CKD Anemia
Conditions
Keywords
anemia, chronic kidney disease (CKD), non-dialysis, Hemoglobin (Hb), End-Stage Renal Disease, erythropoeitin, ASP1517, erythropoeisis stimulating-agent, AZD9941
Brief summary
The purpose of this study is to determine whether roxadustat is safe and effective in the treatment of anemia in participants with chronic kidney disease and not on dialysis.
Detailed description
There is a screening period of up to 6 weeks, a variable treatment period for individual participants. In order to complete the treatment period simultaneously for all study participants, the minimum treatment duration may be less than 52 weeks, with a maximum treatment duration of up to 3 years after the last participant is randomized, and a post-treatment follow-up period of 4 weeks. Participants who prematurely discontinued from treatment will be expected to complete the Early Termination (ET) and End of Study (EOS) visits. Such participants will be considered non-completers, but they will be expected to participate in long-term follow-up (LTFU) for cardiovascular events (CV) of interest, vital status, and hospitalizations until overall study closure unless the participant withdrew consent for this LTFU data collection. Participants were randomized in a 2:1 ratio to receive either roxadustat or placebo in a double-blind manner.
Interventions
DRUGRoxadustat
Oral tablets
DRUGPlacebo
Oral tablets
Sponsors
Astellas Pharma Europe B.V.
AstraZeneca
Kyntra Bio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Chronic kidney disease Stages 3, 4, or 5 and not receiving dialysis * Anemia qualified by measurements of hemoglobin values during screening * Additional blood work must be in a safe range for study entry * Body weight 45 to 160 kilograms (kg) * Willingness to use contraception if of child-bearing potential
Exclusion criteria
* Treatment with an erythropoiesis-stimulating agent (ESA) within 12 weeks prior to study participation * More than 1 dose of intravenous iron within 12 weeks prior to study participation * Blood transfusion within 8 weeks prior to study participation * Active infection * Chronic liver disease * Severe congestive heart failure, recent heart attack, stroke, seizure, or blood clot * Uncontrolled blood pressure within 2 weeks prior to study participation * Renal cell carcinoma * History of malignancy, including multiple myeloma or other myelodysplastic syndrome * Chronic inflammatory disease that could impact red blood cell production * Any prior organ transplant or a scheduled organ transplantation * Anticipated elective surgery that is expected to lead to significant blood loss or anticipated elective heart procedure * Gastrointestinal bleeding * Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) * Recent use of an investigational drug or treatment, or participation in an investigational study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| United States (US FDA) Submission: Mean Change From Baseline in Hb (g/dL) Over Weeks 28 to 52 Regardless of Rescue Therapy | Baseline (Day 1, Week 0), Weeks 28 to 52 | 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. |
| Ex-US Submission: Number (%) of Participants Who Achieved a Hb Response During the First 24-Weeks of Treatment Censoring for Rescue Therapy | Baseline up to Week 24 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number (%) of Participants With Hb ≥10 g/dL Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy | Weeks 28 to 36 | Hb values under the influence of a rescue therapy were censored by Cochran-Mantel-Haenszel Test for up to 6 weeks. Responder was defined as: Hb ≥10.0 g/dL, which was based on central laboratory values. |
| Mean 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 LDL cholesterol value prior to the first dose of study drug. |
| Rate of Change in eGFR From Baseline up to 12 Months (Linear Random Coefficient Model With Observed Data) | Baseline, Month 12 | Progression of chronic kidney disease was measured by rate of change in eGFR over time adjusted by baseline eGFR, with censoring for chronic dialysis or kidney transplant, using random slope and intercept model. Least Square Mean of change from baseline at 1 year was derived based on a random slopes and intercepts model using all available eGFR values (1 baseline and all post-treatment values up to end of treatment period + 7 days or start of dialysis) adjusted on treatment, baseline Hb, baseline eGFR, geographical region, cardiovascular events history at Baseline (yes vs. no), time (continuous value), the interaction terms of baseline eGFR by time, baseline Hb by time, and treatment by time as fixed effects, with random effects of intercept and linear slope of time. All assessments collected after the start of stable dialysis or kidney transplant were excluded from the analysis. |
| Number of Participants Who Received Blood/RBC Transfusion in the First 52 Weeks of Treatment | Baseline up to Week 52 | Participants with any use of blood/RBC transfusion were reported. |
