Table 2.
Efficacy endpoints.
| Endpoint/Parameter | Roxadustat | ESA |
|---|---|---|
| CFB in Hb (g/dL) to Weeks 28–36, without rescue therapy | ||
| N | 169 | 165 |
| Baseline a, mean (SD) | 9.75 (1.22) | 9.65 (1.24) |
| CFB, mean (SD) | 1.37 (1.44) | 0.98 (1.59) |
| LS mean (95% CI) | 1.38 (1.21, 1.56) | 0.97 (0.78, 1.16) |
| LSMD b (95% CI) | 0.41 (0.16, 0.67) | |
| Non-inferiority margin (−0.75) for lower limit of LSMD 95% CI | −0.75 < 0.16, non-inferiority is met | |
| CFB in Hb (g/dL) to Weeks 28–52, regardless of rescue therapy | ||
| N | 215 | 207 |
| Baseline a, mean (SD) | 9.76 (1.22) | 9.65 (1.23) |
| CFB, mean (SD) | 1.27 (1.38) | 1.02 (1.49) |
| LS mean (95% CI) | 1.31 (1.15, 1.47) | 1.00 (0.82, 1.17) |
| LSMD c (95% CI) | 0.32 (0.08, 0.55) | |
| Non-inferiority margin (−0.75) for lower limit of LSMD 95% CI | −0.75 < 0.08, non-inferiority is met | |
| CFB in Hb (g/dL) to Weeks 18–24, regardless of rescue therapy, for patients with baseline hsCRP >ULN | ||
| N | 78 | 66 |
| Baseline a, mean (SD) | 9.84 (1.15) | 9.56 (1.32) |
| CFB, mean (SD) | 1.34 (1.31) | 1.21 (1.50) |
| LS mean (95% CI) | 1.42 (1.14, 1.70) | 1.08 (0.74, 1.42) |
| LSMD c (95% CI) | 0.34 (−0.08, 0.77) | |
| Non-inferiority margin (−0.75) for lower limit of LSMD 95% CI | −0.75 < −0.08, non-inferiority is met | |
| CFB in LDL-C (mg/dL) to Weeks 12–28 | ||
| N | 199 | 194 |
| Baseline d, mean (SD) | 115.03 (47.36) | 108.52 (47.98) |
| CFB, mean (SD) | −11.76 (33.23) | −3.92 (32.07) |
| LS mean (95% CI) | −7.82 (−13.23, −2.40) | 1.66 (−4.48, 7.80) |
| LSMD e (95% CI) | −9.47 (−17.41, −1.54) | |
| p value | 0.019 | |
| Proportion of patients receiving intravenous iron supplementation during treatment | ||
| N | 212 | 203 |
| Patients with events, n (%) | 88 (41.5) | 166 (81.8) |
| 95% CI f | 9.3, 13.9 | 19.4, 25.6 |
| Treatment effect, response rate difference (95% CI) f | −11.0 (−14.72, −7.22) | |
| p value g | <0.0001 | |
| Time to first RBC/blood transfusion during treatment | ||
| N | 212 | 203 |
| Patients with events h, n (%) | 17 (8.0) | 28 (13.8) |
| Total PEY i | 336.1 | 323.7 |
| IR/100 PEY | 5.1 | 8.7 |
| Treatment effect, HR (95% CI) j | 0.49 (0.25, 0.93) | |
| p value j | 0.030 | |
| Time to first ESA use during treatment | ||
| N | 212 | 203 |
| Patients with events h, n (%) | 5 (2.4) | 1 (0.5) |
| Total PEY i | 336.1 | 323.7 |
| IR/100 PEY | 1.5 | 0.3 |
| Treatment effect, HR (95% CI) j | 6.96 (0.80, 60.58) | |
| p value j | 0.079 | |
| Time to first rescue therapy (RBC/blood transfusion or ESA use) during treatment | ||
| N | 212 | 203 |
| Patients with events h | 22 (10.4) | 28 (13.8) |
| Total PEY i | 336.1 | 323.7 |
| IR/100 PEY | 6.5 | 8.7 |
| Treatment effect, HR (95% CI) j | 0.70 (0.39, 1.27) | |
| p value j | 0.244 | |
| Time to first RBC/blood transfusion during treatment for patients with hsCRP > ULN | ||
| N | 78 | 66 |
| Patients with events h | 7 (9.0) | 6 (9.1) |
| Total PEY i | 122.6 | 100.9 |
| IR/100 PEY | 5.7 | 5.9 |
| Treatment effect, HR (95% CI) j | 0.74 (0.19, 2.89) | |
| p value j | 0.667 | |
| Time to first ESA use during treatment for patients with hsCRP > ULN | ||
| N | 78 | 66 |
| Patients with events h | 4 (5.1) | 0 (0.0) |
| Total PEY i | 122.6 | 100.9 |
| IR/100 PEY | 3.3 | 0.0 |
| Treatment effect, HR (95% CI) j | NA (NA, NA) k | |
| p value | NA k | |
| Time to first rescue therapy (RBC/blood transfusion or ESA use) during treatment for patients with hsCRP > ULN | ||
| N | 78 | 66 |
| Patients with events h | 11 (14.1) | 6 (9.1) |
| Total PEY i | 122.6 | 100.9 |
| IR/100 PEY | 9.0 | 5.9 |
| Treatment effect, HR (95% CI) j | 1.43 (0.45, 4.51) | |
| p value j | 0.546 | |
PEY for each patient = ([last dose date − first dose date] + 1)/365.25. ANCOVA, analysis of covariance; CFB, change from baseline; CI, confidence interval; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HR, hazard ratio; hsCRP, high-sensitivity C-reactive protein; IR, incidence rate; IR/100 PEY = 100 × number of patients with events/PEY; OT-28, on-treatment period plus 28 days; LDL-C, low-density lipoprotein cholesterol; LS, least squares; LSMD, least squares mean difference; NA, not applicable; PEY, patient exposure years; RBC, red blood cell; SD, standard deviation; ULN, upper limit of normal. a Baseline Hb is defined as the mean of up to four last central lab values prior to the first dose of study treatment. b Treatment comparison was made using a mixed model of repeated measures with baseline Hb as a covariate, and study, treatment, visit, visit-by-treatment interaction, study-by-treatment interaction, and history of cardiovascular/cerebrovascular/thromboembolic disease (yes vs. no) as fixed effects. c Treatment comparison was made using the multiple imputation strategy by combining the results of an ANCOVA model with baseline Hb as covariate and study, treatment, study-by-treatment interaction, and history of cardiovascular/cerebrovascular/thromboembolic disease (yes vs. no) as fixed effects. d Baseline is defined as the last available value prior to the first dose of study treatment. e Treatment comparison was made using an ANCOVA model with baseline Hb, baseline LDL-C as covariates and study, treatment, study-by-treatment interaction, and history of cardiovascular/cerebrovascular/thromboembolic disease (yes vs. no) as fixed effects. f 95% CI for responder rate for roxadustat and ESA was based on the exact method of Clopper-Pearson. g p value was determined using chi-square testing. h Subjects with no event were censored at the date of minimum (last dose date, last visit date, death date). i Total PEY was calculated as ([last dose date − first dose date] + 1)/365.25. j From a stratified Cox proportional hazards model adjusting for treatment stratified by study, baseline hemoglobin (<10 g/dL vs. ≥10 g/dL), and history of cardiovascular/cerebrovascular/thromboembolic disease (yes vs. no). k Not applicable because proportional hazards assumption was violated.