Abstract
Background:
Chronic kidney disease (CKD)-associated anemia (CKD-anemia) is associated with poor survival, and hemoglobin targets are often not achieved with current therapies. Phase 3 trials have demonstrated the treatment efficacy of roxadustat for CKD-anemia. This phase 4 study aims to evaluate the long-term (52-week) safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China.
Methods:
This Phase 4 multicenter, open-label, prospective study, conducted from 24 November 2020 to 11 November 2022, evaluated the long-term safety and effectiveness of roxadustat for CKD-anemia in China. Patients aged ≥18 years with CKD-anemia with or without dialysis were included. The initial oral dose was 70–120 mg (weight-based followed by dose adjustment) over 52 weeks. The primary endpoint was safety based on adverse events (AEs). The secondary endpoints were hemoglobin changes from baseline and the proportion of patients who achieved mean hemoglobin ≥100 g/L. Effectiveness evaluable populations 1 (EE1) and EE2 included roxadustat-naïve and previously roxadustat-treated patients, respectively. The safety analysis set (SAF) included all patients who received ≥1 occasion.
Results:
The EE1, EE2, and SAF populations included 1804, 193, and 2021 patients, respectively. In the SAF, the mean age was 50 ± 14 years, and 1087 patients (53.8%) were male. Mean baseline hemoglobin was 96.9 ± 14.0 g/L in EE1 and 100.3 ± 12.9 g/L in EE2. In EE1, the mean (95% confidence interval) hemoglobin changes from baseline over weeks 24–36 and 36–52 were 14.2 (13.5–14.9) g/L and 14.3 (13.5–15.0) g/L, respectively. Over weeks 24–36 and 36–52, 83.3% and 86.1% of patients in EE1 and 82.7% and 84.7% in EE2 achieved mean hemoglobin ≥100 g/L, respectively. In the SAF, 1643 (81.3%) patients experienced treatment-emergent AEs (TEAEs). Overall, 219 (10.8%) patients experienced drug-related TEAEs. Thirty-eight (1.9%) patients died of TEAEs (unrelated to the study drug). Vascular access thrombosis was uncommon.
Conclusions:
Roxadustat (52 weeks) increased hemoglobin and maintained the treatment target in Chinese patients with CKD-anemia with acceptable safety, supporting its use in real-world settings.
Registration:
Chinese Clinical Trial Registry (www.chictr.org.cn) ChiCTR2100046322; CDE (www.chinadrugtrials.org.cn) CTR20201568
Keywords: Anemia, Chronic kidney disease, Effectiveness, Roxadustat, Safety
Introduction
Chronic kidney disease (CKD) is life-threatening and has an increasing prevalence,[1] affecting >10% of the worldwide population,[2] and around 10.8% of Chinese individuals aged ≥18 years.[3] CKD-associated anemia (CKD-anemia) results from a deficiency in erythropoietin production by the kidneys.[4,5] The overall prevalence of anemia in patients with non-dialysis-dependent (NDD)-CKD is about 51.1% for stage 3, 79.2% for stage 4, and 90.2% for stage 5 CKD.[6] The prevalence of anemia in patients with DD-CKD is as high as 91.6–98.2%.[7–9] Anemia correlates strongly with CKD progression and patient survival,[10] and it directly affects the quality of life (QoL) before and during dialysis.[11–15] Therefore, guidelines recommend effective anemia management in patients with CKD.[15–19]
Over the past 30 years, the mainstay treatments for CKD-anemia have included iron therapy and/or erythropoiesis-stimulating agents (ESAs).[17,20] However, ESAs are limited by the increased cardiovascular risk at higher doses and ESA hyporesponsiveness, and there are concerns over treatment safety and possible iron overload with intravenous iron therapy.[21] According to Kidney Disease Improving Global Outcomes guidelines, ESAs should be initiated when the hemoglobin concentration is <100 g/L.[22,23] ESAs should not be used to increase hemoglobin to >130 g/L or to maintain hemoglobin at >115 g/L in adults with CKD.[23] According to Chinese guidelines for renal anemia, the target hemoglobin concentration for anemia treatment is ≥110 g/L, but it should not exceed 130 g/L.[22] However, many patients with CKD-anemia do not achieve hemoglobin targets with existing treatments.[24,25] In China, only 39.8% of patients with NDD-CKD receive ESAs and 27.1% receive iron therapy, with only 12.1% of treated patients achieving hemoglobin targets. In the DD-CKD population, although >90% of patients (91.7% with peritoneal dialysis [PD] and 98.7% with hemodialysis [HD]) use ESAs, the treat-to-target rate is low (37.7% for HD, 32.5% for PD).[6,22] These findings suggest that the traditional treatments for CKD-anemia have limitations.
Roxadustat is a potent, reversible hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis in a manner similar to the body’s normal homeostatic response to anemia,[20] and it also prolongs the erythrocyte lifespan.[26] Meta-analyses have suggested that patients with DD-CKD or NDD-CKD treated with roxadustat have higher hemoglobin concentrations than those treated with ESAs or placebo. Moreover, roxadustat is not associated with higher adverse event (AE) rates than ESAs or placebo.[27–29]
In China, roxadustat was approved for the treatment of DD-CKD-anemia in 2018 and for NDD-CKD-anemia in 2019.[30] By 2023, three other phase 4 studies (ChiCTR2100045359, ChiCTR2100044799, and NCT04059913) of roxadustat in patients with CKD had been completed in China. The present phase 4 study aims to evaluate the long-term (52-week) safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China. The primary objective is to evaluate roxadustat’s long-term safety, and the secondary objectives are to evaluate the effectiveness of roxadustat and investigate its impact on QoL.
Methods
Study design
This was a national, phase 4, multicenter, open-label, prospective study (clinical trial registrations [www.chictr.org.cn] ChiCTR2100046322, CDE [www.chinadrugtrials.org.cn] CTR20201568) conducted from 24 November 2020 to 11 November 2022 with a treatment period of 52 weeks.
The study was approved by the Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (approval number: 2020 EC No. 189). Approval was also obtained from each of the 61 participating sites [Supplementary Table 1, http://links.lww.com/CM9/C491]. All patients provided written informed consent. The procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the 1975 Helsinki Declaration (as revised in 2013).
