Lower vs. standard starting dose oral roxadustat for treating anemia in Chinese patients with chronic kidney disease on dialysis: A prospective, randomized clinical trial

To the Editor: Anemia is a critical complication of chronic kidney disease (CKD), causing high mortality and morbidity.[1] The standard treatment involves erythropoiesis-stimulating agents (ESAs) and iron supplementation. However, concurrent inflammation is always associated with a poor response to ESA therapy, requiring a higher ESA dosage to maintain hemoglobin (Hb) level.[1] Roxadustat, the first oral hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), presents an effective alternative. It physiologically promotes endogenous erythropoietin production, improves iron metabolism, and demonstrates reduced susceptibility to inflammation.[1–3] HIF-PHIs are recommended by various guidelines and consensuses for treating renal anemia; with some suggesting HIF-PHI initiation at lower doses. This prospective, randomized, open-label, multicenter phase 4 study (No. NCT04059913) evaluated the efficacy and safety of a one-step lower dose, compared to the approved standard starting roxadustat dose, in Chinese dialysis patients with anemia, suggesting a potential for optimized dosing regimen. The study consisted of two treatment parts: Part 1 assessed lower vs. standard dose (weeks 1–20); Part 2 evaluated different dosing frequencies (weeks 21–36). Only the results of Part 1 are presented here. The study design was approved by national and institutional regulatory authorities and ethics committees at each study site. All patients provided written informed consent. The study was approved by Ethics Committee of Zhongda Hospital, Southeast University (No. 2019ZDSYLL017-P01). Eligible patients were adults aged 18–75 years with end-stage renal disease (ESRD) receiving dialysis. They were categorized into two groups: ESA-naive (hereafter “naive”) group (patients without ESA within four weeks prior to day 1 and with Hb values ≥70–100 g/L); and ESA-treated (hereafter “converted”) group (patients with stable ESA for at least six weeks prior to day 1 and with 90 g/L <Hb values ≤120 g/L). Key exclusion criteria included recent cardiovascular events, blood transfusion, ferritin <50 μg/mL, transferrin saturation (TSAT) <10%, etc. Full inclusion/exclusion criteria are provided in the Supplementary Material, https://links.lww.com/CM9/C587. Patients were enrolled (naive:converted = 1:2) and randomized to lower or standard roxadustat starting dose arms in a 1:1 ratio. Block randomization was performed centrally in sequence using an interactive web response system and stratified by dialysis method, baseline Hb in naive patients, and baseline ESA dose in converted patients. The lower roxadustat dose was 70 mg (45 kg <dry weight <60 kg) or 100 mg three times a week (TIW) (dry weight ≥60 kg); the standard dose was 100 mg (45 kg <dry weight <60 kg) or 120 mg TIW (dry weight ≥60 kg). Dose adjustment was made every four weeks starting from day 1 to maintain Hb in the target level [Supplementary Table 1, https://links.lww.com/CM9/C587]. Oral iron rather than intravenous iron supplementation was allowed. Efficacy analyses were based on the full analysis set (FAS), which included all randomized patients receiving roxadustat and having post-baseline Hb value. The primary efficacy endpoint was the proportion of naive patients achieving Hb ≥110 g/L (at least once) during the first 20 weeks and converted patients achieving mean Hb ≥100 g/L averaged over weeks 17–21 visits. Secondary efficacy endpoints included mean change from baseline (CFB) in Hb level averaged over weeks 17–21 visits and the proportion of naive patients with mean Hb (averaged weeks 17–21 visits) ≥100 g/L. We exploratorily examined Hb CFB over time, and the proportion of converted patients with Hb increased by ≥10 g/L. Hb outcomes by C-reactive protein (CRP) subgroups and changes in iron parameters were analyzed ad hoc. Safety analyses were based on the safety analysis set (SAF) which included all subjects receiving roxadustat, including all treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), laboratory measures, vital signs, and electrocardiograms. The study sample size was determined for the statistical tests in Part 2, with detailed calculations provided in Supplementary Material, https://links.lww.com/CM9/C587. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc. Cary, NC. USA). No formal pre-defined hypotheses were formulated for Part 1; all comparisons with inferential statistics in Part 1 were ad hoc on parameters of interest. The last-observation-carried-forward (LOCF) approach was used to determine CFB in Hb. Descriptive statistics are presented for all the efficacy endpoints and adverse events (AEs). Continuous variables are presented using mean ± standard deviation (SD) or median (interquartile range [IQR]). Categorical variables are presented by frequency counts and percentages unless otherwise specified. A total of 318 patients were enrolled (naive group, 57 vs. 56; converted group, 103 vs. 102), with over 90% completing 20 weeks of treatment [Supplementary Figure 1, https://links.lww.com/CM9/C587]. Baseline age, gender, BMI, CKD duration, and dialysis modality were comparable between the lower dose and the standard dose arms. Baseline Hb levels were also comparable (87.7 g/L vs. 86.2 g/L in naive patients and 104.8 g/L vs. 105.3 g/L in converted patients) [Supplementary Table 2, https://links.lww.com/CM9/C587]. Treatment compliance was good in all treatment arms [Supplementary Table 3, https://links.lww.com/CM9/C587]. The weekly dose of roxadustat decreased from 282.0 mg to 260.8 mg in the pooled lower dose arms, and from 357.4 mg to 311.5 mg in the pooled standard dose arms [Supplementary Table 4 and Supplementary Figure 2, https://links.lww.com/CM9/C587]. The average weekly doses over 20 weeks were about 40–50 mg lower in the lower dose arms than standard dose