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Roxadustat in the Treatment of Anemia in Chronic Kidney Disease (CKD) Patients, Not on Dialysis, in Comparison to Darbepoetin Alfa (Dolomites)

Primary Purpose

Anemia in Chronic Kidney Disease in Non-dialysis Patients

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Roxadustat

Darbepoetin alfa

About this trial

This is an interventional treatment trial for Anemia in Chronic Kidney Disease in Non-dialysis Patients focused on measuring Non-dialysis, Roxadustat, ASP1517, Chronic Kidney Disease (CKD), Anemia, Hemoglobin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Subject has a diagnosis of CKD, with Kidney Disease Outcomes Quality Initiative (KDOQI) Stage 3, 4 or 5, not on dialysis; with an Estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m^2 estimated using the abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) equation.
The mean of the subject's two most recent (prior to randomization) Hb values during the screening period, obtained at least 4 days apart, must be less than or equal to 10.5 g/dL, with a difference of less than or equal to 1.0 g/dL. The last Hb value must be within 10 days prior to randomization.
Subject is deemed suitable for treatment with Erythropoiesis Stimulating Agent (ESA) using the criteria specified in the Kidney Disease Improving Global Outcomes (KDIGO) 2012 recommendation considering the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anemia.
Subject has a serum folate level greater than or equal to lower limit of normal (LLN) at screening.
Subject has a serum vitamin B12 level greater than or equal to LLN at screening.
Subject's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are less than or equal to 3 x upper limit of normal (ULN), and total bilirubin (TBL) is less than or equal to 1.5 x ULN.
Subject's body weight is 45.0 kg to a maximum of 160.0 kg.
Male subject must not donate sperm starting from screening, throughout the study period and up to 12 weeks after final study drug administration.

Exclusion Criteria:

Subject has received any Erythropoiesis Stimulating Agent (ESA) treatment within 12 weeks prior to randomization.
Subject has received any dose of IV iron within 6 weeks prior to randomization.
Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to randomization.
Subject has a known history of myelodysplastic syndrome or multiple myeloma.
Subject has a known hereditary hematologic disease such as thalassemia or sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than Chronic Kidney Disease (CKD).
Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or hypercoagulable condition.
Subject has a known chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission.
Subject is anticipated to undergo elective surgery that is expected to lead to significant blood loss during the study period or anticipated elective coronary revascularization.
Subject has active or chronic gastrointestinal bleeding.
Subject has received any prior treatment with roxadustat or a Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI).
Subject has been treated with iron-chelating agents within 4 weeks prior to randomization.
Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver).
Subject has known New York Heart Association Class III or IV congestive heart failure.
Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
Subject has one or more contraindications for treatment with darbepoetin alfa:
- Uncontrolled hypertension, or two or more blood pressure values of SBP greater than or equal to 160 mmHg or DBP greater than or equal to 95 mmHg (within 2 weeks prior to randomization).
- Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or any of the excipients.
Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or higher) of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to randomization.
Subject has a history of malignancy, except for the following: cancers determined to be cured or in remission for greater than or equal to 5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.
Subject is positive for any of the following:
- human immunodeficiency virus (HIV).
- hepatitis B surface antigen (HBsAg).
- or anti-hepatitis C virus antibody (anti-HCV Ab).
Subject has an active clinically significant infection that is manifested by White Blood Count (WBC) > Upper Limit of Normal (ULN), and/or fever, in conjunction with clinical signs or symptoms of infection within one week prior to randomization.
Subject has a known untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration or retinal vein occlusion.
Subject has had any prior organ transplant (that has not been explanted), subject is scheduled for organ transplantation, or subject is likely to initiate renal replacement therapy including dialysis within the first year of the study.
Subject will be excluded from participation if any of the following apply:
- subject has received investigational therapy within 30 days or 5 half lives or limit set by national law, whichever is longer, prior to initiation of screening, or
- any condition which makes the subject unsuitable for study participation.
Subject has an anticipated use of dapsone in any dose amount or chronic use of acetaminophen/paracetamol >2.0 g/day during the treatment or follow-up period of the study.
Subject has a history of alcohol or drug abuse within 2 years prior to randomization

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Roxadustat

Darbepoetin alfa

Arm Description

Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg (milligram) given thrice weekly (TIW) to participants weighing up to 70 kg (kilogram) and 100 mg given TIW to participants weighing more than 70 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL (gram per deciliter) and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat up to a maximum of 104 weeks.

Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 μg/kg (microgram per kilogram), as a single subcutaneous or intravenous (IV) injection once weekly or 0.75 μg/kg, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.

Outcomes

Primary Outcome Measures

Percentage of Participants With a Hb Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy

Hb response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb change from baseline by ≥ 1.0 g/dL, for participants with baseline Hb > 8.0 g/dL; or Hb change from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at two consecutive visits with available data separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell [RBC] transfusion for all participants or darbepoetin for roxadustat treated participant).

Secondary Outcome Measures

Change From Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).

Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28

Baseline LDL-C was defined as the LDL-C value on day 1. If this value was missing, the latest value prior to first study drug administration was used.

Time to First Intravenous Iron Use

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to end of treatment (EOT) Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had received more than one intravenous iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Change From Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub Score in Weeks 12 to 28

Baseline SF-36 PF was defined as the SF-36 PF value on Day 1.The SF-36 is a Quality of Life (QoL) instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 contains 36 items that measured eight scales: (1) physical functioning; (2) role limitations due to physical health problems; (3) bodily pain; (4) social functioning; (5) general health perceptions; (6) role limitations due to emotional problems; (7) vitality, energy or fatigue; and (8) mental health. Each scale is transformed into 0-100 score, with higher scores indicating better health status. The SF-36 PF consisted of 11 questions that focused on health and ability to do usual activities, with higher scores indicating better health status.

Change From Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in Weeks 12 to 28

Baseline VT Subscore was defined as the VT value on Day 1. The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 vitality has four questions with score range from 0-100 with higher scores indicating better vitality status.

Change From Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set

Baseline MAP was defined as the MAP value on Day 1. If this value was missing, the latest value prior to first study drug administration was used. MAP was derived as: MAP = (2/3)*diastolic blood pressure (DBP) + (1/3)*systolic blood pressure (SBP).

Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set

Hypertension was defined as either SBP ≥ 170 mmHg and an increase from baseline ≥ 20 mmHg or as DBP ≥ 110 mmHg and an increase from baseline ≥ 15 mmHg. For participants who had experienced more than one event, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.

Change From Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set

Baseline MAP was defined as the MAP value on Day 1. If this value was missing, the latest value prior to first study drug administration was used. MAP was derived as: MAP = (2/3)*DBP + (1/3)*SBP.

Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set

Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless of Rescue Therapy

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose).

Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.

Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.

Hb Level Averaged Over Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 Without Rescue Therapy

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).

Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose).

Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104 Regardless of Use of Rescue Therapy

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).

Percentage of Hb Values >=10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy

Percentage for each participant was calculated from the number of Hb values within 10.0-12.0 g/dL / total number of Hb values*100 in weeks 28 to 36, 44 to 52 and 96 to 104 without use of rescue therapy within 6 weeks prior to and during the 8 week evaluation period.

Time to First Hb Rate of Rise > 2 g/dL Within 4 Weeks

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Number of Hospitalizations

The number of hospitalizations per participant were calculated during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).

Number of Days of Hospitalization Per Year

The number of days of hospitalization per year was calculated as the sum of the durations of all hospitalizations in days (minimum [date of discharge, end of efficacy of emergent period] - date of admission + 1) / (duration of efficacy emergent period in days / 365.25). The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).

Time to First Hospitalization

Time to first hospitalization in years was defined in years as: (first event date during the efficacy emergent period - analysis date of first dose intake +1)/365.25, and the 'first event date' was defined as 'date of first admission and 'analysis date of first dose intake. Date of end of efficacy emergent period was defined as as the treatment period up to the EOT visit. For participants who have experienced more than one hospitalization, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Time to First Use of RBC Transfusion

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one RBC transfusion, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Number of RBC Packs

The number of RBC packs were calculated as the sum of units transfused during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT visit or last non-missing Hb assessment (for participants who died during the treatment period). Participants with no medication records of RBC have their number of RBC packs set to 0.

Volume of RBC Transfused

The volume of blood transfused was calculated as the sum of blood volume transfused during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). Participants with no medication records of RBC have their volume set to 0.