Patient selection
The planned sample size was at least 2000 patients to fulfill the requirement of the National Medical Products Administration (NMPA) regarding post-market surveillance (drug registration approval Nos. 2018S00669 and 2019S00473). PD, HD, and NDD patients were included to reflect the real-world setting, with the minimum number in each subgroup set to 400. The inclusion criteria were (1) adult patients with CKD-associated anemia (aged ≥18 years); (2) receipt of written informed consent; and (3) a diagnosis of CKD-anemia treated with roxadustat or considered suitable for roxadustat treatment (hemoglobin <120 g/L for patients treated with ESAs or roxadustat for ≥6 weeks before enrolment, or hemoglobin <100 g/L for those who had not previously undergone ESA or roxadustat treatment or who had been treated for <6 weeks). The exclusion criteria are described in the Supplementary Methods, http://links.lww.com/CM9/C491.
Study procedures
The roxadustat (FibroGen [China] Medical Technology Development Co., Ltd., Beijing, China) dose was decided according to the approved product package insert [Supplementary Methods, http://links.lww.com/CM9/C491],[31] or the investigator’s clinical judgment. For dialysis patients, the starting dose was 100 mg three times per week (TIW) for those weighing 45 to <60 kg, and 120 mg TIW for those weighing ≥60 kg. For non-dialysis patients, the starting dose was 70 mg TIW for those weighing 45 to <60 kg and 100 mg TIW for those weighing ≥60 kg. Patients were treated for 4 weeks with the initial weight-based dose. Every 4 weeks thereafter, each patient’s dose was continued or adjusted based on the hemoglobin change from 4 weeks prior and the current hemoglobin concentration [Supplementary Methods, http://links.lww.com/CM9/C491]. The hemoglobin treatment target was 100–120 g/L according to the approved product insert.[31] Oral iron could be administrated at any time according to clinical practice. Routine intravenous iron was not needed while taking roxadustat, but it was administered if clinically indicated according to the investigator’s judgment.
The patients attended visits every 4 weeks in the first 12 weeks and every 12 weeks thereafter. For patients who discontinued treatment earlier than week 52, follow-up data were collected 28 days after discontinuation to assess delayed AEs. Otherwise, no further safety follow-up was conducted as roxadustat is already marketed.
Effectiveness assessments
The effectiveness evaluable population (EE) included all enrolled patients who received roxadustat on at least one occasion and who had an available baseline hemoglobin measurement and at least one post-baseline hemoglobin measurement. EE1 included all roxadustat-naïve patients who had not undergone stable roxadustat treatment for ≥6 weeks prior to enrolment, and was divided into PD, HD, and NDD subgroups. EE2 included all stable previously roxadustat-treated patients who met the inclusion criteria.
All effectiveness analyses were performed in the overall EE1 and in the EE1 subgroups. Selected effectiveness analyses were performed in EE2, but no subgroup analyses were performed because of the small sample size. In EE1, hemoglobin changes from baseline averaged over weeks 24–36 (i.e., the average of week 24 and week 36) and 36–52 (i.e., the average of week 36, week 48 and week 52/end of treatment) were assessed. In both EE1 and EE2, the proportion of patients with a mean hemoglobin concentration ≥100 g/L averaged over weeks 24–36, 36–52, and 24–52 was assessed. QoL was assessed by measuring changes from baseline to weeks 12 and 24 in the Short Form (SF)-36 Vitality and physical functioning subscales, as well as in the self-reported Rapid Assessment of Physical Activity (RAPA) score.
Safety assessments
The safety results are reported for the overall safety analysis set ([SAF]; all enrolled patients who received roxadustat on at least one occasion) and include the number (%) of patients with treatment-emergent AEs (TEAEs), TE serious AEs (TESAEs), and AEs of special interest ([AESI]; see Supplementary Methods, http://links.lww.com/CM9/C491 for definitions). Changes from baseline in vital signs, electrocardiography, and laboratory measures were also evaluated.
Statistical analysis
Continuous data are expressed as the mean ± standard deviation (SD) (where mean ± standard error [SE] is used, this is specified), mean (95% confidence interval [CI]), or median (min, max). Categorical data are expressed as numbers (%). For the effectiveness assessment, the mean change in hemoglobin from baseline to average over weeks 24–36, and 36–52 was calculated as the difference (95% CI). The proportion (95% CI) of patients with a mean hemoglobin concentration ≥100 g/L averaged over weeks 24–36, 36–52, and 24–52 is described. The 95% CI was based on the normal approximation to the binomial probability distribution. Missing hemoglobin values were imputed by multiple imputations [Supplementary Methods, http://links.lww.com/CM9/C491]. The methods used to handle intercurrent events (e.g., ESA/intravenous iron use) are also described in the Supplementary Methods, http://links.lww.com/CM9/C491. The QoL assessment results are summarized as changes from baseline to weeks 12 and 24. Missing QoL values were imputed by multiple imputations [Supplementary Methods, http://links.lww.com/CM9/C491]. Observed cases of the effectiveness endpoints and QoL were used for the sensitivity analyses. For safety, the frequency, severity, organ systems affected, and relationship of TEAEs to roxadustat were recorded. All data analyses were conducted using SAS software, version 9.2 (SAS Institute Inc., Cary, NC, US).
Results
Population
Overall, 2347 patients were screened for eligibility, of whom 323 failed. Therefore, 2024 patients were enrolled, and 2021 received roxadustat on at least one occasion. Of these, 1592 completed treatment. The main reasons for roxadustat discontinuation were non-compliance or withdrawal by the patient (n = 170), intolerable AEs (n = 105), death (n = 32), kidney transplantation (n = 31), prohibited drug use (n = 24), and loss to follow-up (n = 24) [Supplementary Figure 1, http://links.lww.com/CM9/C491].
