blood cells, mean
ulonephritis and hypertensive nephropathy were the main
corpuscular volume (MCV), platelet count and parathyroid
causes of end-stage renal disease in this center.
hormone (PTH) were conducted. The safety assessment
included clinical laboratory tests, physical examinations and
the incidence of adverse events (AEs) recorded from the Roxadustat effectively corrected anemia regardless
beginning of treatment to the end of follow-up. of previous ESAs treatment

At week 24, the mean Hb level (SD) was 11.5  1.0 g/dL in
Statistical analyses
the roxadustat group and 11.2  1.0 g/dL in the ESAs group.
Roxadustat treatment led to a numerically greater increase in
The primary efficacy end point analysis was conducted
the Hb level of 2.5  0.2 g/dL compared with ESAs treatment
using the full analysis seteintention (hereafter, the
(2.2  0.2 g/dL), and their treatment difference was
intention-to-treat population, ITT), which included all pa-
0.2  0.3 g/dL (95% confidence interval [CI], 0.3 to 0.8); the
tients who received at least one dose of study drug and who
lower limit of the 95% CI was above the predefined non-
had data for at least one efficacy variable measured during
inferiority margin of 0.4 g/dL, confirming the noninferiority
the treatment. Safety analysis was conducted on the safety
of roxadustat to ESA. A significant difference in Hb levels
analysis set, defined as patients taking one or more doses of
between the roxadustat group and the ESAs group was found
the study drug. Statistical analyses were conducted in SPSS
at week 8 and 12 (shown in Fig. 2A). The cumulative response
(version 25.0; IBM, Chicago, IL, USA). A value of P < 0.05
rate (Hb level 10.0 g/dL and change in Hb from baseline
was considered statistically significant in all statistical
1.0 g/dL) was 96% for the roxadustat group (72 patients)
analyses. Continuous variables are expressed as the
and 92% for the ESAs group (35 patients) at week 24. Based on
mean  standard deviation (SD), and classified variables are
two-way repeated measure analysis of variance, there were
described as numbers and percentages. When the data fit
significant changes in hemoglobin over time (P < 0.05), and
the normal distribution, an independent two-sample t test
there was a significant difference in the efficacy of the two
was used in the comparison of means between groups and a
drugs on hemoglobin (P Z 0.046). There was no interaction
paired t test was used to analyze changes in each group
between the time factor and grouping factor (P > 0.05).
during treatment. When the data did not conform to a
For the roxadustat-treated subjects, the mean Hb level
normal distribution, the ManneWhitney U test was used for
was 11.5  1.0 g/dL in the ESA-Converted group and
unpaired continuous variables between groups, and the
11.6  0.9 g/dL in the ESA-Naı̈ve group at week 24. The
Wilcoxon signed rank test was applied for time-related
change from baseline (CFB) in the mean Hb level was
paired samples. Nominal variables were made by Pearson
2.4  1.6 g/dL in the ESA-Converted group and 2.7  0.7 g/
chi-square test and presented as n (%). Clinically relevant
dL in the ESA-Naı̈ve group, and their treatment difference
variables between the two groups were compared by two-
was 0.2  0.3 g/dL (95% CI, 0.8 to 0.3) (shown in Fig. 2B).
way repeated measure analysis of variance.
The cumulative response rate was 95% for the ESA-Converted
group and 100% for the ESA-Naı̈ve group at week 24.
Results
Roxadustat effectively improved iron metabolism
Patient demographics and baseline characteristics by reducing hepcidin

In this study, 151 patients were screened, and 129 were In the roxadustat group, the mean serum iron level was
randomized for treatment with roxadustat (n Z 86) or ESAs stably maintained, TIBC rose significantly and TSAT was
(n Z 43). Of those randomized, 129 patients were enrolled basically stable with some slight decreases (shown in Table
in the ITT population (86 in the roxadustat group and 43 in 2). The CFB in serum iron in the two groups showed no

