Anemia
Conditions
Keywords
Renal,, CKD,, Roxadustat,, anemia,, non-dialysis
Brief summary
The purpose of the study is to evaluate the safety and efficacy of roxadustat for treatment of anemia in patients with chronic kidney disease not on dialysis
Detailed description
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in anemic patients with Stage 3, 4 or 5 chronic kidney disease (CKD) who are not on dialysis.
Interventions
DRUGRoxadustat
The initial study drug dose is 70 mg three times a week (TIW). The dose is subsequently adjusted to achieve and maintain Hb 11±1 g/dL.
DRUGPlacebo
The initial study drug dose is 70 mg three times a week (TIW). The dose is subsequently adjusted to achieve and maintain Hb 11±1 g/dL.
Sponsors
Kyntra Bio
AstraZeneca
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 130 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of informed consent prior to any study specific procedures. 2. Age ≥18 years at screening visit 1 3. eGFR \<60 mL/min/1.73 m2, (calculated by central lab) corresponding to stage 3, 4 or 5CKD according to the Kidney Disease Outcomes Quality Initiative (KDOQI), not receiving dialysis 4. Mean of 2 most recent central laboratory Hb values during the screening period, obtained at least 7 days apart, must be \<10.0 g/dL 5. Ferritin ≥50 ng/mL at randomization (obtained from screening visit) 6. TSAT ≥15 % at randomization (obtained from screening visit) 7. Serum folate level ≥ lower limit of normal (LLN) at randomization (obtained from screening visit) 8. Serum vitamin B12 level ≥LLN at randomization (obtained from screening visit) 9. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) and total bilirubin (Tbili) ≤1.5 x ULN at randomization (obtained from screening visit) 10. Body weight 45 to 160 kg
Exclusion criteria
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) 2. Previous randomization in the present study 3. Any erythropoietin analogue treatment within 6 weeks of randomization 4. New York Heart Association Class III or IV congestive heart failure at enrollment 5. Myocardial infarction (MI), acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization 6. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic auto- immune liver disease, cirrhosis or fibrosis of the liver) 7. Known hereditary hematologic disease such as thalassemia, sickle cell anemia, a history of pure red cell aplasia or other known causes for anemia other than CKD 8. Known and untreated retinal vein occlusion or known and untreated proliferative diabetic retinopathy (risk for retinal vein thrombosis) 9. Diagnosis or suspicion (e.g. complex kidney cyst of Bosniak Category IIF, III or IV) of renal cell carcinoma on renal ultrasound (or other imaging procedure e.g. CT scan or MRI) conducted at screening or within 12 weeks prior to randomization 10. Systolic BP ≥160 mmHg or diastolic BP ≥95 mmHg (confirmed by repeated measurement), within 2 weeks prior to randomization. Patients may be rescreened once BP controlled 11. History of prostate cancer, breast cancer or any other malignancy, except the following: cancers determined to be cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps 12. Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus antibody (anti-HCV Ab) 13. Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), ankylosing spondylitis, psoriatic arthritis or inflammatory bowel disease that is determined to be the principal cause of anemia 14. Known hemosiderosis, hemochromatosis or hypercoagulable condition 15. Any prior organ transplant or a scheduled organ transplantation date 16. Any red blood cell transfusion (RBC) during the screening period 17. Any current condition leading to active significant blood loss 18. Any treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) 19. Has received another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment within at least 1 month of the first administration of IP in this study. (Note: patients consented and screened, but not randomized in this study or a previous study are not excluded) 20. History of alcohol or drug abuse within 2 years prior to randomization 21. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence 22. Pregnant or breastfeeding females 23. Known allergy to the investigational product or any of its ingredients 24. Any medical condition, including active, clinically significant infection, that in the opinion of the investigator or Sponsor may pose a safety risk to a patient in this study, which may confound efficacy or safety assessment or may interfere with study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 | Baseline (Day 1, Week 0) and Week 28 to Week 52. | Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value from Week 28 to Week 52 was analyzed using a missing at random (MAR) based multiple imputation analysis of covariance (ANCOVA) model with baseline Hb, baseline estimated glomerular filtration rate (eGFR), cardiovascular (CV) history, geographic region and treatment group as fixed effect covariates. The adjusted least squares (LS) mean estimates of change from baseline to mean during Week 28 to Week 52 are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 in Participants With Baseline High Sensitivity C-Reactive Protein (hsCRP) Greater Than the Upper Limit of Normal (ULN) | Baseline (Day 1, Week 0) and Week 28 to Week 52. | Baseline hsCRP was quantified from stored biomarker samples obtained at randomization. Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value during Week 28 to Week 52 was analyzed using a MAR based multiple imputation ANCOVA model with baseline Hb, baseline eGFR, CV history, geographic region and treatment group as fixed effect covariates. The adjusted LS mean estimates of change from baseline in participants with baseline hsCRP \>ULN to mean during Week 28 to Week 52 are presented. |