The analysis population is shown in Figure 1. All 2021 treated patients were included in the SAF. Of these, 851 (42.1%), 676 (33.4%), and 494 (24.4%) were in the HD, PD, and NDD subgroups, respectively. In the SAF, 1827 were previously roxadustat-naïve (of whom 1804 entered EE1; 23 were excluded from EE1 because of missing post-baseline hemoglobin data), 193 were previously roxadustat-treated (all entered EE2), and one had an unknown previous roxadustat treatment status. Among the 1804 patients in EE1, there were 600 (33.3%) in the PD subgroup, 764 (42.4%) in the HD subgroup, and 440 (24.4%) in the NDD subgroup.
Figure 1.
Flowchart of patient inclusion. EE: Effectiveness evaluable; HD: Hemodialysis; NDD: Non-dialysis-dependent; PD: Peritoneal dialysis; SAF: Safety analysis set.
Demographic and baseline characteristics
In the SAF (n = 2021), the mean age was 50 ± 14 years, and 1087 patients (53.8%) were male [Table 1]. The median CKD duration was 5 (range: 1, 52) years. The mean baseline hemoglobin concentration was 97.2 ± 14.0 g/L. The median transferrin saturation was 26.77% (0.73%, 103.76%), and the median ferritin was 167.30 (3.30, 3966.00) ng/mL. The median dialysis duration was 20.88 (0.03, 173.96) months in the PD subgroup and 33.61 (0.16, 427.93) months in the HD subgroup. The mean weekly Kt/V in the PD subgroup was 1.86 ± 1.24, and the mean single pool Kt/V in the HD subgroup was 1.37 ± 0.57 [Table 1]. Chronic glomerulonephritis (839 [41.5%]) and diabetic kidney disease (383 [19.0%]) were the most common CKD etiologies. Overall, 552 patients (27.3%) had a diabetes mellitus history, and most patients had cardio-cerebrovascular disease (1948 [96.4%]) or hypertension (1932 [95.6%]) [Table 2].
Table 1.
Demographic and baseline characteristics of patients with CKD-associated anemia (safety analysis set).
| Characteristic | PD (n = 676) | HD (n = 851) | NDD (n = 494) | Overall (n = 2021) |
|---|---|---|---|---|
| Age (years), Mean ± SD | 47 ± 12 | 50 ± 13 | 55 ± 14 | 50 ± 14 |
| Sex, n (%) | ||||
| Male | 360 (53.3) | 531 (62.4) | 196 (39.7) | 1087 (53.8) |
| Female | 316 (46.7) | 320 (37.6) | 298 (60.3) | 934 (46.2) |
| Height (cm), Mean ± SD | 164.31 ± 8.14 | 166.42 ± 8.40 | 163.11 ± 8.08 | 164.90 ± 8.34 |
| Body weight (kg), Mean ± SD | 63.33 ± 12.47 | 64.87 ± 13.68 | 61.82 ± 12.37 | 63.61 ± 13.02 |
| Body mass index (kg/m2), Mean ± SD | 23.36 ± 3.73 | 23.29 ± 3.90 | 23.13 ± 3.66 | 23.28 ± 3.78 |
| CKD duration (years), n | 673 | 842 | 485 | 2000 |
| Median (min, max) | 5 (1, 32) | 7 (1, 43) | 4 (1, 52) | 5 (1, 52) |
| CKD etiology, n (%) | ||||
| Chronic glomerulonephritis | 337 (49.9) | 311 (36.5) | 191 (38.7) | 839 (41.5) |
| Other primary glomerular disease | 37 (5.5) | 31 (3.6) | 28 (5.7) | 96 (4.8) |
| Diabetic kidney disease | 81 (12.0) | 189 (22.2) | 113 (22.9) | 383 (19.0) |
| Hypertensive renal disease | 92 (13.6) | 90 (10.6) | 38 (7.7) | 220 (10.9) |
| Polycystic kidney disease | 7 (1.0) | 7 (0.8) | 4 (0.8) | 18 (0.9) |
| Obstructive nephropathy | 12 (1.8) | 40 (4.7) | 25 (5.1) | 77 (3.8) |
| Lupus nephritis | 7 (1.0) | 6 (0.7) | 9 (1.8) | 22 (1.1) |
| Other | 103 (15.2) | 177 (20.8) | 86 (17.4) | 366 (18.1) |
| Previous ESA treatment, n (%) | ||||
| Yes | 288 (42.6) | 450 (52.9) | 108 (21.9) | 846 (41.9) |
| No | 388 (57.4) | 401 (47.1) | 386 (78.1) | 1175 (58.1) |
| Dialysis duration (months), n | 676 | 851 | NA | NA |
| Median (min, max) | 20.88 (0.03, 173.96) | 33.61 (0.16, 427.93) | NA | NA |
| Heart rate (bpm), Mean ± SD | 79.2 ± 10.0 | 77.3 ± 9.5 | 77.5 ± 10.1 | 78.0 ± 9.8 |
| SBP (mmHg), Mean ± SD | 139.6 ± 16.5 | 144.4 ± 17.4 | 137.2 ± 15.5 | 141.0 ± 16.9 |
| DBP (mmHg), Mean ± SD | 85.9 ± 10.8 | 82.5 ± 11.2 | 80.1 ± 10.3 | 83.0 ± 11.1 |
| BP group (mmHg), n (%) | ||||
| SBP <140 and DBP <90 | 287 (42.5) | 300 (35.3) | 272 (55.1) | 859 (42.5) |
| SBP ≥140 and DBP ≥90 | 190 (28.1) | 191 (22.4) | 64 (13.0) | 445 (22.0) |
| SBP ≥140 and DBP <90 | 148 (21.9) | 340 (40.0) | 141 (28.5) | 629 (31.1) |
| SBP <140 and DBP ≥90 | 51 (7.5) | 20 (2.4) | 17 (3.4) | 88 (4.4) |
| Hemoglobin (g/L), Mean ± SD | 96.4 ± 14.3 | 98.9 ± 14.4 | 95.3 ± 12.2 | 97.2 ± 14.0 |
| Hemoglobin group (g/L), n (%) | ||||