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Y.-P. Hou, X.-Y. Mao, C. Wang et al.
Figure 1 Patient randomization and treatment protocol. A total of 129 patients with peritoneal dialysis were randomly
assigned to either the roxadustat group (n Z 86) or the ESAs group (n Z 43). ESAs: erythropoiesis-stimulating agents.
significant differences (0.8 vs. 1.4 mmol/L), while TIBC
(7.1 vs. 2.6 mmol/L) rose significantly in the roxadustat
group. The CFB for TSAT in the roxadustat-treated subjects
was 0.7% compared with 4.2% in the ESAs group. The
mean serum iron level in the ESAs group declined without
an obvious change in TIBC. This resulted in a greater
decline in TSAT in the ESAs group than in the roxadustat
group. The changes from baseline in ferritin in the two
groups were not significantly different (P Z 0.405). At
baseline, the mean hepcidin level was 142.8  112.5 ng/mL
in the roxadustat group and 122.0  82.2 ng/mL in the ESAs
group. Compared with the ESAs group, hepcidin was obvi-
ously decreased by 12 weeks of roxadustat treatment, with
a CFB of 46.6  79.7 ng/mL (95% CI, 67.7 to 25.4) in
the roxadustat group and 5.9  87.6 ng/mL (95% CI, 39.2
to 27.5) in the ESAs group (shown in Fig. 2D).
Roxadustat improved Hb levels independent of
inflammation state
The proportion of patients with CRP levels above the ULN
range was similar at baseline in the roxadustat group (38 of
86 patients) and the ESAs group (18 of 43 patients) (shown
in Table 1). Comparing the subgroups based on the CRP
level, the average Hb levels in patients treated with rox-
adustat for 24 weeks were similar between the patients
with an elevated CRP level (11.4  1.1 g/dL) and those with
a normal CRP level (11.6  1.0 g/dL) (shown in Fig. 2E).
Based on two-way repeated measure analysis of variance,
there were significant changes in hemoglobin over time
4
(P < 0.05), and there was no significant difference in the
efficacy of the two groups on hemoglobin (P Z 0.932).
There was no interaction between the time factor and
grouping factor (P > 0.05). Patients with elevated CRP level
had a lower mean Hb level than those with normal CRP level
(10.7  1.1 vs. 11.5  0.8 g/dL) in the ESAs group (shown in
Fig. 2F). Based on two-way repeated measure analysis of
variance, there were significant changes in hemoglobin
over time (P < 0.05), and there was a significant difference
in the efficacy of the two groups on hemoglobin
(P Z 0.042). There was no interaction between the time
factor and grouping factor (P > 0.05). Compared with the
subgroups of patients with elevated CRP level, the CFB in
the Hb level of roxadustat was higher than that of ESAs
(2.5  1.5 g/dL vs. 1.9  1.2 g/dL), and their treatment
difference was 0.7  0.4 g/dL (95% CI, 0.2 to 1.5).
Roxadustat reduced total cholesterol and LDL-
cholesterol levels
At baseline, the mean total cholesterol level was
4.8  1.1 mmol/L in the roxadustat group (N Z 78) and
5.0  1.6 mmol/L in the ESAs group (N Z 39), and the mean
LDL-cholesterol level was 2.7  0.8 mmol/L in the rox-
adustat group and 2.8  0.9 mmol/L in the ESAs group. At
week 12, the CFB in total cholesterol was 0.6  1.0 mmol/
L in the roxadustat group and 0.1  1.2 mmol/L in the
ESAs group (P Z 0.007) (shown in Fig. 3A). The CFB in the
LDL-cholesterol level was 0.4  0.7 mmol/L in the rox-
adustat group and 0.2  0.7 mmol/L in the ESAs group
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Table 1 Demographic, clinical, and laboratory characteristics of the patients at baseline.

