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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
922
Oral tablets
Oral tablets
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
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
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
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)
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Investigational Site
Huntsville, Alabama, United States
Investigational Site
Tempe, Arizona, United States
Investigational Site
Alhambra, California, United States
Investigational Site
Chula Vista, California, United States
Investigational Site
Inglewood, California, United States
Investigational Site
La Mesa, California, United States
Investigational Site
La Palma, California, United States
Investigational Site
Lynwood, California, United States
Investigational Site
Northridge, California, United States
Investigational Site
Paramount, California, United States
...and 135 more locations
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
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
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
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
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
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
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
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
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