| <70 | 32 (4.7) | 29 (3.4) | 20 (4.0) | 81 (4.0) |
| ≥70 and <100 | 329 (48.7) | 373 (43.8) | 291 (58.9) | 993 (49.1) |
| ≥100 | 315 (46.6) | 449 (52.8) | 183 (37.0) | 947 (46.9) |
| TSAT (%), n | 571 | 736 | 435 | 1742 |
| Median (min, max) | 27.50 (1.50, 103.76) | 29.87 (2.23, 99.40) | 23.31 (0.73, 89.38) | 26.77 (0.73, 103.76) |
| TSAT group, n (%) | ||||
| <5% | 4 (0.6) | 9 (1.1) | 7 (1.4) | 20 (1.0) |
| 5–20% | 165 (24.4) | 167 (19.6) | 149 (30.2) | 481 (23.8) |
| >20% | 402 (59.5) | 560 (65.8) | 279 (56.5) | 1241 (61.4) |
| Data missing | 105 (15.5) | 115 (13.5) | 59 (11.9) | 279 (13.8) |
| Ferritin (ng/mL), n | 656 | 841 | 486 | 1983 |
| Median (min, max) | 169.21 (4.20, 3966.00) | 200.00 (3.30, 2701.70) | 119.13 (3.42, 1505.00) | 167.30 (3.30, 3966.00) |
| Ferritin group (ng/mL), n (%) | ||||
| <50 | 106 (15.7) | 120 (14.1) | 124 (25.1) | 350 (17.3) |
| 50–100 | 109 (16.1) | 122 (14.3) | 95 (19.2) | 326 (16.1) |
| >100 | 441 (65.2) | 599 (70.4) | 267 (54.0) | 1307 (64.7) |
| Data missing | 20 (3.0) | 10 (1.2) | 8 (1.6) | 38 (1.9) |
| CRP/hs-CRP group, n (%) | ||||
| CRP/hs-CRP ≤ULN | 511 (75.6) | 649 (76.3) | 419 (84.8) | 1579 (78.1) |
| CRP/hs-CRP>ULN | 157 (23.2) | 196 (23.0) | 75 (15.2) | 428 (21.2) |
| Missing | 8 (1.2) | 6 (0.7) | 0 | 14 (0.7) |
| Diabetes patients only | ||||
| Fasting blood glucose (mmol/L), n | 127 | 247 | 168 | 542 |
| Mean ± SD | 8.25 ± 3.34 | 8.75 ± 4.43 | 7.40 ± 3.37 | 8.21 ± 3.92 |
| HbA1c (%), n | 119 | 243 | 160 | 522 |
| Mean ± SD | 6.64 ± 1.28 | 7.06 ± 1.60 | 6.66 ± 1.20 | 6.84 ± 1.43 |
| Peritoneal dialysis patients only | ||||
| Weekly Kt/V, n | 579 | NA | NA | NA |
| Mean ± SD | 1.86 ± 1.24 | NA | NA | NA |
| Peritoneal transport type, n (%) | ||||
| High | 49 (7.2) | NA | NA | NA |
| High-average | 209 (30.9) | NA | NA | NA |
| Low-average | 277 (41.0) | NA | NA | NA |
| Low | 59 (8.7) | NA | NA | NA |
| Missing | 82 (12.1) | NA | NA | NA |
| Hemodialysis only | ||||
| Single pool Kt/V, n | NA | 805 | NA | NA |
| Mean ± SD | NA | 1.37 ± 0.57 | NA | NA |
| Current vascular access type, n (%) | ||||
| Autologous arteriovenous fistula | NA | 758 (89.1) | NA | NA |
| Arteriovenous graft | NA | 4 (0.5) | NA | NA |
| Long-term catheter | NA | 50 (5.9) | NA | NA |
| Temporary hemodialysis catheter | NA | 39 (4.6) | NA | NA |
| Hemodialysis frequency group, n (%) | ||||
| <3/week | NA | 125 (14.7) | NA | NA |
| ≥3/week | NA | 726 (85.3) | NA | NA |
BP: Blood pressure; bpm: Beats per minute; CKD: Chronic kidney disease; CRP: C-reactive protein; DBP: Diastolic blood pressure; ESA: Erythropoiesis-stimulating agent; HbA1c: Glycated hemoglobin; HD: Hemodialysis; hs-CRP: High-sensitivity C-reactive protein; NA: Not applicable; NDD: Non-dialysis-dependent; PD: Peritoneal dialysis; SBP: Systolic blood pressure; SD: Standard deviation; TSAT: Transferrin saturation; ULN: Upper limit of normal.
Table 2.
Medical history of patients with CKD-associated anemia (safety analysis set).
| Medical history | PD (n = 676) | HD (n = 851) | NDD (n = 494) | Overall (n = 2021) |
|---|---|---|---|---|
| Diabetes mellitus | 128 (18.9) | 255 (30.0) | 169 (34.2) | 552 (27.3) |
| Type 1 diabetes mellitus | 5 (0.7) | 12 (1.4) | 6 (1.2) | 23 (1.1) |
| Type 2 diabetes mellitus | 118 (17.5) | 233 (27.4) | 156 (31.6) | 507 (25.1) |
| Other | 5 (0.7) | 12 (1.4) | 7 (1.4) | 24 (1.2) |
| Cardio-cerebral vascular disease | 659 (97.5) | 835 (98.1) | 454 (91.9) | 1948 (96.4) |
| Hypertension | 656 (97.0) | 826 (97.1) | 450 (91.1) | 1932 (95.6) |
| Coronary atherosclerotic heart disease | 85 (12.6) | 205 (24.1) | 85 (17.2) | 375 (18.6) |
| Myocardial infarction | 6 (0.9) | 18 (2.1) | 9 (1.8) | 33 (1.6) |
| Stroke and transient ischemic attack | 56 (8.3) | 111 (13.0) | 61 (12.3) | 228 (11.3) |
| Heart failure | 146 (21.6) | 207 (24.3) | 44 (8.9) | 397 (19.6) |
| Atrial fibrillation | 5 (0.7) | 24 (2.8) | 6 (1.2) | 35 (1.7) |
| Venous thromboembolic events | 7 (1.0) | 56 (6.6) | 7 (1.4) | 70 (3.5) |
| Arteriovenous fistula site complication | 2 (0.3) | 31 (3.6) | 0 | 33 (1.6) |
| Malignant neoplasm | 4 (0.6) | 11 (1.3) | 9 (1.8) | 24 (1.2) |
CKD: Chronic kidney disease; HD: Hemodialysis; NDD: Non-dialysis-dependent; PD: Peritoneal dialysis.