Number of Particpants Who Received RBC Transfusions

Participants who received RBC transfusions during the efficacy emergent period were reported. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).

Time to First Use of Rescue Therapy

Rescue therapy for participants in the roxadustat group included RBC transfusion or ESA therapy and for participants in the darbepoetin alfa group included RBC transfusion only. Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who have experienced more than one use of rescue therapy (i.e. RBC and ESA), only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Number of Participants Who Received Rescue Therapy (Composite of RBC Transfusions (All Participants) and Darbepoetin Alfa Use (Roxadustat Treated Participants Only)

Mean Monthly Intravenous Iron Per Participant During Weeks 37 to 52 and 53 to 104

Participants with no or missing medication records of IV Iron had their monthly IV Iron use set to 0 mg.

Time to First Use of IV Iron Supplementation

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had received more than one IV iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Percentage of Participants With Oral Iron Use Only

Percentage of participants with oral iron use only were calculated based on total number of participants within the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).

Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein Cholesterol (HDL-C) Ratio

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1)

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB)

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Number of Participants With Mean LDL Cholesterol < 100 mg/dL

Missing category for fasting only includes non-fasting participants and the participants with missing values.

Number of Participants Who Had Achieved Antihypertensive Treatment Goal

Achieved antihypertensive treatment goal was defined as SBP < 130 mmHg and DBP < 80 mmHg over an evaluation period defined as the average of available values in weeks 12 to 28 and 36 to 52.

Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in SF-36 Physical Component Score (PCS)

Baseline SF-36 PCS was defined as the SF-36 PCS value on day 1.The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 contains 36 items that measured eight scales: (1) physical functioning; (2) role limitations due to physical health problems; (3) bodily pain; (4) social functioning; (5) general health perceptions; (6) role limitations due to emotional problems; (7) vitality, energy or fatigue; and (8) mental health. Each scale is transformed into 0-100 score, with higher scores indicating better health status. The PCS was calculated based on all 8 scales and ranged from 5.02-79.78. For each of these above scales, higher scores always indicated better health status.

Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in Anemia Subscale (AnS) (Additional Concerns) of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score

Baseline FACT-An AnS was defined as the FACT-An AnS value on day 1. Together with the functional assessment of cancer therapy - general (FACT-G), the AnS is referred to as the FACT-An Total. The AnS scale contains 13 fatigue specific items (the fatigue score) plus 7 items related to anemia. The Anemia AnS score range is 0 to 80. Higher scores indicated better QoL.

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Total Score

Baseline FACT-An total score was defined on day 1. Total Fact-An score is composed of FACT-G and Ans scales. FACT-G contains 27 items that cover four dimensions of well-being: physical well being (PWB) - 7 items, functional well being (FWB) - 7 items, social/family well being (SWB) - 7 items, and emotional well being (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score was obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range was 0-188. A higher score indicated better QoL.

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Trial Outcome Index (TOI) Score

Baseline FACT-An total TOI Score was defined on day 1. Total FACT-An TOI score is a sum of PWB subscale score, FWB subscale score and Ans scale score. Fact-An TOI scale contains 14 items that cover four dimensions of well-being: PWB -7 items, FWB -7 items, where score range for each PWB subscale and FWB subscale is 0-28. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia, where score range for Ans scale is 0-80. The total score was obtained by summation of the scores from PWB, FWB and AnS. The FACT-An Total TOI score range was 0-136. A higher score indicated better QoL.

Change From Baseline to the Average Value of Weeks 12 to 28 in Euroqol Questionnaire-5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score

Baseline assessment was defined as the value on day 1. The EQ-5D-5L is a self-reported questionnaire, used as a measure of respondents' health related quality of life (HRQoL) and utility values. The EQ-5D consists of the descriptive system and the VAS. The EQ-5D descriptive system comprises 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems. The VAS records the respondent's self rated health status on a graduated (0-100) scale, where the endpoints are labeled 'best imaginable health state' and 'worst imaginable health state' with higher scores for higher HRQoL.

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) Score: Percent Work Time Missed

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Multiply scores by 100 to express in percentages. Percent work time missed due to problem: Q2/(Q2+Q4).