Characteristic Roxadustat ESAs group P
group (n Z 43)
ESA-Converted ESA-Naı̈ve All Roxadustat
group (n Z 67) group (n Z 19) group (n Z 86)
Age(y) 49  13 44  8 48  12 48.3  13 0.839
Male: female 30:37 17:2 47:39 25:18 0.707
BMI (kg/m2) 23.3  3.6 25.1  2.9 23.7  3.5 24.1  3.2 0.559
Etiology of CKD [n (%)]
Hypertensive nephropathy 24 (36) 5 (26) 29 (34) 14 (33) 0.919
Glomerulonephritis 29 (43) 9 (47) 38 (44) 18 (42)
Diabetic nephropathy 8 (12) 4 (21) 12 (14) 8 (19)
Other 6 (9) 1 (5) 7 (8) 3 (7)
Systolic Blood 148.2  15.0 149.3  14.2 148.4  14.7 146.4  10.4 0.376
pressure (mm Hg)
Diastolic Blood 92.4  11.0 92.9  9.8 92.5  10.7 91.5  7.0 0.662
pressure (mm Hg)
Baseline ESA dose (IU/w) 6649.3  2640.0 0 6649.3  2640.0 6511.6  2700.3 0.792
Hemoglobin (g/dL) 9.1  1.5 8.8  0.8 9.0  1.4 9.0  1.2 0.952
MCV (fL) 90.5  5.4 90.3  6.3 90.5  5.6 89.9  5.0 0.561
White blood cells (109/L) 7.2  2.4 6.5  2.1 7.1  2.3 7.8  2.3 0.083
Platelet count (109/mL) 204.5  65.6 230.4  77.0 210.2  68.7 226.4  99.7 0.697
K (mmol/L) 4.5  0.7 4.3  0.6 4.5  0.6 4.4  0.6 0.736
Na (mmol/L) 139.9  2.9 139.5  3.6 139.8  3.1 139.8  3.4 0.976
Cl (mmol/L) 99.9  4.2 102.1  5.0 100.4  4.5 101.0  5.0 0.469
Ca (mmol/L) 2.1  0.2 2.0  0.2 2.1  0.2 2.0  0.3 0.092
P (mmol/L) 1.9  0.6 2.1  0.6 1.9  0.6 1.7  0.5 0.080
Total cholesterol (mmol/L) 4.8  1.2 4.5  0.9 4.7  1.1 5.0  1.5 0.534
Triglycerides (mmol/L) 1.8  1.6 1.6  0.7 1.7  1.4 1.6  0.6 0.577
HDL-cholesterol (mmol/L) 1.2  0.3 0.9  0.3 1.1  0.3 1.1  0.4 0.780
LDL-cholesterol (mmol/L) 2.6  0.8 2.7  0.7 2.6  0.8 2.8  0.9 0.303
Serum iron (mmol/L) 12.7  4.9 12.1  5.6 12.6  5.0 11.4  5.0 0.060
TIBC (mmol/L) 43.3  12.7 39.7  6.7 42.5  11.7 41.3  14.9 0.212
Transferrin saturation (%) 31.2  13.3 31.7  17.4 31.3  14.2 29.6  13.2 0.487
20% [n (%)] 16 (24) 4 (21) 20 (23) 10 (23) >0.99
>20% [n (%)] 51 (76) 15 (79) 66 (77) 33 (77)
Ferritin (ng/mL) 265.1  312.0 281.9  245.1 268.8  297.2 257.4  190.8 0.653
PTH (pg/mL) 429.6  314.7 336.2  214.3 408.9  296.9 350.3  211.3 0.566
Transferrin (g/L) 2.0  0.6 1.8  0.2 2.0  0.5 1.9  0.6 0.549
C-reactive protein [n (%)]a
>ULN 30 (45) 8 (42) 38 (44) 18 (42) 0.802
ULN 37 (55) 11 (58) 48 (56) 25 (58)
Abbreviations: BMI, Body Mass Index; CKD, Chronic Kidney Disease; ESAs, Erythropoiesis-Stimulating Agents; HDL, High-Density Lipo-
protein; LDL, Low-Density Lipoprotein; MCV, Mean Corpuscular Volume; PTH, Parathyroid Hormone; TIBC, Total Iron-Binding Capacity;
ULN, Upper Limit of Normal.
a
The upper limit of ULN for the C-reactive protein level was 3.0 mg per liter. A value of p < 0.05 was defined as statistically
significant.

(P Z 0.037) (shown in Fig. 3D). However, the CFB in tri-
glycerides was not significantly different between the two
groups ( 0.2  1.4 vs. 0.0  1.1 mmol/L) (shown in
Fig. 3B). In addition, roxadustat reduced HDL-cholesterol
levels in contrast to the ESAs group (shown in Fig. 3C).
Roxadustat increased MCV and platelet count and
reduced PTH levels
At baseline, the mean white blood cell level was
7.1  2.4*109/L in the roxadustat group (N Z 78) and
7.8  2.3)109/L in the ESAs group (N Z 39), and the mean
MCV level was 90.6  5.1 fL in the roxadustat group and
89.6  5.0 fL in the ESAs group. At week 12, the mean white
blood cell level was 7.0  2.0)109/L in the roxadustat group
(N Z 78) and 7.7  1.6)109/L in the ESAs group (N Z 39), and
the mean MCV level was 93.9  6.8 fL in the roxadustat group
and 91.7  4.6 fL in the ESAs group. There was no significant
change in white blood cells between the two groups compared
with 12 weeks prior. MCV counts increased significantly in the
two groups during the 12-week treatment period. In the rox-
adustat group, the baseline mean platelet count was 212.8)