| Mean Change From Baseline in Hb Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy | Baseline (Day 1, Week 0), Weeks 28 to 36 | For Ex-US submission only: Hb values under the influence of a rescue therapy were censored by mixed effect model of repeated measures (MMRM) for up to 6 weeks. Baseline Hb was defined as the mean of up to 4 last central laboratory values prior to the first dose of study drug. |
| 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, bodily pain, role limitations due to physical problems, role limitations due to emotional problems, general health perceptions, mental health, social function, and vitality. The physical functioning subscore and vitality subscore are reported. The scores ranged from 0 (worst) to 100 (Best). A higher score indicates a general improvement of life quality or well-being. Baseline score was defined as the last physical functioning value or vitality value, as applicable, prior to the first dose of study drug. |
| Number (%) of Participants Who Experienced Exacerbation of Hypertension | Baseline up to Week 52 | Exacerbation of hypertension was defined as an increase from baseline of ≥20 millimeter of mercury (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 ≥110 mmHg. |
| Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 | Baseline, Weeks 20 to 28 | Baseline MAP was defined as the last MAP value prior to the first dose of study drug. |
| Number (%) of Participants Who Received Rescue Therapy in the First 24 Weeks and in the First 52 Weeks of Treatment | Baseline (Day 1, Week 0) up to Week 24 and up to Week 52 | Rescue therapy included any use of RBC transfusion, ESA, or IV iron. |
| Mean Change From Baseline in Hb Averaged Over Weeks 28 to 52 Regardless of Rescue Therapy in Participants With Baseline C-Reactive Protein (CRP) >Upper Limit of Normal (ULN) | Baseline (Day 1, Week 0), Weeks 28 to 52 | Hb values under the influence of a rescue therapy were not censored in the analysis. The intermittent missing hemoglobin data were 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. Baseline Hb was defined as the mean of up to 4 last central laboratory values prior to the first dose of study treatment. |
Countries
Argentina, Australia, Chile, Colombia, Hong Kong, Malaysia, Mexico, New Zealand, Peru, Philippines, Puerto Rico, Singapore, South Korea, Taiwan, Thailand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Roxadustat Participants received roxadustat tablets orally TIW. The initial dose was according to the tiered weight-based approach, with starting roxadustat doses of 70 mg TIW to participants weighing \<70 kg and roxadustat doses of 100 mg TIW to participants weighing ≥70 kg. Dose-titration (up to a maximum dose of 300 mg) was performed based upon regular measurement of Hb levels until the participant achieved central Hb value of ≥11.0 g/dL and Hb increase from BL of ≥1.0 g/dL at 2 consecutive study visits, separated by at least 5 days. Once target Hb level was reached, the participant entered the maintenance period during which roxadustat dosage will be adjusted every 4 weeks to maintain participant's Hb level within the target range of 10.0 g/dL and 12.0 g/dL. The maximum treatment duration was 234.9 weeks. | 616 |
| Placebo Participants received roxadustat-matching placebo tablets orally TIW. The initial dose was according to the tiered weight-based approach, with starting roxadustat-matching placebo doses of 70 mg TIW to participants weighing \<70 kg and roxadustat-matching placebo doses of 100 mg TIW to participants weighing ≥70 kg. Dose-titration (up to a maximum dose of 300 mg) was performed based upon regular measurement of Hb levels until the participant achieved central Hb value of ≥11.0 g/dL and Hb increase from BL of ≥1.0 g/dL at 2 consecutive study visits, separated by at least 5 days. Once target Hb level was reached, the participant entered the maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participant's Hb level within the target range of 10.0 g/dL and 12.0 g/dL. The maximum treatment duration was 208.1 weeks. | 306 |
| Total | 922 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 47 | 19 |
| Overall Study | Death | 38 | 11 |
| Overall Study | Dialysis | 22 | 8 |
| Overall Study | Kidney Transplant | 8 | 4 |
| Overall Study | Lack of Efficacy (Including Erythropoiesis-Stimulating Agent Rescue) | 2 | 43 |
| Overall Study | Lost to Follow-up | 28 | 7 |
| Overall Study | Other than Specified | 13 | 4 |
| Overall Study | Physician Decision | 16 | 17 |
| Overall Study | Protocol Violation | 6 | 5 |
| Overall Study | Study/Site Terminated by Sponsor | 4 | 1 |
| Overall Study | Withdrawal by Subject | 83 | 89 |
Baseline characteristics
| Characteristic | Placebo | Total | Roxadustat |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 160 Participants | 505 Participants | 345 Participants |
| Age, Categorical Between 18 and 65 years | 146 Participants | 417 Participants | 271 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 84 Participants | 249 Participants | 165 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 222 Participants | 673 Participants | 451 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian/ Alaskan Native | 1 Participants | 7 Participants | 6 Participants |
