CKD Anemia in Stable Dialysis Patients
Conditions
Keywords
Anemia, Chronic Kidney Disease, Dialysis, hemodialysis, peritoneal dialysis, hemoglobin, End stage renal disease, Stable Dialysis, erythropoietins, erythropoiesis stimulating agent
Brief summary
The primary objective of this study is to evaluate the efficacy and safety of roxadustat compared with active control (epoetin alfa) for the maintenance treatment of anemia in participants with ESRD on dialysis.
Detailed description
This study will consist of three study periods as follows: 1. Screening Period of up to 6 weeks (8 weeks if on Mircera) 2. Treatment Period: a minimum of 52 weeks, a maximum of up to 3 years from the date last participant is randomized. Minimum study duration for participants enrolled under Protocol Amendment 1 or 2 may be less than 52 weeks 3. A Follow-up period of 4 weeks. Participants will be randomized in a 1:1 ratio to receive either roxadustat or epoetin alfa (active control) in an open-label manner.
Interventions
DRUGEpoetin Alfa
Epoetin alfa will be administered per dose and schedule specified in the arm.
DRUGRoxadustat
Roxadustat will be administered per dose and schedule specified in the arm.
Sponsors
Astellas Pharma Europe B.V.
AstraZeneca
Kyntra Bio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Receiving dialysis for ESRD for ≥3 months. Incident dialysis participants (under Amendment 1 and 2) receiving dialysis for ESRD for ≥ 2 weeks but ≤ 4 months at the time of randomization * Participants must be on ESA for ≥ 8 weeks prior to screening; incident dialysis participants must be on ESA for ≥ 4 weeks prior to screening. * Mean of the 3 most recent central lab Hb values during the Screening Period must be ≥ 9.0 g/dL and ≤ 12.0 g/dL (for incident dialysis participants, mean of the 2 most recent Hb values must be ≥ 8.5 g/dL and ≤ 12.0 g/dL); with an absolute difference of ≤ 1.3 g/dL between the highest and the lowest value. Samples are obtained at least 4 days apart (2 days under Amendment 2) and the last Hb value must be within 10 days prior to the randomization visit * Participants with ferritin level ≥ 100 nanograms (ng)/milliliter (mL) (\<100 ng/mL under Amendment 2) or transferrin saturation (TSAT) ≥ 20% (\<20% under Amendment 2) at screening may qualify upon receiving iron supplement (per local standard of care) * Participants with a serum folate and Vitamin B12 ≥ lower limit of normal (LLN) (\< LLN under Amendment 2) at screening may qualify upon receiving supplement (per local standard of care) * Participant's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤3x the upper limit of normal (ULN), and total bilirubin (TBL) is ≤1.5x ULN at screening * Participant's body weight is 45 kilograms (kg) to 160 kg.
Exclusion criteria
* Participant has received an red blood cell (RBC) transfusion within 8 weeks (4 weeks under Amendment 2) prior to randomization * Participant has known history of myelodysplastic syndrome or multiple myeloma * Participant has known inherited disease such as thalassemia or sickle cell anemia or other known causes for anemia other than chronic kidney disease. * Participant has known hemosiderosis, hemochromatosis, coagulation disorder,or hypercoagulable condition * Participant has known chronic inflammatory disease that could cause anemia * Participant has anticipated surgery that is expected to cause blood loss * Participant has known gastrointestinal bleeding * Participant has history of chronic liver disease (for example, chronic infectious hepatitis,chronic auto-immune liver disease,cirrhosis, or fibrosis of the liver) * Participant with New York Heart Association (NYHA) Class III or IV congestive heart failure * Participant has had a heart attack, stroke, seizure, or a thrombotic/thromboembolic event (for example, deep vein thrombosis or pulmonary embolism) within 12 weeks prior to participating in the study * Participant has uncontrolled high blood pressure within 2 weeks prior to participating in the study * Participant has a history of malignancy, except for the following: cancers determined to be cured or in remission for ≥2 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.) * Participant is positive for human immunodeficiency virus (HIV), Hepatitis B surface antigen, or anti-hepatitis C virus antibody * Participant with prior organ transplant who experience rejection within 6 months or on high doses of immunosuppressive therapy * Participant has any of the following known untreated conditions; proliferative diabetic retinopathy, diabetic macular edema, macular degeneration or retinal vein occlusion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Weeks 28 to 52), Regardless of Rescue Therapy | Baseline (Day 1, Week 0), Weeks 28 to 52 | 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. |
| Ex-U.S. Submission: Mean Hb Change From Baseline to the Average Weeks 28 to 36, Without Having Received Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period for Participants Enrolled Under the Original Protocol | Baseline (Day 1, Week 0), Weeks 28 to 36 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28 | Baseline (Day 1, Week 0), Weeks 12 to 28 | Baseline LDL Cholesterol was defined as the last available value prior to the first dose of study treatment. |
| Change From Baseline in Hb Levels Averaged Over Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN) | Baseline (Day 1, Week 0), Weeks 18 to 24 | 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 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 MCMC imputation model, Monotone missing data were imputed by regression from its own treatment group. |