arms [Supplementary Table 3, https://links.lww.com/CM9/C587]. Roxadustat produced numerically similar treatment effects in dialysis patients in both dose arms. The proportion of naive patients achieving Hb ≥110 g/L during the first 20 weeks was numerically comparable between the lower dose and standard dose arms (77.2% [44/57] vs. 73.2% [41/56], P = 0.81) [Supplementary Table 5, https://links.lww.com/CM9/C587]. The percentage of naive patients with mean Hb ≥100 g/L averaged over weeks 17–21 were also similar between the two dose arms (78.9% [45/57] vs. 67.9% [38/56], P = 0.25) [Supplementary Table 6, https://links.lww.com/CM9/C587]. Similar results were found in the converted group (82.5% [85/103] vs. 79.0% [79/100], P = 0.52). In the naive group, Hb CFB over weeks 17–21 was 20.7 ± 10.4 g/L in the lower dose arm and 21.6 ± 14.9 g/L in the standard dose arm. In the converted group, the corresponding values were 4.9 ± 11.8 g/L and 6.0 ± 12.6 g/L [Supplementary Table 7, https://links.lww.com/CM9/C587]. In both naive and converted patients, Hb CFB to week 5 was slightly lower in the lower dose arm compared to the standard dose arm. However, the difference decreased progressively from week 5 through 9, becoming indistinguishable thereafter [Figure 1 and Supplementary Tables 8 and 9, https://links.lww.com/CM9/C587]. Most of the converted patients in both dose arms could maintain a Hb CFB of >−10 g/L [Supplementary Table 10, https://links.lww.com/CM9/C587].Figure 1: Mean Hb CFB at select visits (FAS) in naïve patients (A) and in converted patients (B). CFB: Change from baseline; ESA: Erythropoiesis-stimulating agent; FAS: Full analysis set; Hb: Hemoglobin; LOCF: Last-observation-carried-forward. The line plot shows the mean ± standard error of Hb.Hb analysis by baseline CRP groups showed that the lower dose arm achieved a similar Hb increase and Hb response [Supplementary Tables 11 and 12, https://links.lww.com/CM9/C587] overall. After treatment, serum ferritin decreased, while total iron-binding capacity (TIBC) and transferrin increased. TSAT level changed to approximately 30% in both dose arms [Supplementary Table 13, https://links.lww.com/CM9/C587]. The AEs observed were typical for the CKD dialysis population and consistent with the known safety profile of roxadustat, with no unexpected safety signal observed. The proportion of patients experiencing ≥1 TEAE with lower compared to standard dose (82.5% [47/57] vs. 92.9% [52/56] in the naive group, 73.8% [76/103 ]vs. 80.4% [82/102] in the converted group) [Supplementary Table 14, https://links.lww.com/CM9/C587]. Overall, the proportion of patients experiencing ≥1 SAE was similar between dose groups: in the naive group, lower dose arm vs. standard dose was 21.1% [12/57] vs. 19.6% [11/56]; in the converted group, 16.5% [17/103] vs. 18.6% [19/102]. SAEs reported in >3 subjects were arteriovenous fistula thrombosis (1.9%, 6/318), arteriovenous fistula site complication (1.6%, 5/318), hypertension (1.6%, 5/318), arteriovenous fistula occlusion (1.3%, 4/318), and end-stage renal disease (1.3%, 4/318) [Supplementary Table 15, https://links.lww.com/CM9/C587]. One patient died prior to week 21 from respiratory failure considered by the investigator to be unlikely related to study drug or study procedure. Most of the commonly reported (≥10%) AEs occurred less frequently in the lower dose group of both naive and converted patients [Supplementary Table 16, https://links.lww.com/CM9/C587]. This study evaluated the efficacy and safety of different roxadustat starting doses for the treatment of anemia in Chinese dialysis patients. Efficacy analyses demonstrated comparable efficacy between the two roxadustat dose regimens. As anticipated, the rate of rise (ROR) of Hb in naive and treated patients during weeks 1–9 was more gradual using the lower dose regimen; thereafter, achieved Hb levels were similar to those with standard dose. The lower starting dose could effectively correct anemia at the recommended rate of 10–20 g/L Hb increase per month for ESA naive patients according to Chinese and international guidelines, while maintaining stable Hb levels for patients converted from ESA. The average weekly dose over 20 weeks was about 40–50 mg lower in the lower dose arm compared to the standard dose arm, indicating potential cost savings for healthcare systems. The smoother and slower Hb increase observed with the lower starting dose may be desirable for many patients. Inflammation plays a role in anemia and can lead to ESA hyporesponse. Despite inflammation affecting about 25% of patients in this study, both the lower and standard doses of roxadustat effectively raised Hb, reduced hepcidin, and improved iron parameters, achieving a steady-state TSAT of about 30%. Notably, both dose groups, irrespective of CRP, showed a gradual decrease in roxadustat dose between weeks 0–4 and weeks 17–20. The AEs observed were typical for the CKD dialysis population and generally consistent with the known safety profile of roxadustat. Both naive patients and converted patients had similar safety profiles for roxadustat across the two dose arms. Some limitations of this study include the absence of a formal predefined non-inferiority hypothesis test, a relatively small sample size, short treatment duration, and cautious interpretation of ad hoc biomarker analyses. In conclusion, a one-step lower starting roxadustat dose demonstrated a similar efficacy and safety profile for the treatment of anemia as the approved standard starting dose in Chinese CKD patients undergoing dialysis while potentially reducing drug exposure. Acknowledgment Mengmeng Qiao [FibroGen (China) Medical Technology Development Co., Ltd.] provided technical assistance. The authors thank the participating patients and their families, clinicians, and the investigators from the other 21 sites. Funding This study was sponsored by FibroGen (China) Medical Technology Development Co., Ltd. Conflicts of interest None.