Article Figures & Data
Figures
- Figure 1.
Patient disposition. Screened refers to the inclusion and exclusion criteria listed under "Selection of Study Population" in the Supplemental Material. FU, follow-up period. *The adverse events were dizziness in the no-iron cohorts and worsening gastritis in the IV iron cohort. ^Recovery of renal function. Most study patients (54 of 60 [90.0%]) were enrolled in Russia. The most common causes of renal failure (all patients combined) were unspecified GN (41.7%), pyelonephritis (21.7%), hypertensive nephropathy (18.3%), and diabetic nephropathy (15.0%).
- Figure 2.
Mean hemoglobin levels over time are similar through 7 weeks for all treatment groups and thereafter lower for the no-iron vs oral or IV iron groups. Data are for the EE population using last-observation-carried-forward imputation for missing data and are expressed as the mean±SEM Hb value at each time point. Week 0 (baseline) is the mean of three predosing Hb values. *P<0.05 in comparisons between no-iron cohort to the pooled iron cohorts based on the repeated-measures analysis of covariance model with baseline Hb and iron repletion status as covariates, using all observed data collected during treatment.
- Figure 3.
Cumulative Hb responses are similar among the cohorts. Data are for the EE population. Hb response was defined as the first Hb increase from baseline of ≥1.0 g/dl. Median time to first response was 3.0 weeks in all cohorts.
- Figure 4.
ΔHbmax during last 10 weeks of treatment (g/dl) is independent of baseline CRP level. Data are for the EE population. Baseline CRP was defined as the last value before the first dose administration. LR, linear regression on log(CRP) with adjustment of treatment cohort, baseline Hb, and baseline iron repletion. ΔHbmax versus log(baseline CRP): regression slope on log(CRP) = −0.31 (P=0.30). All patients with CRP greater than the upper limit of normal (ULN=5 g/ml) responded to treatment.
- Figure 5.
Weekly roxadustat dose during the last 2 weeks of the treatment period is independent of baseline CRP level. Data are for the EE population. Baseline CRP was defined as the last value before the first dose administration. LR, linear regression on log(CRP) with adjustment of treatment cohort, baseline Hb, and baseline iron repletion. Maintenance dose was defined as total dose during last 2 weeks of treatment. Maintenance dose versus log (baseline CRP): regression slope on log(baseline CRP) = −0.43 (P=0.38). ULN, upper limit of normal (5 ng/ml).
Tables
Characteristic HD, No Iron (n=24) HD, Oral Iron (n=12) HD, IV Iron (n=12) PD, Oral Iron (n=12) Total (n=60) Age (yr) 49.6±17.7 46.8±14.6 53.1±12.6 51.4±12.4 50.1±15.0 Men, n (%) 15 (62.5) 9 (75.0) 5 (41.7) 2 (16.7) 31 (51.7) Race, n (%) White 23 (95.8) 11 (91.7) 11 (91.7) 10 (83.3) 55 (91.7) Other 1 (4.2) 1 (8.3) 1 (8.3) 2 (16.7) 5 (8.3) Weight (kg) 73.2±15.6 77.4±13.6 79.9±22.8 59.9±12.1 72.7±17.4 BMI (kg/m2) 25.7±6.1 26.5±5.3 28.6±6.5 22.9±4.7 25.9±5.9 eGFR at initiation of dialysis (ml/min per 1.73 m2) 10.9±4.7 12.6±6.1 7.6±3.3 7.9±3.8 10.0±4.9 Time since first dialysis (mo) 2.2±0.9 2.1±1.1 2.1±0.9 2.2±1.0 2.2±0.9 Hb (g/dl) 8.0±1.2 8.5±0.9 8.3±0.9 8.8±0.7 8.3±1.0 CRP (mg/L) 3.9 (0.3–53.5) 1.6 (0.5–23.7) 3.1 (0.3–12.7) 3.3 (0.3–28.2) 3.6 (0.3–53.5) Values are expressed as mean±SD, number (percentage), or median (range). The weight was the postdialysis weight for HD patients and the edema-free weight for PD patients. BMI, body mass index.
Roxadustat Dose Levels Low Weight (40–60 kg) Medium Weight (>60–90 kg) Heavy Weight (>90–140 kg) 1 (initial dose) 60 mg 100 mg 140 mg 1.0–1.5 mg/kg 1.1–1.7 mg/kg 1.0–1.6 mg/kg 2 100 mg 140 mg 200 mg 1.7–2.5 mg/kg 1.6–2.3 mg/kg 1.4–2.2 mg/kg 3 140 mg 200 mg 300 mg 2.3–2.5a mg/kg 2.2–2.5a mg/kg 2.1–2.5a mg/kg Dose adjustments for Hb response: if Hb was <11.0 g/dl and the rate of rise of Hb was <1.0 g/dl in the previous 4 weeks, the roxadustat dose was escalated up one dose level. The maximum allowed dose was 2.5 mg/kg. If Hb was >13.0 g/dl or rate of rise of Hb was ≥2.0 g/dl in the previous 4 weeks (excessive response), the roxadustat dose was reduced by one dose level, or by approximately 30% if the patient was at dose level 1.