| Average Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52 | Weeks 28 to 52 | Monthly iron use for each participant= Total IV iron in mg / \[(last dose date - first dose date of study medication in the period)+1\]/ 28. |
| US (FDA Submission): Hb Responder Rate- Percentage of Participants With Mean Hb Level ≥10.0 g/dL Averaged Over Weeks 28 to 52, Regardless of Rescue Therapy | Weeks 28 to 52 | 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 RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. |
| Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 | Baseline (Day 1, Week 0), Weeks 20 to 28 | Baseline MAP was defined as the mean of values obtained within 6 weeks prior to the first dose of study treatment. |
| Time to First Exacerbation of Hypertension During Weeks 28 to 52 | Weeks 28 to 52 | An exacerbation of hypertension was defined as increase from baseline of ≥20 mmHg in systolic blood pressure (sBP) and sBP ≥170 mmHg or an increase from baseline of ≥15 mmHg in diastolic blood pressure (dBP) and dBP ≥100 mmHg. Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates. |
| Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28 | Baseline (Day 1, Week 0), Weeks 12 to 28 | The SF-36 V2 consists of 36 questions covering 8 health domains: physical functioning (10 items), bodily pain (2 items), role limitations due to physical problems (4 items), role limitations due to emotional problems (3 items), general health perceptions (5 items), mental health (5 items), social function (2 items), and vitality (4 items). The physical functioning subscore and vitality subscore are reported. Each scale was transformed into 0-100 score, with higher scores indicating better health status. Baseline score was defined as the last physical functioning value or vitality value, as applicable, prior to the first dose of study drug. |
| Time to First RBC Transfusion | Baseline (Day 1, Week 0) up to last dose of study drug (maximum treatment duration was 183.7 weeks for roxadustat and 180.4 weeks for epoetin alfa) | Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates. |
| Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants With Mean Hb 10.0 to 12.0 g/dL Averaged Over Weeks 28 to 36, Censoring for Rescue Therapy | Weeks 28 to 36 | Hb values under the influence of a 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. |
Countries
Puerto Rico, United States
Participant flow
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive either roxadustat or epoetin alfa.
Participants by arm
| Arm | Count |
|---|---|
| Roxadustat Participants received roxadustat tablets, administered orally TIW. Initial roxadustat dose was based on the participant's average prescribed ESA dose in the 4 weeks (if on epoetin or darbepoetin or 8 weeks (if on Mircera®) prior to randomization. Dose adjustments were permitted to maintain a Hb level of approximately 11 g/dL. The maximum roxadustat dose was 3.0 mg/kg per dose or 400 mg per administration (whichever was lower). The maximum treatment duration was 183.7 weeks. | 370 |
| Epoetin Alfa Participants on HD received epoetin alfa, administered IV TIW and participants on home HD or PD received epoetin alfa, administered SC. Initial epoetin alfa dose was 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 was determined by the investigator per local SOC. Dose adjustments followed the recommendations as per the approved country-specific product label (USPI or SmPC) or local SOC. The maximum treatment duration was 180.4 weeks. | 371 |
| Total | 741 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 27 | 9 |
| Overall Study | Death | 70 | 62 |
| Overall Study | Kidney transplant | 31 | 39 |
| Overall Study | Lack of Efficacy | 6 | 1 |
| Overall Study | Lost to Follow-up | 6 | 3 |
| Overall Study | Other than specified | 28 | 30 |
| Overall Study | Physician Decision | 30 | 15 |
| Overall Study | Protocol Violation | 4 | 0 |
| Overall Study | Withdrawal by Subject | 41 | 29 |
Baseline characteristics
| Characteristic | Roxadustat | Epoetin Alfa | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 117 Participants | 125 Participants | 242 Participants |
| Age, Categorical Between 18 and 65 years | 253 Participants | 246 Participants | 499 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 137 Participants | 129 Participants | 266 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 233 Participants | 242 Participants | 475 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian/Alaskan Native | 10 Participants | 7 Participants | 17 Participants |
| Race/Ethnicity, Customized Race Asian | 21 Participants | 15 Participants | 36 Participants |
| Race/Ethnicity, Customized Race Black/African American | 158 Participants | 156 Participants | 314 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Other | 15 Participants | 6 Participants | 21 Participants |
| Race/Ethnicity, Customized Race White | 165 Participants | 184 Participants | 349 Participants |
| Sex: Female, Male Female | 183 Participants | 156 Participants | 339 Participants |
| Sex: Female, Male Male | 187 Participants | 215 Participants | 402 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 70 / 370 | 62 / 370 |
| other Total, other adverse events | 286 / 370 | 292 / 370 |
| serious Total, serious adverse events | 242 / 370 | 248 / 370 |
Outcome results
Primary
Ex-U.S. Submission: Mean Hb Change From Baseline to the Average Weeks 28 to 36, Without Having Received Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period for Participants Enrolled Under the Original Protocol
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.