Effectiveness assessments
Overall EE1
The mean (95% CI) hemoglobin change from baseline averaged over weeks 24–36 and 36–52 was 14.2 (13.5–14.9) g/L and 14.3 (13.5–15.0) g/L, respectively. The proportion (95% CI) of patients in EE1 who achieved a mean hemoglobin concentration ≥100 g/L for the entire period from weeks 24–52 was 86.3% (84.5–88.2%). Figure 2 shows that the proportion of patients in EE1 who achieved a mean hemoglobin concentration ≥100 g/L during weeks 24–36 (83.3% [81.4–85.2%]) increased by 3% at weeks 36–52 (86.1% [84.2–87.9%]). The mean ± SE hemoglobin concentration in EE1 increased from 96.9 ± 0.3 g/L at baseline to 113.4 ± 0.4 g/L at week 12 and was maintained between 110 and 115 g/L thereafter [Figure 3].
Figure 2.
Proportions with hemoglobin ≥100 g/L over weeks 24–36, 36–52, and 24–52 in the overall EE1, as well as the PD, HD, and NDD subgroups. Data are expressed as mean (95% confidence interval). EE1: Effectiveness evaluable populations 1; HD: Hemodialysis; NDD: Non-dialysis-dependent; PD: Peritoneal dialysis.
Figure 3.
Mean hemoglobin concentrations at the scheduled visits in the overall EE1, as well as in the PD, HD, and NDD subgroups. Data are expressed as mean ± standard error of the mean. EE1: Effectiveness evaluable populations 1; HD: Hemodialysis; NDD: Non-dialysis-dependent; PD: Peritoneal dialysis.
EE1 subgroups
The mean (95% CI) hemoglobin change from baseline over weeks 24–36 in the NDD, PD, and HD subgroups was 16.3 (14.9–17.8) g/L, 15.7 (14.4–17.0) g/L, and 11.8 (10.6–13.0) g/L, respectively. The mean (95% CI) hemoglobin change from baseline over weeks 36–52 remained largely unchanged from weeks 24–36 (NDD: 16.6 [15.2–18.0] g/L; PD: 15.6 [14.4–16.9] g/L; HD: 11.9 [10.7–13.1] g/L).
The proportion of patients with mean hemoglobin ≥100 g/L over weeks 24–36, 36–52, and 24–52 was similar among the three subgroups (82.7–83.9%, 84.8–87.6%, and 85.4–87.3%, respectively; [Figure 2]).
Of the subgroups, the PD subgroup showed the greatest increase in hemoglobin [Figure 3], with a mean ± SE hemoglobin increase from 96.1 ± 0.6 g/L at baseline to 115.8 ± 0.6 g/L at week 12, which was maintained between 110 and 115 g/L thereafter. The same pattern was seen in the HD and NDD subgroups [Figure 3].
EE2
EE2 showed the same pattern as EE1 in terms of the proportion of patients who achieved mean hemoglobin ≥100 g/L [Figure 4]. The proportion of patients in EE2 who achieved mean hemoglobin ≥100 g/L over all periods was >80%, which was not significantly different from the overall EE1 population. Such as EE1, the mean hemoglobin concentration gradually increased from 100.3 ± 0.9 g/L at baseline and stabilized from weeks 12–52 at around 110 g/L [Figure 5].
Figure 4.
Proportions of patients with mean hemoglobin concentrations ≥100 g/L averaged over weeks 24–36, 36–52, and 24–52 in the overall EE2. Data are expressed as mean [95% confidence interval]. EE2: Effectiveness evaluable populations 2.
Figure 5.
Mean hemoglobin concentrations at the scheduled visits in the overall EE2. Data are expressed as mean ± standard error of the mean. EE2: Effectiveness evaluable populations 1.
The results of the sensitivity analyses (observed cases; no imputation) for the effectiveness endpoints in EE1 and EE2 (data not shown) were similar to the primary analyses with multiple imputations for missing data.
QoL
In EE1, the mean (95% CI) SF-36 Vitality subscale score change from baseline to week 12 was 0.1 (–0.4 to 0.6), and from baseline to week 24 was −0.2 (−0.8 to 0.2). For the SF-36 physical functioning subscale score, the mean (95% CI) change from baseline to week 12 was 0.135 (−0.229 to 0.432) and to week 24 was −0.162 (−0.494 to 0.233). The mean (95% CI) self-reported RAPA strength and flexibility score change from baseline to week 12 was 0.1 (0.0–0.1) and to week 24 was 0.0 (0.0–0.1). The QoL results of the EE1 subgroup analyses are shown in the Supplementary Results, http://links.lww.com/CM9/C491.
In EE2, the mean (95% CI) SF−36 Vitality subscale score change from baseline to week 12 was −0.515 (−1.726 to 0.758), and from baseline to week 24 was 0.106 (−1.287 to 1.358). For the SF-36 Physical Functioning subscale score, the mean (95% CI) change from baseline to week 12 was 0.172 (−0.737 to 1.082) and to week 24 was −0.013 (−1.044 to 1.068). The mean (95% CI) self-reported RAPA strength and flexibility score change from baseline to week 12 was 0.1 (−0.10 to 0.21), and from baseline to week 24 was 0.1 (−0.06 to 0.28).
The results of the sensitivity analyses (observed cases; no imputation) for QoL (data not shown) were similar to the primary analyses with multiple imputations for missing data.
Iron therapy and changes in iron metabolism-related indicators
Supplementary Table 2, http://links.lww.com/CM9/C491 shows the changes from baseline to weeks 24 and 52 in iron metabolism-related indicators. During treatment, 52.7% of patients used iron therapy (intravenous: 13.6%, oral: 44.1%). Serum ferritin and transferrin saturation decreased from baseline to week 52, while serum iron, transferrin, and total iron-binding capacity increased.