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Impairment While Working

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent impairment while working due to problem: Q5/10.

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Overall Work Impairment

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent overall work impairment due to problem: Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4))x(Q5/10)].

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Activity Impairment

Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC)

The PGIC is a patient-rated instrument that measured change in participant's overall status on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), when compared to the start of treatment. The percentage of participants presented included very much improved, much improved and minimally improved.

Change From Baseline to Each Scheduled Measurement in Serum Ferritin

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT)

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c)

Percentage of change from baseline to each study visit were calculated for HbA1c. Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR)

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Rate of Progression of Chronic Kidney Disease Measured by eGFR Slope Over Time

Annualized eGFR slope over time was estimated by a random slopes and intercepts model using all available eGFR values (one baseline and all post-treatment values up to EOT period or start of dialysis adjusted on baseline Hb, region, CV history at baseline and the interaction terms (baseline eGFR by timepoint and baseline Hb by timepoint). All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis. Baseline assessment was the assessment from day 1 visit. If this value was missing, the value from screening visit was used.

Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR)

Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline

For participants who had doubled their serum creatinine or had chronic dialysis or renal transplant more than once, only their first occurrence during safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Number of Participants With End Stage Renal Disease (ESRD)

Occurrence of end stage renal disease during the study (i.e from day 1 up to the end of study) was defined as at least one of the following: underwent >30 days dialysis therapy, received kidney transplant, planned kidney transplant, physician recommended renal replacement therapy and participant refused therapy, began dialysis and died < 30 days later.

Time to Chronic Kidney Disease Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death)

Chronic kidney disease progression was defined as date of occurrence of chronic dialysis or date of renal transplant or doubled serum creatinine or date of death, whichever came first. For participants who had chronic dialysis or renal transplant or died, only their first occurrence during the safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Time to Chronic Dialysis or Renal Transplant or Death

For participants who had chronic dialysis or renal transplant or died, only their first occurrence during the safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant

For participants who had at least 40% decrease in eGFR from baseline, chronic dialysis or renal transplant during the safety emergent period, only their first occurrence was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by kaplan-meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

An AE was defined as any untoward medical occurrence in a participant who was given the study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. All AEs collected during the safety emergent period were counted as TEAE. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Based on national cancer institute common terminology criteria (NCI-CTCAE), AEs were graded as grade 1=mild, grade 2=moderate, grade 3 =severe or medically significant, grade 4 =life threatening, grade 5 =death related to AE. All reported deaths after the first study drug administration and up to 28 days after the analysis date of last dose were based on last dosing frequency.

Full Information

NCT ID

NCT02021318

First Posted

December 20, 2013

Last Updated

April 19, 2021

Sponsor

Astellas Pharma Europe B.V.

Collaborators

FibroGen

1. Study Identification

Unique Protocol Identification Number

NCT02021318

Brief Title

Roxadustat in the Treatment of Anemia in Chronic Kidney Disease (CKD) Patients, Not on Dialysis, in Comparison to Darbepoetin Alfa

Acronym

Dolomites

Official Title

A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

March 12, 2014 (Actual)

Primary Completion Date

March 23, 2018 (Actual)

Study Completion Date

November 6, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Astellas Pharma Europe B.V.

Collaborators

FibroGen

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The primary objective of this study was to evaluate the efficacy of roxadustat compared to darbepoetin alfa in the treatment of anemia in nondialysis-dependent chronic kidney disease (NDD CKD) participants.

Detailed Description

This was a phase 3, multicenter, randomized, open-label, active-controlled study. The study was planned to provide key efficacy and safety data for the approval of roxadustat in the treatment of anemia associated with CKD. Participants assigned to roxadustat treatment were administered roxadustat orally as a combination of tablets of different strengths. Participants assigned to darbepoetin alfa treatment were administered darbepoetin alfa subcutaneously or intravenously. The study consisted of 3 study periods: Screening period: up to 6 weeks Treatment period: 104 weeks Follow-up period: 4 weeks until planned study end (end of year 2)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Anemia in Chronic Kidney Disease in Non-dialysis Patients

Keywords

Non-dialysis, Roxadustat, ASP1517, Chronic Kidney Disease (CKD), Anemia, Hemoglobin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

616 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Roxadustat

Arm Type

Experimental

Arm Description

Arm Title

Darbepoetin alfa

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Roxadustat

Other Intervention Name(s)

ASP1517

Intervention Description

Oral tablet.

