Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Roxadustat · 22 trials · 19 indications
Hb response is defined as reaching target values for Hb.
Hb response defined as average Hb within the target range in this outcome
Hb response is defined as reaching target values for Hb and change of Hb from baseline
Baseline Hb was defined as the mean of four central laboratory Hb values; four latest Hb values prior or on the same date as the first study drug intake. For participants who did not have an available Hb value during the week 28-36 period, imputation rules were applied. For analyses without rescue therapy, participants who used rescue therapy after the initiation of rescue therapy were set to missing for 6 weeks from the start date of rescue therapy. If no Hb value was available, an imputation technique was used, with the mean of all available values from Day 1 to minimum (End of Efficacy Emergent Period) carried forward.
Baseline Hb was defined as the mean of four central laboratory Hb values: four latest Hb values prior or on the same date as first study drug intake. Change from baseline to the average Hb are observed values. Missing hemoglobin data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model with treatment, baseline hemoglobin, randomization stratification factors and the available non missing hemoglobin for each scheduled week.
Hb response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb change from baseline by ≥ 1.0 g/dL, for participants with baseline Hb \> 8.0 g/dL; or Hb change from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at two consecutive visits with available data separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell \[RBC\] transfusion for all participants or darbepoetin for roxadustat treated participant).
Hemoglobin (Hb) response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for participants with baseline Hb \> 8.0 g/dL; or Hb increase from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at two consecutive visits with available data separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell (RBC) transfusion, erythropoiesis-stimulating agent (ESA), or intravenous (IV) iron prior to Hb response. This was the primary efficacy endpoint for EU (EMA).
The change from baseline to the average Hb values across weeks 28 to 52 without having received rescue therapy. The Hb values from visit windows at weeks 28, 32, 36, 40, 44, 48 and 52 were used for the calculation of the average of weeks 28 to 52. This was the primary efficacy endpoint for US (FDA).
Percentage of participants with mean Hb value ≥10 g/dL, averaged from Week 16 through Week 24 has been reported. Baseline Hb was defined as the mean of available central laboratory Hb values prior to first dose of study medication including the predose Hb value collected on Day 1. 95% confidence interval (CI) was calculated based on the normal approximation to the binomial distribution.
Baseline Hb was defined as the mean of available central laboratory Hb values prior to first dose of study medication including the predose Hb value collected on Day 1. Missing data was imputed using Monte Carlo Markov Chain (MCMC) imputation model.
Hb values under the influence of rescue therapy were not censored in the analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (ESA) or red blood cell (RBC) transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model, Monotone missing data were imputed by regression from its own treatment group.
Hb values under the influence of rescue therapy were censored up to 6 weeks in the analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment.
Hb values under the influence of rescue therapy were not censored for the primary analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (erythropoiesis-stimulating agent \[ESA\]) or red blood cell (RBC) transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model, Monotone missing data were imputed by regression from its own treatment group.
Hb response was defined, using central laboratory values, as: Hb ≥11.0 g/dL and a Hb increase from baseline by ≥1.0 g/dL in participants whose baseline Hb \>8.0 g/dL, or increase in Hb ≥2.0 g/dL in participants whose baseline Hb ≤8.0 g/dL. Rescue therapy for roxadustat treated participant was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion.
The change in Hb from baseline to the average level during the evaluation period (defined as Week 28 until Week 52) is reported. Hb values under the influence of a rescue therapy were not censored. The intermittent missing hemoglobin data were imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model, Monotone missing data were imputed by regression from its own treatment group. Baseline Hb was defined as the mean of up to 4 last central laboratory values prior to the first dose of study drug.