| Race/Ethnicity, Customized Asian | 151 Participants | 461 Participants | 310 Participants |
| Race/Ethnicity, Customized Black/African American | 28 Participants | 104 Participants | 76 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 4 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 23 Participants | 69 Participants | 46 Participants |
| Race/Ethnicity, Customized White | 99 Participants | 275 Participants | 176 Participants |
| Sex: Female, Male Female | 176 Participants | 551 Participants | 375 Participants |
| Sex: Female, Male Male | 130 Participants | 371 Participants | 241 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 38 / 611 | 11 / 305 |
| other Total, other adverse events | 468 / 611 | 216 / 305 |
| serious Total, serious adverse events | 321 / 611 | 120 / 305 |
Outcome results
Primary
Ex-US Submission: Number (%) of Participants Who Achieved a Hb Response During the First 24-Weeks of Treatment Censoring for Rescue Therapy
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
Time frame: Baseline up to Week 24
Population: FAS Population included of all randomized/enrolled participants who received at least 1 dose of study drug and had baseline and at least 1 postdose Hb assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Roxadustat | Ex-US Submission: Number (%) of Participants Who Achieved a Hb Response During the First 24-Weeks of Treatment Censoring for Rescue Therapy | 523 Participants |
| Placebo | Ex-US Submission: Number (%) of Participants Who Achieved a Hb Response During the First 24-Weeks of Treatment Censoring for Rescue Therapy | 20 Participants |
p-value: <0.000195% CI: [44.73, 134.48]Cochran-Mantel-Haenszel
Primary
United States (US FDA) Submission: Mean Change From Baseline in Hb (g/dL) Over Weeks 28 to 52 Regardless of Rescue Therapy
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.
Time frame: Baseline (Day 1, Week 0), Weeks 28 to 52
Population: ITT Population included all randomized/enrolled participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | United States (US FDA) Submission: Mean Change From Baseline in Hb (g/dL) Over Weeks 28 to 52 Regardless of Rescue Therapy | Change at Weeks 28 to 52 | 2.00 g/dL | Standard Deviation 0.952 |
| Roxadustat | United States (US FDA) Submission: Mean Change From Baseline in Hb (g/dL) Over Weeks 28 to 52 Regardless of Rescue Therapy | Baseline | 9.10 g/dL | Standard Deviation 0.75 |
| Placebo | United States (US FDA) Submission: Mean Change From Baseline in Hb (g/dL) Over Weeks 28 to 52 Regardless of Rescue Therapy | Change at Weeks 28 to 52 | 0.16 g/dL | Standard Deviation 0.895 |
| Placebo | United States (US FDA) Submission: Mean Change From Baseline in Hb (g/dL) Over Weeks 28 to 52 Regardless of Rescue Therapy | Baseline | 9.09 g/dL | Standard Deviation 0.69 |
Comparison: Treatment comparison was made using the multiple imputation strategy by combining the results of analysis of covariance (ANCOVA) model with baseline Hb and baseline estimated glomerular filtration rate (eGFR) as covariates and treatment and other randomization stratification factors, except baseline Hb (≤8 g/dL versus \>8 g/dL) and eGFR (\<30 versus ≥30 milliliters \[mL\]/minutes \[min\]/1.73 meters \[m\]\^2), as fixed effects.p-value: <0.000195% CI: [1.735, 1.967]ANCOVA
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, bodily pain, role limitations due to physical problems, role limitations due to emotional problems, general health perceptions, mental health, social function, and vitality. The physical functioning subscore and vitality subscore are reported. The scores ranged from 0 (worst) to 100 (Best). A higher score indicates a general improvement of life quality or well-being. 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 at the 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 | 41.16 scores on a scale | Standard Deviation 10.121 |
| 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 | 0.33 scores on a scale | Standard Deviation 7.302 |
| 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 | 48.19 scores on a scale | Standard Deviation 10.146 |
| 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 | 1.90 scores on a scale | Standard Deviation 8.705 |
| Placebo | 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 | 1.02 scores on a scale | Standard Deviation 8.334 |
| Placebo | 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 | 41.35 scores on a scale | Standard Deviation 10.07 |
| Placebo | 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 | 47.62 scores on a scale | Standard Deviation 9.774 |
| Placebo | 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 | -0.27 scores on a scale | Standard Deviation 7.363 |
Secondary
Mean Change From Baseline in Hb Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy
For Ex-US submission only: Hb values under the influence of a rescue therapy were censored by mixed effect model of repeated measures (MMRM) for up to 6 weeks. Baseline Hb was defined as the mean of up to 4 last central laboratory values prior to the first dose of study drug.