Safety assessments
The mean treatment duration was 44.06 ± 15.70 weeks (PD: 46.19 ± 13.85 weeks; HD: 42.70 ± 16.84 weeks; NDD: 43.48 ± 15.76 weeks), and the mean weekly roxadustat dose was 254.13 ± 103.16 mg (PD: 240.07 ± 101.43 mg; HD: 290.42 ± 101.00 mg; NDD: 210.84 ± 86.65 mg). [Supplementary Table 3, http://links.lww.com/CM9/C491].
In the SAF (n = 2021), 1643 patients (81.3%) reported TEAEs (PD: 556/676 [82.2%]; HD: 682/851 [80.1%]; NDD: 405/494 [82.0%]). TEAEs were related/possibly related to roxadustat in 219 patients (10.8%). Most patients reported mild or moderate (grade 1 or 2) TEAEs, while 678 patients (33.5%) reported Common Terminology Criteria for AEs (CTCAEs) grade ≥3 TEAEs. TESAEs occurred in 751 patients (37.2%) [Table 3]. TEAEs leading to study discontinuation or drug withdrawal occurred in 103 patients (5.1%).
Table 3.
Overall summary of TEAEs for patients with CKD-associated anemia (safety analysis set).
| Terms | Overall population (n = 2021) |
|---|---|
| Any TEAEs | 1643 (81.3) |
| Drug-related TEAEs* | 219 (10.8) |
| Related | 26 (1.3) |
| Possibly related | 198 (9.8) |
| TEAEs of CTCAE grade ≥3† | 678 (33.5) |
| Serious TEAEs | 751 (37.2) |
| TEAEs leading to death | 38 (1.9) |
| TEAEs leading to study discontinuation or drug withdrawal | 103 (5.1) |
*Related or possibly related TEAEs reported by the investigator; TEAEs with an unknown relationship to the study drug are counted as possibly related. The total number of patients with related and possibly related TEAEs exceeds the total number of patients with drug-related TEAEs because some patients experienced both related and possibly related TEAEs. †TEAEs with unknown CTCAE severity are counted as grade 3. CKD: Chronic kidney disease; CTCAE: Common terminology criteria for adverse events; TEAEs: Treatment-emergent adverse events.
Thirty-eight of the 2021 patients in the SAF (1.9%) had TEAEs leading to death; none were considered roxadustat-related, as evaluated by the investigators and the sponsor according to the description outlined in the Supplementary Methods, http://links.lww.com/CM9/C491.
TEAEs
The most common TEAEs were hyperkalemia (311 [15.4%]), upper respiratory tract infection (202 [10.0%]), and hyperphosphatemia (140 [6.9%]) [Table 4]. The top three TEAEs with an incidence ≥1% and CTCAE grade ≥3 were hyperkalemia (77 [3.8%]), CKD progression/aggravation (63 [3.1%]), and hypertension (62 [3.1%]) [Supplementary Table 4, http://links.lww.com/CM9/C491].
Table 4.
TEAEs with an incidence of ≥5% in any subgroup for patients with CKD-associated anemia of ≥5% in any population (safety analysis set).
| Terms | PD (n = 676) | HD (n = 851) | NDD (n = 494) | Overall (n = 2021) |
|---|---|---|---|---|
| Any TEAE | 556 (82.2) | 682 (80.1) | 405 (82.0) | 1643 (81.3) |
| Hyperkalemia | 70 (10.4) | 133 (15.6) | 108 (21.9) | 311 (15.4) |
| Upper respiratory tract infection | 67 (9.9) | 83 (9.8) | 52 (10.5) | 202 (10.0) |
| Hyperphosphatemia | 45 (6.7) | 38 (4.5) | 57 (11.5) | 140 (6.9) |
| Hypokalemia | 100 (14.8) | 7 (0.8) | 15 (3.0) | 122 (6.0) |
| Hypocalcemia | 44 (6.5) | 41 (4.8) | 31 (6.3) | 116 (5.7) |
| Hypertension | 41 (6.1) | 45 (5.3) | 20 (4.0) | 106 (5.2) |
| Edema peripheral | 57 (8.4) | 13 (1.5) | 35 (7.1) | 105 (5.2) |
| Hyperlipidemia | 43 (6.4) | 38 (4.5) | 20 (4.0) | 101 (5.0) |
| Chronic kidney disease* | 8 (1.2) | 2 (0.2) | 85 (17.2) | 95 (4.7) |
| Diarrhea | 31 (4.6) | 43 (5.1) | 17 (3.4) | 91 (4.5) |
| Nausea | 34 (5.0) | 30 (3.5) | 25 (5.1) | 89 (4.4) |
| Cough | 39 (5.8) | 30 (3.5) | 19 (3.8) | 88 (4.4) |
| Insomnia | 39 (5.8) | 31 (3.6) | 16 (3.2) | 86 (4.3) |
| Vomiting | 37 (5.5) | 15 (1.8) | 25 (5.1) | 77 (3.8) |
| Peritonitis | 69 (10.2) | 3 (0.4) | 3 (0.6) | 75 (3.7) |
| Hypoproteinemia | 37 (5.5) | 32 (3.8) | 6 (1.2) | 75 (3.7) |
| End-stage renal disease† | 9 (1.3) | 4 (0.5) | 57 (11.5) | 70 (3.5) |
| Arteriovenous fistula site complication | 1 (0.1) | 52 (6.1) | 13 (2.6) | 66 (3.3) |
| Metabolic acidosis | 14 (2.1) | 20 (2.4) | 31 (6.3) | 65 (3.2) |
*AEs with the Preferred Term of “chronic kidney disease” were mostly reported as CKD aggravation/progression. †AEs with the Preferred Term of “end-stage renal disease” were mostly reported as stage 5 CKD or stage 5 CKD progression/aggravation. AEs: Adverse events; CKD: Chronic kidney disease; HD: Hemodialysis; NDD: Non-dialysis-dependent; PD: Peritoneal dialysis; TEAE: Treatment-emergent adverse event.
TESAEs
The most common TESAEs with an incidence ≥1% in the SAF were CKD progression/aggravation (83 [4.1%]), end-stage renal disease (69 [3.4%]), and peritonitis (65 [3.2%]) [Table 5].