The number of participants who achieved a Hb response at 2 consecutive visits at least 5 days apart during the first 24 weeks of treatment, without rescue therapy (that is, red blood cell \[RBC\] transfusion, erythropoiesis-stimulating agent \[ESA\], or intravenous \[IV\] iron) are reported. A Hb response is defined, using central laboratory values, as the following: * Hb ≥11 g/dL and Hb increase from baseline by ≥1 g/dL in participants with baseline Hb \>8 g/dL, or * An increase in Hb by ≥2 g/dL in participants with baseline Hb ≤8.0 g/dL
Baseline Hb was defined as the mean of the assessments from central lab prior to first dose of the study treatment, which included up to 2 latest screening values prior to Day 1 and a value on Day 1. All central lab assessments from Day 1 to end of treatment (EOT) or early termination (ET) were included in the evaluation of this endpoint. Hb values within 4 weeks after an RBC transfusion were excluded.
Hb baseline was defined as the mean of the central laboratory Hb value from the baseline visit at Day 1 (prior to receiving the first dose of study drug in this study), plus any other central lab Hb values within 15 days prior to Day 1 regardless of fasting. The specific duration over which the participants were assessed was identified as "over time" for the endpoint in the study protocol. Therefore, to be consistent with the endpoint in the study protocol, an individual timepoint was not identified for this primary outcome measure.
Baseline Hb was defined as the mean of the last 3 central laboratory Hb values prior to the first dose administration. This outcome measure is derived from the maximum change from baseline during Weeks 3-13, without last observation carried forward (LOCF) imputation.
An Hb response was defined as a Hb level of ≥11 g/dL and an increase from BL ≥1 g/dL.
Baseline was defined as the mean of the last 3 Hb values obtained prior to the first dose of study treatment, including Day 1 predose. Last observation carried forward (LOCF) method was used to impute missing values.
Baseline was defined as the mean of the last 3 Hb values obtained prior to the first dose of study treatment, including Day 1 predose. LOCF method was used to impute missing values.
The average of the mean Hb values that were above 11 g/dL at Weeks 17, 18, 19, and 20 are presented. LOCF method was used to impute missing values.
An adverse event (AE) was any untoward medical event in a participant who received study drug whether or not the event is considered drug related. TEAEs defined as an AE beginning after first dose of study drug until 28 days after last dose of study drug or existing AEs that worsened after first dose of study drug until the participant's last study visit. Severe AEs defined as incapacitating, inability to perform usual activities. Drug-related TEAEs defined as TEAEs with possible, probable, or definite relationship to study drug. Serious AE criteria included death, life-threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed here. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Mean Hb change from baseline was analyzed by treatment group and study visit. Baseline was defined as the mean of last 3 available values prior to the first dose.
Mean Hb change from baseline was analyzed by treatment group and study visit. Baseline is defined as the mean of last 3 available values prior to the first dose.
AUCinf is defined as area under the plasma concentration versus time curve from time of dosing (pre-dose) to extrapolated infinite time (0-inf).
AUClast is defined as area under the plasma concentration time-curve from time of dosing to the last measured concentration.
Maximum observed concentration (Cmax) will be reported.