Intervention Type

Drug

Intervention Name(s)

Darbepoetin alfa

Other Intervention Name(s)

Aranesp

Intervention Description

Subcutaneous or intravenous injection.

Primary Outcome Measure Information:

Title

Percentage of Participants With a Hb Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy

Description

Time Frame

Baseline to week 24

Secondary Outcome Measure Information:

Title

Change From Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period

Description

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).

Time Frame

Baseline and weeks 28 to 36

Title

Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28

Description

Baseline LDL-C was defined as the LDL-C value on day 1. If this value was missing, the latest value prior to first study drug administration was used.

Time Frame

Baseline and weeks 12 to 28

Title

Time to First Intravenous Iron Use

Description

Time Frame

Weeks 6, 12, 18, 24, 30 and 36

Title

Change From Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub Score in Weeks 12 to 28

Description

Time Frame

Baseline and weeks 12 to 28

Title

Change From Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in Weeks 12 to 28

Description

Time Frame

Baseline and weeks 12 to 28

Title

Change From Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set

Description

Time Frame

Baseline and weeks 20 to 28

Title

Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set

Description

Time Frame

Weeks 1 to 36

Title

Change From Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set

Description

Baseline MAP was defined as the MAP value on Day 1. If this value was missing, the latest value prior to first study drug administration was used. MAP was derived as: MAP = (2/3)*DBP + (1/3)*SBP.

Time Frame

Baseline and weeks 20 to 28

Title

Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set

Description

Time Frame

Weeks 1 to 36

Title

Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless of Rescue Therapy

Description

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose).

Time Frame

Baseline and weeks 28 to 52

Title

Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy

Description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.

Time Frame

Weeks 1 to 24

Title

Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy

Description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure.

Time Frame

Weeks 1 to 24

Title

Hb Level Averaged Over Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 Without Rescue Therapy

Description

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).

Time Frame

Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104

Title

Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of Rescue Therapy

Description

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose).

Time Frame

Baseline and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104

Title

Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104 Regardless of Use of Rescue Therapy

Description

Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose).

Time Frame

Baseline and weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104

Title

Percentage of Hb Values >=10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy

Description

Time Frame

Weeks 28 to 36, 44 to 52 and 96 to 104

Title

Time to First Hb Rate of Rise > 2 g/dL Within 4 Weeks

Description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Time Frame

Year 0.5, 1, 1.5 and 2

Title

Number of Hospitalizations

Description

Time Frame

Baseline to EOT (up to week 104)

Title

Number of Days of Hospitalization Per Year

Description

Time Frame

Baseline to EOT (up to week 104)

Title

Time to First Hospitalization

Description

Time Frame

Year 0.5, 1, 1.5 and 2

Title

Time to First Use of RBC Transfusion

Description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one RBC transfusion, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Time Frame

Year 0.5, 1, 1.5 and 2

Title

Number of RBC Packs

Description

Time Frame

Baseline to EOT (up to week 104)

Title

Volume of RBC Transfused

Description

Time Frame

Baseline to EOT (up to week 104)

Title

Number of Particpants Who Received RBC Transfusions

Description

Time Frame

Baseline to EOT (up to week 104)

Title

Time to First Use of Rescue Therapy

Description

Time Frame

Year 0.5, 1, 1.5 and 2

Title

Number of Participants Who Received Rescue Therapy (Composite of RBC Transfusions (All Participants) and Darbepoetin Alfa Use (Roxadustat Treated Participants Only)

Description

Time Frame

Baseline to EOT (up to week 104)

Title

Mean Monthly Intravenous Iron Per Participant During Weeks 37 to 52 and 53 to 104

Description

Participants with no or missing medication records of IV Iron had their monthly IV Iron use set to 0 mg.

Time Frame

Weeks 37 to 52 and 53 to 104

Title

Time to First Use of IV Iron Supplementation

Description

Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had received more than one IV iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure.