Time frame: Baseline (Day 1, Week 0), Weeks 28 to 36
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, 'Number Analyzed' signifies participants evaluable at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | Mean Change From Baseline in Hb Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy | Baseline | 9.09 g/dL | Standard Deviation 0.749 |
| Roxadustat | Mean Change From Baseline in Hb Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy | Change at Weeks 28 to 36 | 2.02 g/dL | Standard Deviation 1.067 |
| Placebo | Mean Change From Baseline in Hb Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy | Baseline | 9.09 g/dL | Standard Deviation 0.694 |
| Placebo | Mean Change From Baseline in Hb Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy | Change at Weeks 28 to 36 | 0.20 g/dL | Standard Deviation 0.994 |
Comparison: Treatment comparison was made using MMRM with baseline Hb and baseline eGFR as covariates, and treatment, visit, visit-by-treatment interaction, and the randomization stratification factors, except baseline Hb (≤8 g/dL versus \>8 g/dL) and eGFR (\<30 versus ≥30 mL/min/1.73m\^2), as fixed effects.p-value: <0.000195% CI: [1.73, 2.037]Mixed Models Analysis
Secondary
Mean Change From Baseline in Hb Averaged Over Weeks 28 to 52 Regardless of Rescue Therapy in Participants With Baseline C-Reactive Protein (CRP) >Upper Limit of Normal (ULN)
Hb values under the influence of a rescue therapy were not censored in the analysis. The intermittent missing hemoglobin data were 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. Baseline Hb was defined as the mean of up to 4 last central laboratory values prior to the first dose of study treatment.
Time frame: Baseline (Day 1, Week 0), Weeks 28 to 52
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | Mean Change From Baseline in Hb Averaged Over Weeks 28 to 52 Regardless of Rescue Therapy in Participants With Baseline C-Reactive Protein (CRP) >Upper Limit of Normal (ULN) | Baseline | 9.10 g/dL | Standard Deviation 0.75 |
| Roxadustat | Mean Change From Baseline in Hb Averaged Over Weeks 28 to 52 Regardless of Rescue Therapy in Participants With Baseline C-Reactive Protein (CRP) >Upper Limit of Normal (ULN) | Change at Weeks 28 to 52 | 2.02 g/dL | Standard Deviation 0.933 |
| Placebo | Mean Change From Baseline in Hb Averaged Over Weeks 28 to 52 Regardless of Rescue Therapy in Participants With Baseline C-Reactive Protein (CRP) >Upper Limit of Normal (ULN) | Baseline | 8.99 g/dL | Standard Deviation 0.668 |
| Placebo | Mean Change From Baseline in Hb Averaged Over Weeks 28 to 52 Regardless of Rescue Therapy in Participants With Baseline C-Reactive Protein (CRP) >Upper Limit of Normal (ULN) | Change at Weeks 28 to 52 | 0.18 g/dL | Standard Deviation 0.946 |
Comparison: Treatment comparison was made using the multiple imputation strategy by combining the results of ANCOVA model with baseline Hb and baseline eGFR as covariates , and treatment and other randomization stratification factors, except baseline Hb (≤8 g/dL versus \>8 g/dL) and eGFR (\<30 versus ≥30 mL/min/1.73m\^2 ), as fixed effects.p-value: <0.000195% CI: [1.663, 2.143]ANCOVA
Secondary
Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28
Baseline LDL cholesterol was defined as the last LDL cholesterol value 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, 'Number Analyzed' signifies participants evaluable at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28 | Baseline | 97.74 mg/dL | Standard Deviation 39.09 |
| Roxadustat | Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28 | Change at Weeks 12 to 28 | -18.48 mg/dL | Standard Deviation 29.6 |
| Placebo | Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28 | Baseline | 96.39 mg/dL | Standard Deviation 40.06 |
| Placebo | Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28 | Change at Weeks 12 to 28 | 0.22 mg/dL | Standard Deviation 29.37 |
Comparison: Treatment comparison was made using MMRM with baseline LDL cholesterol as a covariate, and treatment, visit, visit-by-treatment interaction, and the randomization stratification factors as fixed effects.p-value: <0.000195% CI: [-20.65, -13.87]Mixed Models Analysis
Secondary
Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28
Baseline MAP was defined as the last MAP value prior to the first dose of study drug.
Time frame: Baseline, Weeks 20 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, 'Number Analyzed' signifies participants evaluable at the specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Roxadustat | Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 | Baseline | 92.16 mmHg | Standard Deviation 8.538 |
| Roxadustat | Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 | Change at Weeks 20 to 28 | 0.02 mmHg | Standard Deviation 8.648 |
| Placebo | Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 | Baseline | 91.53 mmHg | Standard Deviation 8.077 |
| Placebo | Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28 | Change at Weeks 20 to 28 | -0.12 mmHg | Standard Deviation 7.653 |
Secondary
Number (%) of Participants Who Experienced Exacerbation of Hypertension
Exacerbation of hypertension was defined as an increase from baseline of ≥20 millimeter of mercury (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 ≥110 mmHg.