Cmax: Maximum concentration
Cmax,u: Maximum concentration of unbound compound
AUCinf: Area under the concentration-time curve from the time of dosing extrapolated to time infinity
AUCinf,u: Area under the concentration-time curve from the time of dosing extrapolated to time infinity for unbound concentration
AUClast: Area under the concentration-time curve from the time of dosing to the last measurable concentration (Clast)
AUClast,u: Area under the concentration-time curve from the time of dosing to the last measurable concentration (Clast) for unbound concentration
CL/F: Apparent total systemic clearance after single or multiple extravascular dosing
CLu/F: Apparent total systemic clearance of unbound compound after extravascular dosing
fu: Fraction of parent or metabolite available systemically unbound (= free fraction)
tmax: Time of the maximum concentration
t1/2: Terminal elimination half-life
Vz/F: Apparent volume of distribution during the terminal elimination phase after single extravascular dosing
Vz,u/F: Apparent volume of distribution during the terminal elimination phase of unbound compound after extravascular dosing
tlag: Time prior to the time corresponding to the first measurable (non-zero) concentration
MPR: Metabolite to parent ratio of AUC using AUC (corrected) for the metabolite (corrected by molecular weight ratio of parent to metabolite)
tlag: Time prior to the time corresponding to the first measurable (non-zero) concentration
MPR: Metabolite to parent ratio of AUC using AUC(corrected) for the metabolite (corrected by molecular weight ratio of parent to metabolite)
tlag: Time prior to the time corresponding to the first measurable (non-zero) concentration
CLR: Renal clearance
CLR,u: Renal clearance of unbound drug
Aeinf: Cumulative amount of compound excreted into urine from time of dosing extrapolated to time infinity
Aeinf%: Percent of drug dose excreted into urine (Aeinf) from time of dosing extrapolated to time infinity
Aelast: Cumulative amount of drug excreted into urine from time of dosing up to the collection time of the last measurable concentration
Aelast%: Percent of drug dose excreted into urine (Aelast) from time of dosing up to the collection time of the last measurable concentration
CLD: dialysis clearance. For ESRD subjects on CAPD or APD and for ESRD subjects on HD or HDF (treatment period 2 only)
fD: fraction of dose cleared by dialysis. For ESRD subjects on CAPD or APD and for ESRD subjects on HD or HDF (treatment period 2 only)
Effective t½ 48 hours: Effective half-life based on a dosing interval of 48 hours
Effective t½ 56 hours: Effective half-life based on a dosing interval of 56 hours
TER: Total exposure ratio
| Arm | Type | Description |
|---|---|---|
| rHuEPO or DA to ASP1517 | EXPERIMENTAL | Participants will receive roxadustat according to the prior randomization treatment, with starting doses of 70mg thrice weekly (TIW) to participants on \<4500 IU/week of rHuEPO or \<20 microgram (μg)/week of darbepoetin alfa (DA) and 100mg TIW to participants on ≥4500 IU/week rHuEPO or ≥ 20 μg/week DA. Participants roxadustat dosage will be adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps will be as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300 mg. |
| rHuEPO or DA to DA | EXPERIMENTAL | Participants will receive DA according to the prior randomization treatment, with starting doses of 15 μg/2weeks to participants on ≤ 1500 IU/week of rHuEPO or \<11.25 microgram (μg)/week of DA, 30μg/2weeks to participants on \>1500 to \<6000 IU/week of rHuEPO or ≥ 11.25 to \< 22.5 μg/week of DA, 60μg/2weeks to participants on ≥ 6000 IU/week of rHuEPO or ≥ 22.5 to \< 37.5 μg/week of DA, 90μg/2weeks to participants on ≥ 37.5 to \< 52.5 μg/week of DA, 120μg/2weeks to participants on ≥ 52.5 to \< 75 μg/week of DA, 180μg/2weeks to participants on ≥ 75 μg/week of DA. Participant's roxadustat dosage will be adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps will be as follows: 15, 30, 60, 90, 120, and 180 μg. |