↵a Roxadustat dose subject to a maximum of 2.5 mg/kg thrice weekly.
Variable HD, No Iron (n=22) HD and PD, Oral Iron (n=21) HD, IV Iron (n=9) Baseline OV (ng/ml) 84.1±13.7 107.4±27.1 85.6±24.4 4 wk OV (ng/ml) 16.4±3.2 51.1±14.3 50.9±15.6 Δ (ng/ml) −67.7±12.0 −56.3±19.2 −34.7±12.6 P value* <0.0001 0.0082 0.0252 12 wk (end of treatment) OV (ng/ml) 20.7±6.9 59.2±14.2 73.0±25.9 Δ (ng/ml) −63.4±13.3 −48.2±18.2 −12.6±31.6 P value* <0.0001 0.0156 NS End of study OV (ng/ml) 46.0±6.6 136.9±27.7 183.4±45.2 Δ (ng/ml) −38.2±13.7 29.6±21.7 97.8±26.5 P value* 0.0112 NS 0.0061 Observed values (OV) and changes from baseline (Δ) of plasma hepcidin levels (in ng/ml) are presented as mean±SEM for the EE population. Missing values were imputed using the last-observation-carried-forward method. P values are from paired t test comparing absolute change from baseline. NS, not significant.
Variable HD, No Iron HD, Oral Iron (n=12) HD, IV Iron (n=10) PD, Oral Iron (n=10) Total (n=55) Serum iron Patients (n) 23 12 10 10 55 Baseline (μM) 9.7±0.6 12.8±1.8 10.3±1.0 9.5±0.8 10.4±0.5 ΔEOT(μM) −2.1±0.9 1.2±2.5 1.4±1.6 0.4±1.6 −0.3±0.8 P value for EOT 0.031 NS NS NS NS Ferritin Patients (n) 23 12 10 10 55 Baseline (ng/ml) 156±13 163±31 182±27 137±27 159±11 ΔEOT(ng/ml) −120±12 −51±25 −25±34 −65±29 −78±12 P value for EOT <0.001 NS NS 0.054 <0.001 Transferrin Patients (n) 23 12 10 10 55 Baseline (μM) 26.9±0.9 26.6±0.9 26.7±1.3 26.6±2.4 26.7±0.6 ΔEOT(μM) 9.5±1.2 5.7±1.7 5.5±1.4 5.6±2.9 7.1±0.8 P value for EOT <0.001 0.008 0.004 NS 0.085 TIBC Patients (n) 23 12 10 10 55 Baseline (μM) 44.7±1.6 45.2±1.7 44.4±2.1 45.8±4.2 54.0±1.1 ΔEOT(μM) 17.4±2.0 10.1±3.3 9.7±2.4 9.1±4.8 12.9±1.5 P value for EOT <0.001 0.011 0.003 NS <0.001 sTfR Patients (n) 23 10 10 10 53 Baseline (ng/ml) 3.1±0.3 3.4±0.4 3.7±0.7 3.2±0.4 3.3±0.2 ΔEOT(ng/ml) 4.3±0.9 1.8±1.0 2.5±0.6 2.6±0.8 3.2±0.5 P value for EOT <0.001 NS 0.004 0.011 <0.001 TSAT Patients (n) 23 10 10 10 53 Baseline (%) 18.8±0.8 19.0±1.0 18.1±1.5 19.3±1.8 18.8±0.6 ΔEOT(%) −7.4±1.4 2.6±2.5 0.7±2.9 −1.6±2.6 −2.7±1.2 P value for EOT <0.001 NS NS NS 0.026 Iron-depletea Patients (n) 23 10 10 10 53 Baseline (%) 16±69.6 8±66.7 8±80.0 7±70.0 39±70.9 EOT (%) 23±100 10±83.3 6±60.0 9±90.0 48±87.3 P value for EOT 0.016 NS NS NS NS CHr Patients (n) 21 10 10 10 51 Baseline (pg) 31.0±0.3 31.6±0.5 31.5±0.5 30.5±0.4 31.1±0.2 Δ4wk(pg) −1.3±0.4 −0.5±0.5 −0.4±0.5 −0.7±0.6 −0.8±0.2 P value for 4 wk 0.005 NS NS NS 0.002 ΔEOT(pg) −2.2±0.7 −1.9±0.9 −1.0±0.6 −0.2±0.6 −1.5±0.4 P value for EOT 0.003 NS NS NS <0.001 Unless otherwise noted, data are expressed as mean±SEM for the EE population using the last-observation-carried-forward imputation method. Baseline for iron variables was defined as the mean available values obtained before the first dose. P values are from paired t test: comparison to baseline values, except for iron-deplete, for which P value is from McNemar test. ΔEOT, change from baseline at end of therapy; NS, not significant; EOT, values at end of treatment; TIBC, total iron-binding capacity; sTfR, soluble transferrin receptor; CHr, reticulocyte Hb content; Δ4wk, change from baseline after 4 weeks.
↵a Iron-deplete: TSAT <20% or ferritin <100 ng/ml.
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