| Proportion of Total Time of Interpolated Hb Values Greater Than or Equal To 10 g/dL From Week 28 to Week 52 | Week 28 up to Week 52. | Proportion of total time of interpolated Hb values ≥10 g/dL was calculated as the time the linearly interpolated curve between measurements ≥10 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented. |
| Proportion of Total Time of Interpolated Hb Values Within the Interval of 10 to 12 g/dL From Week 28 to Week 52 | Week 28 up to Week 52. | Proportion of total time of interpolated Hb values within the interval of 10 to 12 g/dL was calculated as the time the linearly interpolated curve between measurements were within 10 to 12 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented. |
| Mean Change in Low-Density Lipoprotein (LDL) Cholesterol From Baseline to Week 24 | Baseline (Day 1, Week 0) and Week 24 | Baseline LDL was defined as the last result obtained prior to randomization. Mean changes in LDL cholesterol from baseline to Week 24 was analyzed using an ANCOVA model with baseline LDL, baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from baseline to Week 24 are presented. |
| Percentage of Participants With Hb Response During the First 24 Weeks of Treatment | Baseline (Day 1, Week 0) up to Week 24. | Hb response 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 2 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, erythropoietin analogue, or intravenous \[IV\] iron) prior to Hb response. The percentage of participants with an Hb response during the first 24 weeks of treatment is presented. |
| Time-To-First Instance of Receiving a RBC Transfusion As Rescue Therapy | Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period) (or up to date of first RBC rescue therapy), with treatment duration up to 4 years. | Time-to-first RBC rescue therapy was calculated as (date of first RBC rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events. |
| Mean Change From Baseline in Short Form 36 (SF-36) Vitality Sub-Score From Week 12 to Week 28 | Baseline (Day 1, Week 0) and Week 12 to Week 28. | SF-36 is a Quality of Life (QoL) scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Vitality sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a mixed model for repeated measures (MMRM) with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction as fixed effects and participant as random effect. The adjusted LS mean estimates of change from baseline to mean score from Week 12 to Week 28 are presented. |
| Annual Rate of eGFR Change From Baseline Prior to the Initiation of Dialysis or Kidney Transplant | Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years. | Baseline eGFR was defined as the mean of all available central laboratory values prior to or at randomization. Rate of change in eGFR from baseline during the entire treatment period (in millilitres/minute/1.73 meters squared/years \[mL/min/1.73m\^2/years\]) was estimated using a random effects model using all post-baseline eGFR values prior to initiation of dialysis/transplant. Baseline eGFR, baseline Hb, geographic region, CV history, treatment group and post-baseline eGFR measurement time were used as fixed effects and participant and time (years) as random effects, ie, random intercept and slope. |
| Mean Change From Baseline in SF-36 Physical Functioning Sub-Score From Week 12 to Week 28 | Baseline (Day 1, Week 0) and Week 12 to Week 28. | SF-36 is a QoL scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Physical Functioning sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a MMRM with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction as fixed effects and participant as random effect. The adjusted LS mean estimates of change from baseline to mean score from Week 12 to Week 28 are presented. |
| Time-To-First Instance of Receiving IV Iron, RBC Transfusion or Erythropoietin Analogue as Rescue Therapy | Baseline (Day1, Week 0) up to End of Study (EOS) visit (4 weeks after the treatment period) (or up to date of first rescue therapy), with treatment duration up to 4 years. | Time-to-first rescue therapy (IV iron, RBC transfusion or erythropoietin analogue) was calculated as (date of first rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events. |
Countries
Argentina, Brazil, Bulgaria, Canada, Colombia, Czechia, Germany, Hungary, India, Malaysia, Mexico, Peru, Philippines, Poland, Puerto Rico, Romania, Russia, Slovakia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States, Vietnam
Participant flow
Recruitment details
This study was conducted at 385 centers in 25 countries worldwide across the United States, Canada, Latin America, Asia and Europe between 26 June 2014 and 04 October 2018. Participants with chronic kidney disease who were not on dialysis were recruited in this study.