| Epoetin beta pegol to ASP1517 | EXPERIMENTAL | Participants will receive roxadustat according to the prior registration treatment, with starting doses of 70mg thrice weekly (TIW) to participants on ≤100 μg/week of Epoetin beta pegol and 100mg TIW to participants on \>100 μg/week of Epoetin beta pegol. Participant's roxadustat dosage will be adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps will be as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300 mg. |
| ASP1517 Low dose group | EXPERIMENTAL | Study drug will be dosed three times weekly for 24 weeks and dose adjustments will be made during the study. |
| ASP1517 High dose group | EXPERIMENTAL | Study drug will be dosed three times weekly for 24 weeks and dose adjustments will be made during the study. |
| ASP1517 Group | EXPERIMENTAL | Subjects will take the study drug at two- or three-day intervals. |
| Darbepoetin alfa Group | EXPERIMENTAL | Subjects will take the study drug once a week. |
| ASP1517 Low Dose Group (ESA Untreated) | EXPERIMENTAL | This group includes subjects who have not received Erythropoieses Stimulating Agents (ESAs). Study drug will be dosed three times weekly and dose adjustments will be made during the study. |
| ASP1517 High Dose Group (ESA Untreated) | EXPERIMENTAL | This group includes subjects who have not received ESAs. Study drug will be dosed three times weekly and dose adjustments will be made during the study. |
| ASP1517 ESAs Treated Group | EXPERIMENTAL | This group includes subjects who have received ESAs. The treatment was converted from ESAs to study drug. Study drug will be dosed three times weekly and dose adjustments will be made during the study. |
| Roxadustat | EXPERIMENTAL | Participants received roxadustat three times a week (TIW) for at least 52 weeks up to a maximum of 104 weeks. Participants received initial dose of roxadustat in doses of 100 mg, 150 mg or 200 mg, according to the average weekly dose of epoetin or darbepoetin alfa prior to randomization. Participants' roxadustat dosage was adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps were as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. Oral iron treatment of 200 mg was allowed for supplementation to support erythropoiesis. Treatment with intravenous iron was allowed only if certain protocol criteria were met. |
| ESA (Erythropoiesis Stimulating Agent) treatment | ACTIVE_COMPARATOR | Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Participants were treated for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant's Hb levels between 10.0 to 12.0 g/dL. Participants were not allowed to switch from the epoetin alfa to darbepoetin alfa or vice versa. |
| Darbepoetin alfa | ACTIVE_COMPARATOR | Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 μg/kg (microgram per kilogram), as a single subcutaneous or intravenous (IV) injection once weekly or 0.75 μg/kg, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks. |
| Placebo | PLACEBO_COMPARATOR | Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received matching placebo for at least 52 weeks up to a maximum of 104 weeks. |
| Epoetin Alfa | ACTIVE_COMPARATOR | Participants on hemodialysis (HD) will receive epoetin alfa, administered intravenously (IV) TIW and participants on home HD or peritoneal dialysis (PD) will receive epoetin alfa, administered subcutaneously (SC). Initial epoetin alfa dose will be based on the participant's average weekly prescribed ESA dose in 4 weeks prior to randomization if on epoetin or darbepoetin, and average monthly (4-week) prescribed ESA dose in 8 weeks prior to randomization if on Mircera®. In case of a change in route of administration from SC to IV (TIW), the initial dose of IV epoetin alfa will be determined by the investigator per local standard of care (SOC). Dose adjustments will follow the recommendations as per the approved country-specific product label (United States Package Insert \[USPI\] or Summary of Product Characteristics \[SmPC\]) or local SOC. |