Time frame: Baseline (Day 1, Week 0), Weeks 28 to 36
Population: Per protocol set (PPS) population included all participants in full analysis set (FAS) population (all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment) who received at least 8 weeks of treatment and were without major protocol violations. 'Overall number of participants analyzed'=participants evaluable for this outcome measure. 'Number analyzed'=participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | Ex-U.S. Submission: Mean Hb Change From Baseline to the Average Weeks 28 to 36, Without Having Received Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period for Participants Enrolled Under the Original Protocol | Baseline | 10.33 g/dL | Standard Deviation 0.639 |
| Roxadustat | Ex-U.S. Submission: Mean Hb Change From Baseline to the Average Weeks 28 to 36, Without Having Received Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period for Participants Enrolled Under the Original Protocol | Change at Weeks 28 to 36 | 0.54 g/dL | Standard Deviation 1.022 |
| Epoetin Alfa | Ex-U.S. Submission: Mean Hb Change From Baseline to the Average Weeks 28 to 36, Without Having Received Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period for Participants Enrolled Under the Original Protocol | Baseline | 10.35 g/dL | Standard Deviation 0.614 |
| Epoetin Alfa | Ex-U.S. Submission: Mean Hb Change From Baseline to the Average Weeks 28 to 36, Without Having Received Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period for Participants Enrolled Under the Original Protocol | Change at Weeks 28 to 36 | -0.03 g/dL | Standard Deviation 0.897 |
Comparison: Treatment comparison was made using a mixed model of repeated measures (MMRM) with baseline Hb as a covariate, and treatment, visit, visit-by-treatment interaction, ESA dependent incident dialysis within ≤4 months vs. \>4 months of starting dialysis when randomized, and randomization stratification factors except mean qualifying screening Hb (≤10.5 vs. \>10.5 g/dL) as fixed effects.p-value: <0.000195% CI: [0.404, 0.687]Mixed Models Analysis
Primary
US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Weeks 28 to 52), Regardless of Rescue Therapy
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.
Time frame: Baseline (Day 1, Week 0), Weeks 28 to 52
Population: ITT Population included all randomized participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Weeks 28 to 52), Regardless of Rescue Therapy | Baseline | 10.30 g/dL | Standard Deviation 0.661 |
| Roxadustat | US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Weeks 28 to 52), Regardless of Rescue Therapy | Change at Weeks 28 to 52 | 0.39 g/dL | Standard Deviation 0.934 |
| Epoetin Alfa | US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Weeks 28 to 52), Regardless of Rescue Therapy | Baseline | 10.31 g/dL | Standard Deviation 0.656 |
| Epoetin Alfa | US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Weeks 28 to 52), Regardless of Rescue Therapy | Change at Weeks 28 to 52 | -0.09 g/dL | Standard Deviation 0.838 |
Comparison: Treatment comparison was made using the multiple imputation (MI) strategy by combining the results of analysis of covariance (ANCOVA) model with baseline Hb as a covariate, and treatment, ESA dependent incident dialysis within ≤4 months vs. \>4 months of starting dialysis when randomized, and other randomization stratification factors except mean qualifying screening hemoglobin (≤10.5 vs. \>10.5 g/dL) as fixed effects.p-value: <0.000195% CI: [0.365, 0.591]ANCOVA
Secondary
Average Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52
Monthly iron use for each participant= Total IV iron in mg / \[(last dose date - first dose date of study medication in the period)+1\]/ 28.