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Y.-P. Hou, X.-Y. Mao, C. Wang et al.

Figure 2 (A) Mean hemoglobin levels over time in the roxadustat group and ESAs group (intention-to-treat population). (B)
Mean hemoglobin levels over time in the ESA-Converted group and ESA-Naı̈ve group (intention-to-treat population). Mean
hepcidin levels (C) and mean change from baseline hepcidin levels (D) at week 12. Mean hemoglobin levels over time in the
roxadustat group (E) and ESAs group (F) according to the CRP subgroup. The intention-to-treat population included all the
patients who underwent randomization and had baseline and postbaseline hemoglobin values assessed during treatment. I bars and
T bars indicate the standard error of the mean. *P < 0.05(A) versus the ESAs group. **P < 0.01(A) versus the ESAs group.
**P < 0.01(C) versus baseline level. *P < 0.05 (F) versus CRP ULN group. **P < 0.01 (F) versus CRP ULN group. CRP: C-reactive
protein; ESAs: erythropoiesis-stimulating agents.

109/mL compared with the 12-week mean platelet count of
232.8)109/mL (P Z 0.031). A significant decrease in PTH was
observed in the roxadustat-treated group compared with the
ESAs group ( 92.2  234.1 vs. 3.6  251.6 pg/mL).
Adverse events and safety
During treatment, serious adverse events (SAEs) were re-
ported in 2 (2%) roxadustat-treated subjects and 1 (2%)
ESAs-treated patient. One SAE of myocardial infarction was
reported in a roxadustat-treated subject, and he dis-
continued the trial. A 66-year-old patient in the roxadustat
group with hypertension died in the intensive care unit
(death cause: acute heart failure) during follow-up. A 61-
year-old patient with diabetes in the ESAs group died on
day 84 due to heart failure. None of the deaths were
determined by the investigators to be related to the study
medication.
Overall, 38 of 86 patients (44%) treated with roxadustat
and 15 of 43 patients (35%) treated with ESAs incurred at
least one adverse event during treatment (shown in Table
3). In the present study, hyperkalemia was more common
in the roxadustat group than in the ESAs group. Two pa-
tients in the roxadustat group had elevated alanine
aminotransferase (ALT) levels, and returned to normal after
treatment. One case of peritonitis in the roxadustat group
was moderate in severity and resolved with antibiotic
treatment. Investigators did not believe that these cases
are related to roxadustat, nor have they led to the with-
drawal of roxadustat. In the roxadustat group, five patients
developed symptoms of insomnia, two of whom were dis-
continued due to this adverse event and three of whom
were relieved after adjusting the time of medication. One

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Table 2 Mean change from baseline of iron biomarker levels.

Mean (SD) levels p
Baseline End of 12-w treatment CFB
Roxadustat N Z 78 N Z 78
Serum iron (mmol/L) 12.7  5.0 13.5  7.3 0.8  5.9 0.872
TIBC (mmol/L) 42.8  12.0 49.9  14.5 7.1  15.7 <0.001
Ferritin (ng/mL) 261.9  294.7 206.5  209.5 55.5  299.5 0.057
TSAT (%) 31.1  13.3 30.4  22.3 0.7  20.4 0.070
ESAs N Z 39 N Z 39
Serum iron (mmol/L) 11.5  5.3 10.1  5.3 1.4  4.2 0.009
TIBC (mmol/L) 40.8  15.2 43.4  16.1 2.6  24.4 0.751
Ferritin (ng/mL) 253.7  189.6 226.1  164.2 27.6  192.3 0.655
TSAT (%) 30.2  13.6 26.0  15.6 4.2  17.8 0.252
A value of p < 0.05 was defined as statistically significant. Abbreviations: CFB, Change From Baseline; ESAs, Erythropoiesis-Stimulating
Agents; SD, Standard Deviation; TIBC, Total Iron-Binding Capacity; TSAT, Transferrin Saturation.