| Arm A + E (Participants on HD): Roxadustat Only, No Iron | EXPERIMENTAL | Participants on HD will receive roxadustat capsules at the applicable dose (up to a maximum roxadustat dose of 140, 200, and 300 mg) based on weight and Hb level, administered orally 3 times weekly (TIW) for 12 weeks. |
| Arm B (Participants on HD): PO Iron (Ferrous Fumarate or Ferrous Gluconate) Between 50 and 195 mg | EXPERIMENTAL | Participants on HD will receive roxadustat capsules at the applicable dose (up to a maximum roxadustat dose of 140, 200, and 300 mg) based on weight and Hb level, administered orally TIW with iron (ferrous fumarate or ferrous gluconate) PO at doses containing elemental iron between 50 and 195 mg daily (depending on the type of iron formulation available in their countries) for 12 weeks. |
| Arm C (Participants on HD): IV Iron (Ferric Gluconate Complex in Sucrose or Equivalent) 60 mg | EXPERIMENTAL | Participants on HD will receive roxadustat capsules at the applicable dose (up to a maximum roxadustat dose of 140, 200, and 300 mg) based on weight and Hb level, administered orally TIW with approximately 60 mg IV iron (ferric gluconate complex in sucrose injection \[for example, Ferrlecit®\] or equivalent) once a week for 12 weeks. |
| Arm D (Participants on PD): PO Iron (Ferrous Fumarate or Ferrous Gluconate) Between 50 and 195 mg | EXPERIMENTAL | Participants on PD will receive roxadustat capsules at the applicable dose (up to a maximum roxadustat dose of 140, 200, and 300 mg) based on weight and Hb level, administered orally TIW with iron (ferrous fumarate or ferrous gluconate) PO at doses containing elemental iron between 50 and 195 mg daily (depending on the type of iron formulation available in their countries) for 12 weeks. |
| Cohort A: Roxadustat Tiered, Weight Based Dosing TIW | EXPERIMENTAL | Participants will receive roxadustat capsules, administered orally 3 times weekly (TIW) for 16 weeks. Initial roxadustat dose will be based on a tiered, weight-based dosing scheme (low-weight \[45 to 60 kilograms (kg)\], medium-weight \[\>60 to 90 kg\], and heavy-weight \[\>90 to 140 kg\] participants will receive 60, 100, and 140 milligrams \[mg\] roxadustat, respectively). Dose adjustments will be implemented (up to a maximum roxadustat dose of 2.2 mg/kg per dose) every 4 weeks starting Week 5 to maintain Hb levels at 11-13 g/dL. |
| Cohort B: Roxadustat Tiered, Weight Based Dosing TIW then BIW | EXPERIMENTAL | Participants will receive roxadustat capsules orally for 16 weeks. Initial roxadustat dose will be based on a tiered, weight-based dosing scheme (low-weight \[45 to 60 kg\], medium-weight \[\>60 to 90 kg\], and heavy-weight \[\>90 to 140 kg\] participants will receive 60, 100, and 140 mg roxadustat, respectively). Dose adjustments will be implemented (up to a maximum roxadustat dose of 2.2 mg/kg per dose) every 4 weeks starting Week 5 to maintain Hb levels at 11-13 g/dL. Participants will have a dose frequency reduction from TIW to 2 times a week (BIW) at the time of the initial Hb response. |
| Cohort C: Roxadustat at 50 mg TIW | EXPERIMENTAL | Participants will receive roxadustat capsules at 50 mg, administered orally TIW for 24 weeks. Dose adjustments will be implemented (up to a maximum roxadustat dose of 2.2 mg/kg per dose) every 4 weeks starting Week 5 to maintain Hb levels at 10.5-12 g/dL. |
| Cohort D: Roxadustat at 100 mg TIW | EXPERIMENTAL | Participants will receive roxadustat capsules at 100 mg, administered orally TIW for 24 weeks. Dose adjustments will be implemented (up to a maximum roxadustat dose of 2.2 mg/kg per dose) every 4 weeks starting Week 5 to maintain Hb levels at 10.5-12 g/dL. |
| Cohort E: Roxadustat Tiered, Weight Based Dosing BIW then QW | EXPERIMENTAL | Participants will receive roxadustat capsules for 24 weeks. Initial roxadustat dose will be based on a tiered, weight-based dosing scheme (low-weight \[45 to 60 kg\], medium-weight \[\>60 to 90 kg\], and heavy-weight \[\>90 to 140 kg\] participants will receive 70, 100, and 150 mg roxadustat, respectively). Dose adjustments will be implemented (up to a maximum roxadustat dose of 2.5 mg/kg per dose) every 4 weeks starting Week 5 to maintain Hb levels at 11-13 g/dL. Participants will have a dose frequency reduction from BIW to 1 time a week (QW) at the time of the initial Hb response. |