Time frame: Baseline up to Week 52
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Roxadustat | Number (%) of Participants Who Experienced Exacerbation of Hypertension | 140 Participants |
| Placebo | Number (%) of Participants Who Experienced Exacerbation of Hypertension | 48 Participants |
Secondary
Number of Participants Who Received Blood/RBC Transfusion in the First 52 Weeks of Treatment
Participants with any use of blood/RBC transfusion were reported.
Time frame: Baseline up to Week 52
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Roxadustat | Number of Participants Who Received Blood/RBC Transfusion in the First 52 Weeks of Treatment | 34 Participants |
| Placebo | Number of Participants Who Received Blood/RBC Transfusion in the First 52 Weeks of Treatment | 47 Participants |
p-value: <0.000195% CI: [0.165, 0.406]Cox Proportional hazards model
Secondary
Number (%) of Participants Who Received Rescue Therapy in the First 24 Weeks and in the First 52 Weeks of Treatment
Rescue therapy included any use of RBC transfusion, ESA, or IV iron.
Time frame: Baseline (Day 1, Week 0) up to Week 24 and up to Week 52
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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Roxadustat | Number (%) of Participants Who Received Rescue Therapy in the First 24 Weeks and in the First 52 Weeks of Treatment | 24 Weeks | 29 Participants |
| Roxadustat | Number (%) of Participants Who Received Rescue Therapy in the First 24 Weeks and in the First 52 Weeks of Treatment | 52 Weeks | 54 Participants |
| Placebo | Number (%) of Participants Who Received Rescue Therapy in the First 24 Weeks and in the First 52 Weeks of Treatment | 24 Weeks | 61 Participants |
| Placebo | Number (%) of Participants Who Received Rescue Therapy in the First 24 Weeks and in the First 52 Weeks of Treatment | 52 Weeks | 88 Participants |
Comparison: First 24 Weeks of Treatmentp-value: <0.000195% CI: [0.108, 0.267]Cox Proportional hazards model
Comparison: First 52 Weeks of Treatmentp-value: <0.000195% CI: [0.138, 0.276]Cox Proportional hazards model
Secondary
Number (%) of Participants With Hb ≥10 g/dL Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy
Hb values under the influence of a rescue therapy were censored by Cochran-Mantel-Haenszel Test for up to 6 weeks. Responder was defined as: Hb ≥10.0 g/dL, which was based on central laboratory values.
Time frame: Weeks 28 to 36
Population: FAS Population consisted of all randomized/enrolled participants who received at least 1 dose of study drug and had baseline and at least 1 postdose Hb assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Roxadustat | Number (%) of Participants With Hb ≥10 g/dL Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy | 467 Participants |
| Placebo | Number (%) of Participants With Hb ≥10 g/dL Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy | 56 Participants |
p-value: <0.000195% CI: [10.79, 22.189]Cochran-Mantel-Haenszel
Secondary
Rate of Change in eGFR From Baseline up to 12 Months (Linear Random Coefficient Model With Observed Data)
Progression of chronic kidney disease was measured by rate of change in eGFR over time adjusted by baseline eGFR, with censoring for chronic dialysis or kidney transplant, using random slope and intercept model. Least Square Mean of change from baseline at 1 year was derived based on a random slopes and intercepts model using all available eGFR values (1 baseline and all post-treatment values up to end of treatment period + 7 days or start of dialysis) adjusted on treatment, baseline Hb, baseline eGFR, geographical region, cardiovascular events history at Baseline (yes vs. no), time (continuous value), the interaction terms of baseline eGFR by time, baseline Hb by time, and treatment by time as fixed effects, with random effects of intercept and linear slope of time. All assessments collected after the start of stable dialysis or kidney transplant were excluded from the analysis.
Time frame: Baseline, Month 12
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roxadustat | Rate of Change in eGFR From Baseline up to 12 Months (Linear Random Coefficient Model With Observed Data) | -2.89 ml/min/1.73 m^2 | Standard Error 0.363 |
| Placebo | Rate of Change in eGFR From Baseline up to 12 Months (Linear Random Coefficient Model With Observed Data) | -3.10 ml/min/1.73 m^2 | Standard Error 0.388 |
p-value: 0.692495% CI: [-0.827, 1.245]ANCOVA