Table 5.
TESAEs with an incidence of ≥1% in any subgroup for patients with CKD-associated anemia of ≥1% in any population (safety analysis set).
| Preferred term | PD (n = 676) | HD (n = 851) | NDD (n = 494) | Overall (n = 2021) |
|---|---|---|---|---|
| Any TESAE | 248 (36.7) | 280 (32.9) | 223 (45.1) | 751 (37.2) |
| Chronic kidney disease* | 8 (1.2) | 2 (0.2) | 73 (14.8) | 83 (4.1) |
| End-stage renal disease† | 9 (1.3) | 4 (0.5) | 56 (11.3) | 69 (3.4) |
| Peritonitis | 62 (9.2) | 1 (0.1) | 2 (0.4) | 65 (3.2) |
| Arteriovenous fistula site complication | 1 (0.1) | 41 (4.8) | 12 (2.4) | 54 (2.7) |
| Pneumonia | 14 (2.1) | 21 (2.5) | 12 (2.4) | 47 (2.3) |
| Arteriovenous fistula thrombosis | 3 (0.4) | 34 (4.0) | 5 (1.0) | 42 (2.1) |
| Cardiac failure | 13 (1.9) | 19 (2.2) | 8 (1.6) | 40 (2.0) |
| Hyperkalemia | 3 (0.4) | 10 (1.2) | 10 (2.0) | 23 (1.1) |
| Peripheral edema | 13 (1.9) | 1 (0.1) | 6 (1.2) | 20 (1.0) |
*AEs with the Preferred Term of “chronic kidney disease” were mostly reported as chronic kidney disease aggravation/progression. †AEs with the Preferred Term of “end-stage renal disease” were mostly reported as stage 5 CKD or stage 5 CKD progression/aggravation. MedDRA Preferred Term “Arteriovenous fistula site complication” refers to arteriovenous fistula stenosis or arteriovenous fistula dysfunction. AEs: Adverse events; CKD: Chronic kidney disease; HD: Hemodialysis; NDD: Non-dialysis-dependent; PD: Peritoneal dialysis; TESAE: Treatment-emergent serious adverse event.
Drug-related TEAEs
The most common TEAEs that were related/possibly related to roxadustat (as assessed by the investigators) that occurred in ≥5 patients were nausea (27 [1.3%]), hypertension (20 [1.0%]), and insomnia (19 [0.9%]) [Table 6]. The incidences of all other drug-related TEAEs were ≤0.5%.
Table 6.
Drug-related (definitely or possibly related) treatment-emergent adverse events that occurred in ≥5 patients with CKD-associated anemia (safety analysis set).
| Preferred term* | Overall population (n = 2021) |
|---|---|
| Patients with any treatment-emergent adverse events | 219 (10.8) |
| Nausea | 27 (1.3) |
| Hypertension | 20 (1.0) |
| Insomnia | 19 (0.9) |
| Arteriovenous fistula thrombosis | 10 (0.5) |
| Hyperkalemia | 9 (0.4) |
| Decreased appetite | 9 (0.4) |
| Vomiting | 9 (0.4) |
| Hypercoagulation | 9 (0.4) |
| Headache | 8 (0.4) |
| Hepatic function abnormal | 7 (0.3) |
| Dizziness | 6 (0.3) |
| Asthenia | 6 (0.3) |
| Palpitations | 6 (0.3) |
| Deep vein thrombosis | 5 (0.2) |
| Blood pressure increase | 5 (0.2) |
| Abdominal distension | 5 (0.2) |
*The Preferred term is a standardized dictionary-derived term used to represent a medical concept (e.g., an adverse event or medical history entry) in a structured, consistent manner. It is the primary level of granularity for analysis and reporting in clinical trials.
AESI
In the SAF, the most common AESI was serious infection (190 [9.4%]), followed by thrombosis (150 [7.4%]), stroke (52 [2.6%]), fatal events (38 [1.9%]), myocardial infarction (33 [1.6%]), malignancy (10 [0.5%]), and seizure (7 [0.3%]). All fatal events were unrelated to roxadustat.
Other safety outcomes
With the exception of renal function parameters and electrolyte abnormalities associated with CKD and changes in anemia/iron parameters due to roxadustat, other baseline laboratory parameters were within normal ranges and did not change in a clinically significant manner. Elevated liver enzymes were transient and rare. Vital signs were stable, and roxadustat had no obvious effect on electrocardiography parameters (data not shown).
Discussion
This is a large-scale phase 4 study to assess the long-term safety and effectiveness of roxadustat, along with changes in QoL, in Chinese patients with CKD-anemia in a real-world clinical setting.
The effectiveness of roxadustat was clearly demonstrated by anemia correction and maintenance of the hemoglobin target. Hemoglobin increased most in the NDD subgroup. For dialysis patients, hemoglobin increased more in the PD subgroup than in the HD subgroup at weeks 24–36 and 36–52, which may be explained by differences in renal function among the three subgroups. However, official comparisons were not performed between these subgroups. Additionally, hemoglobin was maintained at ≥100 g/L in around 85% of patients, independent of subgroup (PD, HD, or NDD). These results are consistent with previous phase 3 randomized controlled trials on roxadustat,[32,33] but this study extends these findings to a larger population with a high prevalence of comorbidities owing to the broader eligibility and longer (52-week) roxadustat use in real-world settings in China. Importantly, hemoglobin increased over the first 12 weeks upon roxadustat initiation, gradually stabilized at 110–115 g/L (within the recommended range of 100–120 g/L,[31]) by week 12, and was maintained through week 52. This is important as current Chinese CKD-anemia diagnosis and treatment guidelines recommend a hemoglobin concentration of >110 g/L and <130 g/L.[23] In China, the current CKD-anemia treat-to-target rate is suboptimal,[6,24,25] and roxadustat may help to overcome this issue, with several potential advantages over ESAs or iron therapy.