| Cohort F: Roxadustat at 70 mg BIW then QW | EXPERIMENTAL | Participants will receive roxadustat capsules at 70 mg for 24 weeks. Dose adjustments will be implemented (up to a maximum roxadustat dose of 2.5 mg/kg per dose) every 4 weeks starting Week 5 to maintain Hb levels at 11-13 g/dL. Participants will have a dose frequency reduction from TIW to BIW at the time of the initial Hb response. Then after \>8 weeks of stable Hb, dose frequency will be reduced from BIW to QW. |
| Cohort A-1 (Roxadustat 1.0 mg/kg TIW) | EXPERIMENTAL | Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.0 milligrams (mg)/kg, administered orally 3 times weekly (TIW) in the morning of the day after dialysis (interdialytic days) for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 grams \[g\]/deciliter \[dL\]) will be based upon regular monitoring of Hb. |
| Cohort A-2 (Roxadustat 1.5 mg/kg TIW) | EXPERIMENTAL | Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.5 mg/kg, administered orally TIW for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohort A-3 (Roxadustat 2.0 mg/kg TIW) | EXPERIMENTAL | Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 2.0 mg/kg, administered orally TIW for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohort A-4 (Roxadustat 1.8 mg/kg TIW) | EXPERIMENTAL | Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.8 mg/kg, administered orally TIW for 6 weeks. Participants who have not completed 6-week treatment at the time of Amendment 2, will continue treatment for up to 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohort A-5 (Roxadustat 1.8 mg/kg TIW) | EXPERIMENTAL | Normoresponsive participants (with baseline epoetin alfa dosage 85-115 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.8 mg/kg, administered orally TIW for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohort A-6 (Roxadustat 1.3 mg/kg TIW) | EXPERIMENTAL | Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.3 mg/kg, administered orally TIW for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohort A-7 (Weight Tiered Roxadustat 70-100-150 mg) | EXPERIMENTAL | Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive tiered, weight-based initial doses of roxadustat (approximately 1.3 mg/kg/dose TIW). Low weight (40 to 60 kg), medium weight (\>60 to 90 kg), and heavy weight (\>90 to 140 kg) participants will receive roxadustat 70 mg, 100 mg, and 150 mg, respectively, administered as oral capsules for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohort A-8 (Weight Tiered Roxadustat 70-120-200 mg) | EXPERIMENTAL | Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive tiered, weight-based initial doses of roxadustat (approximately 1.5 mg/kg/dose TIW). Low weight (40 to 60 kg), medium weight (\>60 to 90 kg), and heavy weight (\>90 to 140 kg) participants will receive roxadustat 70 mg, 120 mg, and 200 mg, respectively, administered as oral capsules for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohort A-9 (Roxadustat 2.0 mg/kg) | EXPERIMENTAL | Normoresponsive participants (with baseline epoetin alfa dosage 85-150 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 2.0 mg/kg, administered orally TIW for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohort A-10 (Weight Tiered Roxadustat 70-120-200 mg) | EXPERIMENTAL | Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive tiered, weight-based initial doses of roxadustat (approximately 1.5 mg/kg/dose TIW). Low weight (40 to 60 kg), medium weight (\>60 to 90 kg), and heavy weight (\>90 to 140 kg) participants will receive roxadustat 70 mg, 120 mg, and 200 mg, respectively, administered as oral capsules for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohorts A (Epoetin Alfa) | ACTIVE_COMPARATOR | Normoresponsive participants will receive IV epoetin alfa treatments on Day 1, at their prestudy dose and according to their prestudy dosing schedule (TIW). Epoetin alfa dosing will occur on dialysis days in each Cohort A. Dose adjustment will be per local standard of care (exclusive of IV iron) for routine maintenance of stable Hb levels on dialysis participants. |