Pre-assignment details
Study had a screening period (up to 6 weeks), treatment period (up to 4 years) and follow-up period (4 weeks after treatment period for those who completed treatment). 2781 participants were randomized, of which 2761 were included in the analysis and 20 were excluded. Only participants included in the analysis are presented in the participant flow.
Participants by arm
| Arm | Count |
|---|---|
| Roxadustat Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values. | 1,384 |
| Placebo Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values. | 1,377 |
| Total | 2,761 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Incorrect enrolment before randomization | 0 | 1 |
| Overall Study | Missing | 0 | 1 |
| Overall Study | Participant decision | 84 | 128 |
Baseline characteristics
| Characteristic | Roxadustat | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 60.9 years STANDARD_DEVIATION 14.67 | 61.7 years STANDARD_DEVIATION 14.43 | 62.4 years STANDARD_DEVIATION 14.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 344 Participants | 701 Participants | 357 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1040 Participants | 2060 Participants | 1020 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 24 Participants | 53 Participants | 29 Participants |
| Race/Ethnicity, Customized Asian | 544 Participants | 1082 Participants | 538 Participants |
| Race/Ethnicity, Customized Black or African American | 112 Participants | 227 Participants | 115 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 81 Participants | 163 Participants | 82 Participants |
| Race/Ethnicity, Customized White | 623 Participants | 1234 Participants | 611 Participants |
| Sex: Female, Male Female | 820 Participants | 1594 Participants | 774 Participants |
| Sex: Female, Male Male | 564 Participants | 1167 Participants | 603 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 284 / 1,384 | 245 / 1,377 |
| other Total, other adverse events | 839 / 1,384 | 757 / 1,377 |
| serious Total, serious adverse events | 795 / 1,384 | 749 / 1,377 |
Outcome results
Primary
Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52
Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value from Week 28 to Week 52 was analyzed using a missing at random (MAR) based multiple imputation analysis of covariance (ANCOVA) model with baseline Hb, baseline estimated glomerular filtration rate (eGFR), cardiovascular (CV) history, geographic region and treatment group as fixed effect covariates. The adjusted least squares (LS) mean estimates of change from baseline to mean during Week 28 to Week 52 are presented.
Time frame: Baseline (Day 1, Week 0) and Week 28 to Week 52.
Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roxadustat | Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 | 1.75 g/dL | Standard Error 0.033 |
| Placebo | Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 | 0.40 g/dL | Standard Error 0.034 |
Comparison: Difference between groups (roxadustat minus placebo) in LS mean changes; MAR-based multiple imputation ANCOVA model.p-value: <0.00195% CI: [1.27, 1.43]ANCOVA
Secondary
Annual Rate of eGFR Change From Baseline Prior to the Initiation of Dialysis or Kidney Transplant
Baseline eGFR was defined as the mean of all available central laboratory values prior to or at randomization. Rate of change in eGFR from baseline during the entire treatment period (in millilitres/minute/1.73 meters squared/years \[mL/min/1.73m\^2/years\]) was estimated using a random effects model using all post-baseline eGFR values prior to initiation of dialysis/transplant. Baseline eGFR, baseline Hb, geographic region, CV history, treatment group and post-baseline eGFR measurement time were used as fixed effects and participant and time (years) as random effects, ie, random intercept and slope.
Time frame: Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years.
Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roxadustat | Annual Rate of eGFR Change From Baseline Prior to the Initiation of Dialysis or Kidney Transplant | -3.70 eGFR rate (mL/min/1.73m^2/years) |
| Placebo | Annual Rate of eGFR Change From Baseline Prior to the Initiation of Dialysis or Kidney Transplant | -3.19 eGFR rate (mL/min/1.73m^2/years) |
Comparison: Difference between groups (roxadustat minus placebo) in rate of change in eGFR; random effects analysis.p-value: 0.04695% CI: [-1, -0.01]Random Effects Analysis
Secondary
Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 in Participants With Baseline High Sensitivity C-Reactive Protein (hsCRP) Greater Than the Upper Limit of Normal (ULN)
Baseline hsCRP was quantified from stored biomarker samples obtained at randomization. Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value during Week 28 to Week 52 was analyzed using a MAR based multiple imputation ANCOVA model with baseline Hb, baseline eGFR, CV history, geographic region and treatment group as fixed effect covariates. The adjusted LS mean estimates of change from baseline in participants with baseline hsCRP \>ULN to mean during Week 28 to Week 52 are presented.
Time frame: Baseline (Day 1, Week 0) and Week 28 to Week 52.
Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Only participants who consented to the use of donated biomarker samples and had baseline hsCRP \>ULN were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roxadustat | Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 in Participants With Baseline High Sensitivity C-Reactive Protein (hsCRP) Greater Than the Upper Limit of Normal (ULN) | 1.75 g/dL | Standard Error 0.087 |
| Placebo | Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 in Participants With Baseline High Sensitivity C-Reactive Protein (hsCRP) Greater Than the Upper Limit of Normal (ULN) | 0.62 g/dL | Standard Error 0.091 |
Comparison: Difference between groups (roxadustat minus placebo) in LS mean changes; MAR-based multiple imputation ANCOVA model.p-value: <0.00195% CI: [0.91, 1.35]ANCOVA
Secondary
Mean Change From Baseline in SF-36 Physical Functioning Sub-Score From Week 12 to Week 28
SF-36 is a QoL scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Physical Functioning sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a MMRM with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction as fixed effects and participant as random effect. The adjusted LS mean estimates of change from baseline to mean score from Week 12 to Week 28 are presented.
Time frame: Baseline (Day 1, Week 0) and Week 12 to Week 28.
Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roxadustat | Mean Change From Baseline in SF-36 Physical Functioning Sub-Score From Week 12 to Week 28 | 0.14 scores on a scale | Standard Error 0.222 |
| Placebo | Mean Change From Baseline in SF-36 Physical Functioning Sub-Score From Week 12 to Week 28 | -0.39 scores on a scale | Standard Error 0.224 |
Comparison: Difference between groups (roxadustat minus placebo) in LS mean changes; MMRM analysis.p-value: 0.05195% CI: [0, 1.05]Mixed Models Analysis
Secondary
Mean Change From Baseline in Short Form 36 (SF-36) Vitality Sub-Score From Week 12 to Week 28
SF-36 is a Quality of Life (QoL) scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Vitality sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a mixed model for repeated measures (MMRM) with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction as fixed effects and participant as random effect. The adjusted LS mean estimates of change from baseline to mean score from Week 12 to Week 28 are presented.
Time frame: Baseline (Day 1, Week 0) and Week 12 to Week 28.
Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roxadustat | Mean Change From Baseline in Short Form 36 (SF-36) Vitality Sub-Score From Week 12 to Week 28 | 1.59 scores on a scale | Standard Error 0.231 |
| Placebo | Mean Change From Baseline in Short Form 36 (SF-36) Vitality Sub-Score From Week 12 to Week 28 | 1.15 scores on a scale | Standard Error 0.233 |
Comparison: Difference between groups (roxadustat minus placebo) in LS mean changes; MMRM analysis.p-value: 0.1295% CI: [-0.11, 0.99]Mixed Models Analysis
Secondary
Mean Change in Low-Density Lipoprotein (LDL) Cholesterol From Baseline to Week 24
Baseline LDL was defined as the last result obtained prior to randomization. Mean changes in LDL cholesterol from baseline to Week 24 was analyzed using an ANCOVA model with baseline LDL, baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from baseline to Week 24 are presented.
Time frame: Baseline (Day 1, Week 0) and Week 24
Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roxadustat | Mean Change in Low-Density Lipoprotein (LDL) Cholesterol From Baseline to Week 24 | -0.38 millimole per liter | Standard Error 0.028 |
| Placebo | Mean Change in Low-Density Lipoprotein (LDL) Cholesterol From Baseline to Week 24 | -0.02 millimole per liter | Standard Error 0.027 |
Comparison: Difference between groups (roxadustat minus placebo) in LS mean changes; ANCOVA model.p-value: <0.00195% CI: [-0.42, -0.29]ANCOVA
Secondary
Percentage of Participants With Hb Response During the First 24 Weeks of Treatment
Hb response 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 2 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, erythropoietin analogue, or intravenous \[IV\] iron) prior to Hb response. The percentage of participants with an Hb response during the first 24 weeks of treatment is presented.
Time frame: Baseline (Day 1, Week 0) up to Week 24.
Population: The Full Analysis Set (FAS) included all participants in the ITT analysis set who received at least 1 dose of IP and had baseline Hb and at least 1 post-dose Hb assessment. Participants from the FAS, with data available for analysis are presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roxadustat | Percentage of Participants With Hb Response During the First 24 Weeks of Treatment | 77.0 Percentage of participants |
| Placebo | Percentage of Participants With Hb Response During the First 24 Weeks of Treatment | 8.5 Percentage of participants |
Comparison: Comparison of the percentage of responders for roxadustat versus placebo was analysed using a Cochran-Mantel-Haenszel test adjusting for baseline Hb, baseline eGFR, geographic region and CV history.p-value: <0.00195% CI: [7.63, 10.89]Cochran-Mantel-Haenszel
Secondary
Proportion of Total Time of Interpolated Hb Values Greater Than or Equal To 10 g/dL From Week 28 to Week 52
Proportion of total time of interpolated Hb values ≥10 g/dL was calculated as the time the linearly interpolated curve between measurements ≥10 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented.