Roxadustat has demonstrated comparable cardiovascular safety to placebo or ESAs in global studies, including pooled analyses of randomized controlled trials in patients with NDD- and DD-CKD, and the TEAEs of roxadustat have been demonstrated to be generally comparable to those of ESAs.[34,35] In this 52-week study, roxadustat had an acceptable safety profile in the Chinese population with no important new risks. The AEs observed are typical of the CKD population and are consistent with the known safety characteristics of roxadustat. No new safety signals were detected by measuring vital signs, electrocardiography, and laboratory parameters. Although the TEAE incidence was high (81.3%), all TEAEs with an incidence of ≥5% are typical of patients with CKD,[36,37] and most TEAEs were mild or moderate (grade 1–2). The incidence of drug-related TEAEs was low (10.8%), and the top three most common were nausea, hypertension, and insomnia; however, these could have been related to dialysis, although this was not formally investigated. Importantly, no drug-related TEAEs led to death, supporting that roxadustat has a tolerable safety profile in patients with CKD-anemia. Vascular access thrombosis events were uncommon, which may be because the majority of vascular access cases in the HD subgroup (89.1%) were via autologous arteriovenous fistula, which lowers the risk of vascular access thrombosis events. The in-hospital mortality rate of CKD inpatients is 2.56% in China.[36] In the present study, 38 patients (1.9%) had TEAEs leading to death. Therefore, roxadustat did not appear to increase the mortality risk for these patients as the predominant population was DD, and the annual mortality rate of such patients in China is 8.8%.[38]
In EE1 and EE2, no clinically meaningful changes in SF–36 Vitality or Physical Functioning subscale scores or in the RAPA self-reported strength and flexibility scores were observed at weeks 12 or 24. This result was disappointing but not unexpected. Health-related QoL incorporates assessments of symptoms, functional capacity, and wellbeing, and although some patients may benefit in their overall wellbeing from increased hemoglobin, this improvement is difficult to quantify.[39] Furthermore, the incidence of CKD complications other than anemia increases with deteriorating kidney function, making it difficult to separate the impact of anemia on health-related QoL from the impact of other factors.[40] Moreover, kidney function decline (estimated glomerular filtration rate decline of >3 mL·min–1·1.73 m–2 year) in CKD has been associated with deterioration in health-related QoL.[41] In the present study, the mean estimated glomerular filtration rate change from baseline for NDD patients at week 52 was −3.3 (95% CI −4.0, −2.6) mL·min–1·1.73 m–2. Another consideration is that dialysis negatively impacts all aspects of QoL in patients with CKD. Patients on HD should visit the hospital or a dialysis center 2–3 times/week for dialysis lasting for around 3–4 hours. PD is performed every 4–5 hours for about 30 minutes, which affects patients’ social and professional lives. Dialysis patients suffer from several symptoms, including fatigue, sleep disorders, decreased appetite, malnutrition, sexual dysfunction, and depression,[42] and QoL declines as dialysis vintage lengthens.[43,44] In the present study, around three-quarters of patients were on dialysis, which could explain why there was no QoL improvement. The absence of any QoL improvement might also be explained by the high prevalence of comorbidities in patients with CKD. The baseline characteristics were close to those observed in the real-world clinical setting, and no strict restrictions on baseline comorbidities (except severe liver dysfunction, pregnancy, or roxadustat allergy) were applied. Therefore, the medical history of the patients may have made it difficult to detect any meaningful improvement in QoL through anemia correction. Another consideration is that this study was conducted during the COVID-19 pandemic, and compared with healthy individuals, QoL was worse for patients with CKD during that time.[45] It may also be useful to evaluate whether other kidney disease-specific questionnaires, such as the Kidney Disease QoL-36, or anemia-related fatigue-specific questionnaires, such as Functional Assessment of Chronic Illness Therapy-Fatigue, detect improvements in QoL after anemia correction with roxadustat.
This study has some limitations that should be considered. First, this was a single-arm study. Therefore, the incidences of TEAEs/TESAEs were only summarized; they were not compared with those observed with current standard-of-care treatments. Despite no comparator, anemia correction and maintenance of hemoglobin at a concentration of ≥100 g/L is sufficient to assess the effectiveness of roxadustat. Second, we only evaluated whether AEs were related, possibly related, or unrelated to roxadustat. We did not evaluate the association between AEs and other drug treatments; therefore, we cannot exclude the possibility that some AEs were caused by treatment with other drugs. Third, the inclusion criteria were quite broad; therefore, the patients had various underlying diseases and medical histories that could contribute to poor QoL, thus preventing any improvement in QoL resulting from hemoglobin correction from being detected. Fourth, we did not perform multivariate analysis. However, we did incorporate several covariates, including baseline hemoglobin, dialysis status, baseline DM, and iron repletion status, in imputation models for the effectiveness endpoints. Moreover, we did not perform a sensitivity analysis to explore the influence of potential confounding factors, though we have reported the results of a relevant sensitivity analysis previously.[46,47] Finally, the target population was Chinese individuals, so the results may not be generalizable to other populations.
In conclusion, Roxadustat effectively increased hemoglobin to ≥100 g/L in Chinese people with CKD-anemia over weeks 24–52 with a tolerable safety profile. This phase 4 study supports that roxadustat has good safety and effectiveness for anemia treatment in Chinese patients with CKD with or without dialysis in real-world settings. These findings validate roxadustat as a reliable therapeutic option and highlight its potential to address the unmet needs of traditional anemia treatments in diverse CKD populations.
Acknowledgments
The authors would like to thank Emily Woodhouse, PhD, of Edanz (www.edanz.com) for providing medical writing services.
Conflicts of interest
This study was sponsored by FibroGen China. Changyun Qian, Yiqing Wu, and Shuting Pan are employees of FibroGen China.
Supplementary Material
Footnotes
How to cite this article: Du XY, Wang YM, Yu HF, Yang JR, He WM, Wang ZS, Zheng DW, Li XW, Shen SJ, Sun D, Yu WM, Li DT, Qian CY, Wu YQ, Pan ST, Chen JH. Long-term safety and effectiveness of roxadustat in Chinese patients with chronic kidney disease-associated anemia: The ROXSTAR registry. Chin Med J 2025;138:1465–1476. doi: 10.1097/CM9.0000000000003672
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