Time frame: Weeks 28 to 52
Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Roxadustat | Average Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52 | 17.07 mg/PEM | Standard Deviation 53.375 |
| Epoetin Alfa | Average Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52 | 37.02 mg/PEM | Standard Deviation 106.778 |
Comparison: Treatment comparison was made using an ANCOVA model with baseline iron repletion status, treatment, ESA dependent incident dialysis within ≤4 months vs. \>4 months of starting dialysis when randomized, and randomization stratification factors as fixed effects.p-value: 0.0009195% CI: [-33.842, -6.445]Rank ANCOVA
Secondary
Change From Baseline in Hb Levels Averaged Over Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN)
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 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 MCMC imputation model, Monotone missing data were imputed by regression from its own treatment group.
Time frame: Baseline (Day 1, Week 0), Weeks 18 to 24
Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | Change From Baseline in Hb Levels Averaged Over Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN) | Baseline | 10.30 g/dL | Standard Deviation 0.616 |
| Roxadustat | Change From Baseline in Hb Levels Averaged Over Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN) | Change at Weeks 18-24 | 0.61 g/dL | Standard Deviation 1.02 |
| Epoetin Alfa | Change From Baseline in Hb Levels Averaged Over Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN) | Baseline | 10.24 g/dL | Standard Deviation 0.63 |
| Epoetin Alfa | Change From Baseline in Hb Levels Averaged Over Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN) | Change at Weeks 18-24 | -0.03 g/dL | Standard Deviation 0.94 |
Comparison: Treatment comparison was made using the MI strategy by combining the results of ANCOVA model with baseline Hb as a covariate, and treatment, ESA dependent incident dialysis within ≤4 months vs. \>4 months of starting dialysis when randomized, and other randomization stratification factors except mean qualifying screening Hb (≤10.5 vs. \>10.5 g/dL) as fixed effects.p-value: <0.000195% CI: [0.503, 0.869]ANCOVA
Secondary
Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28
Baseline LDL Cholesterol was defined as the last available value prior to the first dose of study treatment.
Time frame: Baseline (Day 1, Week 0), Weeks 12 to 28
Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28 | Baseline | 84.53 mg/dL | Standard Deviation 34.009 |
| Roxadustat | Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28 | Change at Weeks 12 to 28 | -13.70 mg/dL | Standard Deviation 23.068 |
| Epoetin Alfa | Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28 | Change at Weeks 12 to 28 | 1.23 mg/dL | Standard Deviation 22.389 |
| Epoetin Alfa | Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28 | Baseline | 84.45 mg/dL | Standard Deviation 34.124 |
Comparison: Treatment comparison was made using a MMRM with baseline as a covariate, and treatment, visit, visit-by-treatment interaction, ESA dependent incident dialysis within ≤4 months vs. \>4 months of starting dialysis when randomized, and randomization stratification factors as fixed effects.p-value: <0.000195% CI: [-17.64, -11.695]Mixed Models Analysis
Secondary
Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28
Baseline MAP was defined as the mean of values obtained within 6 weeks prior to the first dose of study treatment.
Time frame: Baseline (Day 1, Week 0), Weeks 20 to 28
Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 | Baseline | 101.41 millimeters of mercury (mmHg) | Standard Deviation 12.591 |
| Roxadustat | Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 | Change at Weeks 20 to 28 | 0.46 millimeters of mercury (mmHg) | Standard Deviation 10.933 |
| Epoetin Alfa | Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 | Baseline | 100.34 millimeters of mercury (mmHg) | Standard Deviation 12.35 |
| Epoetin Alfa | Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 | Change at Weeks 20 to 28 | 0.04 millimeters of mercury (mmHg) | Standard Deviation 10.489 |
Comparison: Treatment comparison was made using MMRM with baseline as a covariate, and treatment, visit, visit-by-treatment interaction, ESA dependent incident dialysis within ≤4 months vs. \>4 months of starting dialysis when randomized, and randomization stratification factors as fixed effects.p-value: 0.3595% CI: [-0.76, 2.142]Mixed Models Analysis
Secondary
Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28
The SF-36 V2 consists of 36 questions covering 8 health domains: physical functioning (10 items), bodily pain (2 items), role limitations due to physical problems (4 items), role limitations due to emotional problems (3 items), general health perceptions (5 items), mental health (5 items), social function (2 items), and vitality (4 items). The physical functioning subscore and vitality subscore are reported. Each scale was transformed into 0-100 score, with higher scores indicating better health status. Baseline score was defined as the last physical functioning value or vitality value, as applicable, prior to the first dose of study drug.