| Cohort B-1 (Roxadustat 1.5 mg/kg TIW) | EXPERIMENTAL | Hyporesponsive participants (with baseline epoetin alfa dosage 125-400 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.5 mg/kg, administered orally TIW for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohort B-2 (Roxadustat 2.0 mg/kg TIW) | EXPERIMENTAL | Hyporesponsive participants (with baseline epoetin alfa dosage \>115 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 2.0 mg/kg, administered orally TIW for 6 weeks. Participants who have not completed 6-week treatment at the time of Amendment 2, will continue treatment for up to 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb. |
| Cohort B (Epoetin Alfa) | ACTIVE_COMPARATOR | Hyporesponsive participants will receive IV epoetin alfa treatments on Day 1, at their prestudy dose and according to their prestudy dosing schedule (TIW). Epoetin alfa dosing will occur on dialysis days in each Cohort B. Dose adjustment will be per local standard of care (exclusive of IV iron) for routine maintenance of stable Hb levels on dialysis participants. |
| Cohort B (Placebo) | PLACEBO_COMPARATOR | Hyporesponsive participants will receive placebo matched to roxadustat, administered orally TIW for 19 weeks. |
| Roxadustat 0.7 mg/kg BIW | EXPERIMENTAL | Participants will receive roxadustat 0.7 mg/kg BIW orally with doses administered at least 68 hours apart for 29 days. |
| Roxadustat 0.7 mg/kg TIW | EXPERIMENTAL | Participants will receive roxadustat 0.7 mg/kg TIW orally with doses administered at least 46 hours apart for 26 days. |
| Roxadustat 1.0 mg/kg BIW | EXPERIMENTAL | Participants will receive roxadustat 1.0 mg/kg BIW orally with doses administered at least 72 hours apart for 29 days. |
| Roxadustat 1.0 mg/kg TIW | EXPERIMENTAL | Participants will receive roxadustat 1.0 mg/kg TIW orally with doses administered at least 48 hours apart for 26 days. |
| Roxadustat 1.5 mg/kg BIW | EXPERIMENTAL | Participants will receive roxadustat 1.5 mg/kg BIW orally with doses administered at least 68 hours apart for 29 days. |
| Roxadustat 1.5 mg/kg TIW | EXPERIMENTAL | Participants will receive roxadustat 1.5 mg/kg TIW orally with doses administered at least 46 hours apart for 26 days. |
| Roxadustat 2.0 mg/kg BIW | EXPERIMENTAL | Participants will receive roxadustat 2.0 mg/kg BIW orally with doses administered at least 68 hours apart for 29 days. |
| Roxadustat 2.0 mg/kg TIW | EXPERIMENTAL | Participants will receive roxadustat 2.0 mg/kg TIW orally with doses administered at least 46 hours apart for 26 days. |
| Treatment Sequence 1 (ABCD) | EXPERIMENTAL | Participants will receive single dose of 100 mg roxadustat pediatric azo dye-free tablet (A), orally on day 1 in period 1 followed by 100 mg roxadustat pediatric azo dye-free mini-tablet suspension (B), orally on day 1 in period 2 followed by 100 mg roxadustat pediatric azo dye-free mini-tablet solid (C), orally on day 1 in period 3 followed by 100 mg roxadustat azo dye-containing tablet (D), orally on day 1 in period 4. Each period will be of 6 days. A washout period of 7 days will be included between each period. |
| Treatment Sequence 2 (BDAC) | EXPERIMENTAL | Participants will receive 100 mg roxadustat pediatric azo dye-free mini-tablet suspension (B), orally on day 1 in period 1 followed by single dose of 100 mg roxadustat azo dye-containing tablet (D), orally on day 1 in period 2 followed by 100 mg roxadustat pediatric azo dye-free tablet (A), orally on day 1 in period 3 followed by 100 mg roxadustat pediatric azo dye-free mini-tablet solid (C), orally on day 1 in period 4. Each period will be of 6 days. A washout period of 7 days will be included between each period. |