Figure 3 Mean total cholesterol level (A), triglycerides level (B), HDL-cholesterol level (C) and LDL-cholesterol level (D) at
baseline and week 12. T bars indicate the standard error of the mean. *P < 0.05 versus baseline level. **P < 0.01 versus baseline
level. HDL: high-density lipoprotein; LDL: low-density lipoprotein.

patient in the roxadustat-treated group discontinued the
treatment due to an adverse event of headache.
Discussion
This clinical trial is the first report in China to specifically
evaluate the efficacy and safety of roxadustat for treating PD-
CKD with anemia. Our results suggest that self-administration
of oral roxadustat in PD-CKD patients is effective. The mean
average Hb levels at week 24 and the average Hb change from
baseline to week 24 were 11.5 g/dL and 2.5 g/dL in the rox-
adustat group and 11.2 g/dL and 2.2 g/dL in the ESAs group,
respectively. Furthermore, patients in the roxadustat group
had a higher proportion of Hb response than those in the ESAs
group. At similar baseline levels, Hb levels in the roxadustat
group were significantly higher than those in the ESAs group at
week 12, suggesting that roxadustat could improve anemia

7
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Y.-P. Hou, X.-Y. Mao, C. Wang et al.

reduces trivalent iron ions to ferrous ions for absorption by

Table 3 Summary of treatment-emergent adverse events
intestinal cells.13 Recent studies on HIF-2a knockout mice
(safety analysis set).a
also showed that HIF plays a critical role in iron absorption
Preferred term Roxadustat ESAs and utilization.21
(N Z 86) (N Z 43) In addition to the erythropoietic effects of roxadustat, it
Subjects with AE(s) [n (%)] 38 (44) 15 (35) was associated with lower plasma cholesterol levels, which is
Upper respiratory 2 (2) 1 (2) consistent with previous studies of roxadustat in patients
tract infection with nondialysis-dependent CKD and dialysis-dependent
Hypertension 5 (6) 3 (7) CKD.18 None of the enrolled patients took lipid-lowering
Hyperkalemia 8 (9) 2 (5) drugs during the whole study period. The underlying mech-
Chest discomfort 2 (2) 1 (2) anisms of roxadustat involved in lowering cholesterol levels
Vomiting 3 (3) 1 (2) may be related to the degradation of acetyl coenzyme A and
Asthenia 2 (2) 1 (2) 3-hydroxy-3-methylglutaryl coenzyme A reductase, which
Alanine aminotransferase 2 (2) 0 are involved in cholesterol synthesis.22 Another explanation
increased is that HIF increases the expression of the target gene ATP-
Dizziness 0 1 (2) binding cassette transporter A1, which mediates the over-
Hypotension 1 (1) 1 (2) flow of intracellular cholesterol and phospholipid to apoli-
Muscle spasms 0 1 (2) poprotein deficiency, resulting in a decrease in intracellular
Constipation 1 (1) 0 cholesterol.23 This response might be of crucial importance
Pruritus 1 (1) 0 for protection against atherosclerosis.24 Apart from that,
Peritonitis 1 (1) 1 (2) roxadustat could also reduce LDL-cholesterol, which is in
Ostealgia 2 (2) 0 agreement with results from a recent phase III study in
Headache 3 (3) 2 (5) China.12 The potential of this ancillary effect of roxadustat
Insomnia 5 (6) 0 still needs to be further investigated.
a Even though receiving higher doses of ESAs, patients
Adverse events during treatment were defined as those that
with higher CRP level in the ESAs group had a lower Hb
occurred from randomization up to and including follow-up
days. Abbreviations: AE, Adverse Event; ESAs, Erythropoiesis- response than those with normal CRP level, suggesting that
Stimulating Agents. inflammation suppresses the response to ESAs. Interest-
ingly, among patients with elevated CRP level, the rox-
adustat group had a greater increase in Hb level than the
faster. Repeated measures analysis of variance showed sig- ESAs group, consistent with a previous study.12 The eryth-
nificant differences between the two groups. The efficacy ropoietic response of roxadustat was independent of the
results of our study confirm earlier findings that roxadustat inflammatory status of the patients, meaning that the drug
is effective for anemia in patients with CKD (nondialysis- is still effective in patients with an inflammatory compo-
dependent and dialysis-dependent).12,16 According to the nent of CKD.
Kidney Disease: Improving Global Outcomes 2012 guideline, Additionally, among the roxadustat-treated subjects, a