Time frame: Baseline (Day 1, Week 0), Weeks 12 to 28
Population: FAS Population included all randomized/enrolled participants who received at least 1 dose of study drug and had baseline and at least 1 postdose Hb assessment. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable for this outcome measure at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28 | Physical functioning subscore: Baseline | 38.55 score on a scale | Standard Deviation 11.202 |
| Roxadustat | Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28 | Physical functioning subscore: Change at Weeks 12 to 28 | -0.15 score on a scale | Standard Deviation 7.443 |
| Roxadustat | Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28 | Vitality subscore: Baseline | 51.65 score on a scale | Standard Deviation 10.111 |
| Roxadustat | Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28 | Vitality subscore: Change at Weeks 12 to 28 | -0.92 score on a scale | Standard Deviation 7.007 |
| Epoetin Alfa | Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28 | Vitality subscore: Change at Weeks 12 to 28 | 0.30 score on a scale | Standard Deviation 7.041 |
| Epoetin Alfa | Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28 | Physical functioning subscore: Baseline | 39.63 score on a scale | Standard Deviation 11.368 |
| Epoetin Alfa | Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28 | Vitality subscore: Baseline | 51.27 score on a scale | Standard Deviation 9.841 |
| Epoetin Alfa | Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28 | Physical functioning subscore: Change at Weeks 12 to 28 | -0.20 score on a scale | Standard Deviation 6.38 |
Secondary
Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants With Mean Hb 10.0 to 12.0 g/dL Averaged Over Weeks 28 to 36, Censoring for Rescue Therapy
Hb values under the influence of a 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.
Time frame: Weeks 28 to 36
Population: The PPS population included all participants in the FAS population (all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment) who received at least 8 weeks of treatment, had at least 1 valid postdose Hb assessment and were without major protocol violations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roxadustat | Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants With Mean Hb 10.0 to 12.0 g/dL Averaged Over Weeks 28 to 36, Censoring for Rescue Therapy | 64.1 percentage of participants |
| Epoetin Alfa | Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants With Mean Hb 10.0 to 12.0 g/dL Averaged Over Weeks 28 to 36, Censoring for Rescue Therapy | 60.8 percentage of participants |
Comparison: For the difference of responder rates between 2 treatment groups, the CI analyzed was from the Miettinen \& Nurminen approach adjusting for randomization stratification factors.95% CI: [-4.3, 9.7]
Secondary
Time to First Exacerbation of Hypertension During Weeks 28 to 52
An exacerbation of hypertension was defined as increase from baseline of ≥20 mmHg in systolic blood pressure (sBP) and sBP ≥170 mmHg or an increase from baseline of ≥15 mmHg in diastolic blood pressure (dBP) and dBP ≥100 mmHg. Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates.
Time frame: Weeks 28 to 52
Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roxadustat | Time to First Exacerbation of Hypertension During Weeks 28 to 52 | NA weeks |
| Epoetin Alfa | Time to First Exacerbation of Hypertension During Weeks 28 to 52 | NA weeks |
Secondary
Time to First RBC Transfusion
Median time to event (weeks) was calculated using Kaplan Meier Survival Estimates.
Time frame: Baseline (Day 1, Week 0) up to last dose of study drug (maximum treatment duration was 183.7 weeks for roxadustat and 180.4 weeks for epoetin alfa)
Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Roxadustat | Time to First RBC Transfusion | NA weeks |
| Epoetin Alfa | Time to First RBC Transfusion | NA weeks |
Comparison: Analysis was done using a Cox Proportional Hazards model adjusting for baseline Hb and other stratification factors except mean qualifying screening Hb (≤10.5 vs. \>10.5 g/dL) as fixed effects.p-value: 0.033795% CI: [0.466, 0.97]Cox Proportional Hazards model
Secondary
US (FDA Submission): Hb Responder Rate- Percentage of Participants With Mean Hb Level ≥10.0 g/dL Averaged Over Weeks 28 to 52, Regardless of Rescue Therapy
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 RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion.
Time frame: Weeks 28 to 52
Population: FAS population included all randomized participants who received at least 1 dose of study drug and had at least 1 postdose Hb assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roxadustat | US (FDA Submission): Hb Responder Rate- Percentage of Participants With Mean Hb Level ≥10.0 g/dL Averaged Over Weeks 28 to 52, Regardless of Rescue Therapy | 66.1 percentage of participants |
| Epoetin Alfa | US (FDA Submission): Hb Responder Rate- Percentage of Participants With Mean Hb Level ≥10.0 g/dL Averaged Over Weeks 28 to 52, Regardless of Rescue Therapy | 58.6 percentage of participants |
Comparison: For the difference of responder rates between 2 treatment groups, the CI analyzed was from the Miettinen \& Nurminen approach adjusting for randomization stratification factors.95% CI: [0.9, 14.3]