| Treatment Sequence 3 (CADB) | EXPERIMENTAL | Participants will receive single dose of 100 mg roxadustat pediatric azo dye-free mini-tablet solid (C), orally on day 1 in period 1 followed by 100 mg roxadustat pediatric azo dye-free tablet (A), orally on day 1 in period 2 followed by 100 mg roxadustat azo dye-containing tablet (D), orally on day 1 in period 3 followed by 100 mg roxadustat pediatric azo dye-free mini-tablet suspension (B), orally on day 1 in period 4. Each period will be of 6 days. A washout period of 7 days will be included between each period. |
| Treatment Sequence 4 (DCBA) | EXPERIMENTAL | Participants will receive single dose of 100 mg roxadustat azo dye-containing tablet (D), orally on day 1 in period 1 followed by 100 mg roxadustat pediatric azo dye-free mini-tablet solid (C), orally on day 1 in period 2 followed by 100 mg roxadustat pediatric azo dye-free mini-tablet suspension (B), orally on day 1 in period 3 followed by 100 mg of roxadustat pediatric azo dye-free tablet (A), orally on day 1 in period 4. Each period will be of 6 days. A washout period of 7 days will be included between each period. |
| Roxadustat: subjects with normal renal function | EXPERIMENTAL | Normal renal function: eGFR is equal to or greater than 90 mL/min/1.73 m\^2. Single dose of roxadustat |
| Roxadustat: subjects with severely impaired renal function | EXPERIMENTAL | Severely impaired renal function: eGFR is less than 30 mL/min/1.73 m\^2. Single dose of roxadustat |
| Roxadustat: subjects with ESRD on CAPD or APD | EXPERIMENTAL | ESRD subjects on CAPD or APD need to be on the same mode of dialysis for at least 4 months. Single dose of roxadustat |
| Roxadustat: subjects with ESRD on HD or HDF | EXPERIMENTAL | ESRD subjects on HD or HDF need to be on the same mode of dialysis for at least 4 months and should have dialysis sessions three times weekly. Single dose of roxadustat, in both treatment periods |
| Name | Type | Description |
|---|---|---|
| roxadustat | DRUG | Oral administration |
| DA | DRUG | Subcutaneous administration |
| Darbepoetin alfa | DRUG | Intravenous |
| Epoetin alfa | DRUG | Participants received epoetin alfa via intravenous or subcutaneous injection, once a week, twice a week, or three times a week (TIW). Epoetin alfa dosage was adjusted to maintain Hb level within the target range. Dosing of epoetin alfa was per UK SmPC of Eprex®. Participants received IV iron supplementation according to the standard of care. |
| Iron | DRUG | Oral iron treatment was recommended for supplementation to support erythropoiesis and as first-line treatment for iron deficiency, unless participant was intolerant to this treatment. For participants receiving roxadustat the recommended daily dose was 200 mg of elemental iron. Participants were advised to take roxadustat at least 1 hour before or 1 hour after oral iron. Intravenous iron supplementation for participants receiving roxadustat was allowed if all of the following criteria were met: The participant's Hb level had not responded adequately to roxadustat following two consecutive dose increases or reached the maximum dose limit, and participant's ferritin was \< 100 ng/mL (\< 220 pmol/L) or TSAT \< 20%, or the participant was intolerant of oral iron therapy. For participants treated with epoetin alfa or darbepoetin alfa, IV iron supplementation was given according to standard of care. |
| Placebo | DRUG | Placebo was administered initially according to the tiered weight-based dosing, where participants with weight from ≥ 45 to ≤ 70 kg received 70 mg and participants with \> 70 to ≤ 160 kg received 100 mg of roxadustat. Dose-titration based upon regular measurement of Hb levels was performed until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. |
| Oral Iron | DRUG | Administered per oral dose and schedule specified in the arm. |
| IV Iron | DRUG | Administered per IV dose and schedule specified in the arm. |
Inclusion Criteria: * Subjects who were diagnosed with non-dialysis Chronic Kidney Disease and who are considered not to require renal replacement therapy during the study period * Subjects with renal anemia who have been receiving erythropoiesis stimulating agent (ESA) by subcutaneous injection an...
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