all CKD patients treated with ESAs should maintain a target Hb small increase in platelet levels was observed, which is in
level of 10e11.5 g/dL, while the target Hb level for any CKD contrast with other studies.11 This difference is thought to
patient should not be > 13 g/dL.17 In the roxadustat group, be related to platelet-derived growth factor, a HIF target
the mean Hb change for the first four weeks was 1.0  1.4 g/ gene.25 Patients in the two groups took drugs to correct
dL. However, in patients with an initial Hb of 10e12 g/dL, secondary hyperparathyroidism during the study period,
only a maintenance dose is required, and we recommend but PTH levels showed a significant decrease in the rox-
that the initial dose be reduced by one dose step for those adustat group. Julie L Frey et al. stated that HIF -1a re-
patients. stricts the anabolic actions of PTH,26 and potential related
Although intravenous iron supplementation was pro- mechanisms need to be explored by further study.
hibited in our study, serum iron levels were clinically stable As reported in earlier studies,27 roxadustat was well
in the roxadustat group and significantly decreased in the tolerated in anemia patients with PD-CKD, and the most
ESAs group. Additionally, we found that roxadustat can commonly reported AEs were hyperkalemia (9%), hyper-
reduce the level of hepcidin, which is in line with phase II tension (6%), and insomnia (6%). The AEs that we observed
and III studies.12,16,18,19 This phenomenon indicates that to be reported by a higher proportion of patients in the
roxadustat could increase iron bioavailability via enhanced roxadustat group during treatment were hyperkalemia (9%
intestinal iron absorption and release of iron from func- versus 5%). In particular, roxadustat is banned as a stimu-
tional stores by maintaining stable iron levels, improving lant among athletes,28 which may be the reason that pa-
TIBC, increasing the MCV value and reducing hepcidin. tients suffer from insomnia after taking the drug. Thus, we
Furthermore, roxadustat may reduce the safety risks of recommend taking the medicine in the morning. Long-term
intravenous iron, such as iron overload, oxidative stress, use of PHI may have adverse effects due to persistent
and hypersensitivity reactions.20 The HIF oxygen-sensing activation of HIF-regulated genes. Specifically, the activa-
pathway has been shown to be an important pathway for tion of vascular endothelial growth factor is involved in
iron homeostasis. HIF-1 induces the expression of trans- various biological processes, such as tumor growth,13 cell
ferrin, transferrin receptor 1, and ceruloplasmin to improve differentiation and mitochondrial metabolism.29 However,
iron utilization, while HIF-2 regulates divalent metal- in a phase III study in Japan,30 the rate of new or worsening
regulatory protein 1 and duodenal cytochrome b and retinal hemorrhages was similar between the darbepoetin

8
 + MODEL
Journal of the Formosan Medical Association xxx (xxxx) xxx
alfa and roxadustat groups, and no clinically significant
changes in retinal thickness were found.
This study has some limitations. First, the study was a
single-center study that limited the number of samples;
thus, large-scale prospective studies are required to further
test the conclusions. Second, due to the short-term follow-
up, the safety data are limited in their ability to examine
uncommon potential risks.
In summary, our study demonstrates that roxadustat
can effectively correct and maintain Hb levels in CKD pa-
tients on PD. Previously, Japanese scholars published the
efficacy of roxadustat in PD-CKD patients,27 but there was
no control group. Unlike ESAs, which require cold chain
delivery and storage,31 roxadustat can be stored at room
temperature.
Declaration of competing interest
None.
Acknowledgements
The study was conducted in accordance with the Declara-
tion of Helsinki. The research project was approved by the
Ethics Committee of Harbin Medical University (KY2019-
228). This trial was registered in the Chinese Clinical Trial
Register (ChiCTR2000035054). This study was supported
by research grants from the National Natural Science
Foundation of China (No. 81873598 and No. 81670616)
and Hainan key research and development projects
(ZDYF2020126).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jfma.2021.06.004.
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