Time frame: Week 28 up to Week 52.
Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Participants without any Hb measurements from Week 28 were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roxadustat | Proportion of Total Time of Interpolated Hb Values Greater Than or Equal To 10 g/dL From Week 28 to Week 52 | 0.82 proportion of total time | Standard Error 0.011 |
| Placebo | Proportion of Total Time of Interpolated Hb Values Greater Than or Equal To 10 g/dL From Week 28 to Week 52 | 0.33 proportion of total time | Standard Error 0.011 |
Comparison: Difference between groups (roxadustat minus placebo) in LS mean changes; ANCOVA model.p-value: <0.00195% CI: [0.47, 0.52]ANCOVA
Secondary
Proportion of Total Time of Interpolated Hb Values Within the Interval of 10 to 12 g/dL From Week 28 to Week 52
Proportion of total time of interpolated Hb values within the interval of 10 to 12 g/dL was calculated as the time the linearly interpolated curve between measurements were within 10 to 12 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented.
Time frame: Week 28 up to Week 52.
Population: The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Participants without any Hb measurements from Week 28 were not included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Roxadustat | Proportion of Total Time of Interpolated Hb Values Within the Interval of 10 to 12 g/dL From Week 28 to Week 52 | 0.70 proportion of total time | Standard Error 0.01 |
| Placebo | Proportion of Total Time of Interpolated Hb Values Within the Interval of 10 to 12 g/dL From Week 28 to Week 52 | 0.28 proportion of total time | Standard Error 0.01 |
Comparison: Difference between groups (roxadustat minus placebo) in LS mean changes; ANCOVA model.p-value: <0.00195% CI: [0.4, 0.45]ANCOVA
Secondary
Time-To-First Instance of Receiving a RBC Transfusion As Rescue Therapy
Time-to-first RBC rescue therapy was calculated as (date of first RBC rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.
Time frame: Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period) (or up to date of first RBC rescue therapy), with treatment duration up to 4 years.
Population: The OT+28 analysis set included all participants who received at least 1 dose of randomized IP, except for those excluded from analysis. Participants were censored 28 days after last intake of IP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roxadustat | Time-To-First Instance of Receiving a RBC Transfusion As Rescue Therapy | 7.98 Events per 100 participant years |
| Placebo | Time-To-First Instance of Receiving a RBC Transfusion As Rescue Therapy | 19.61 Events per 100 participant years |
Comparison: Treatments were compared using a Cox proportional hazards model, with baseline Hb and baseline eGFR as continuous variables used as covariates, and treatment group, CV history and geographic region as fixed effects. The Efron method was used for ties and p-values were calculated using the Wald test.p-value: <0.00195% CI: [0.3, 0.44]Regression, Cox
Secondary
Time-To-First Instance of Receiving IV Iron, RBC Transfusion or Erythropoietin Analogue as Rescue Therapy
Time-to-first rescue therapy (IV iron, RBC transfusion or erythropoietin analogue) was calculated as (date of first rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.
Time frame: Baseline (Day1, Week 0) up to End of Study (EOS) visit (4 weeks after the treatment period) (or up to date of first rescue therapy), with treatment duration up to 4 years.
Population: The on-treatment plus 28 days (OT+28) analysis set included all participants who received at least 1 dose of randomized IP, except for those excluded from analysis. Participants were censored 28 days after last intake of IP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Roxadustat | Time-To-First Instance of Receiving IV Iron, RBC Transfusion or Erythropoietin Analogue as Rescue Therapy | 11.90 Events per 100 participant years |
| Placebo | Time-To-First Instance of Receiving IV Iron, RBC Transfusion or Erythropoietin Analogue as Rescue Therapy | 39.76 Events per 100 participant years |
Comparison: Treatments were compared using a Cox proportional hazards model, with baseline Hb and baseline eGFR as continuous variables used as covariates, and treatment group, CV history and geographic region as fixed effects. The Efron method was used for ties and p-values were calculated using the Wald test.p-value: <0.00195% CI: [0.23, 0.31]Regression, Cox