Time Frame

Year 0.5, 1, 1.5 and 2

Title

Percentage of Participants With Oral Iron Use Only

Description

Time Frame

Day 1 to week 36, weeks 37 to 52, weeks 53 to 104, efficacy emergent period (up to week 104)

Title

Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol

Description

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Time Frame

Baseline and weeks 8, 28, 52, 104

Title

Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein Cholesterol (HDL-C) Ratio

Description

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Time Frame

Baseline and weeks 8, 28, 52, 104

Title

Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol

Description

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Time Frame

Baseline and weeks 8, 28, 52, 104

Title

Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1)

Description

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Time Frame

Baseline and weeks 8, 28, 52, 104

Title

Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB)

Description

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Time Frame

Baseline and weeks 8, 28, 52, 104

Title

Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio

Description

Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.

Time Frame

Baseline and weeks 8, 28, 52, 104

Title

Number of Participants With Mean LDL Cholesterol < 100 mg/dL

Description

Missing category for fasting only includes non-fasting participants and the participants with missing values.

Time Frame

Weeks 12 to 28 and 36 to 52

Title

Number of Participants Who Had Achieved Antihypertensive Treatment Goal

Description

Achieved antihypertensive treatment goal was defined as SBP < 130 mmHg and DBP < 80 mmHg over an evaluation period defined as the average of available values in weeks 12 to 28 and 36 to 52.

Time Frame

Weeks 12 to 28 and 36 to 52

Title

Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in SF-36 Physical Component Score (PCS)

Description

Time Frame

Baseline, weeks 12 to 28 and 36 to 52

Title

Change From Baseline to the Average of Weeks 12 to 28 and 36 to 52 in Anemia Subscale (AnS) (Additional Concerns) of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score

Description

Time Frame

Baseline, weeks 12 to 28 and 36 to 52

Title

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Total Score

Description

Time Frame

Baseline, weeks 12 to 28 and 36 to 52

Title

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in FACT-An Trial Outcome Index (TOI) Score

Description

Time Frame

Baseline, weeks 12 to 28 and 36 to 52

Title

Change From Baseline to the Average Value of Weeks 12 to 28 in Euroqol Questionnaire-5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score

Description

Time Frame

Baseline and weeks 12 to 28

Title

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) Score: Percent Work Time Missed

Description

Time Frame

Baseline, weeks 12 to 28 and 36 to 52

Title

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Impairment While Working

Description

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent impairment while working due to problem: Q5/10.

Time Frame

Baseline, weeks 12 to 28 and 36 to 52

Title

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Overall Work Impairment

Description

WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent overall work impairment due to problem: Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4))x(Q5/10)].

Time Frame

Baseline, weeks 12 to 28 and 36 to 52

Title

Change From Baseline to the Average Value of Weeks 12 to 28 and 36 to 52 in WPAI:ANS Score: Percent Activity Impairment

Description

Time Frame

Baseline, weeks 12 to 28 and 36 to 52

Title

Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC)

Description

Time Frame

Weeks 8, 12, 28, 52, 76, 104, last assessment (week 108)

Title

Change From Baseline to Each Scheduled Measurement in Serum Ferritin

Description

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Time Frame

Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and end of study (EOS) (up to 108 weeks)

Title

Change From Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT)

Description

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Time Frame

Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and EOS (up to 108 weeks)

Title

Change From Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c)

Description

Time Frame

Baseline and weeks 12, 28, 36, 44, 60, 84, 104 and EOS (up to 108 weeks)

Title

Change From Baseline to Each Scheduled Measurement in Fasting Blood Glucose

Description

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Time Frame

Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, 106 and EOS (up to 108 weeks)

Title

Change From Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR)

Description

Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Time Frame

Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, 106 and EOS (up to 108 weeks)

Title

Rate of Progression of Chronic Kidney Disease Measured by eGFR Slope Over Time

Description

Time Frame

Baseline up to EOS (up to week 108)

Title

Change From Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR)

Description

Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.

Time Frame

Baseline and weeks 12, 24, 36, 52, 64, 76, 88 and 104

Title

Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline

Description

Time Frame

Year 0.5, 1, 1.5 and 2

Title

Number of Participants With End Stage Renal Disease (ESRD)

Description

Time Frame

Baseline up to EOS (up to week 108)

Title

Time to Chronic Kidney Disease Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death)

Description

Time Frame

Year 0.5, 1, 1.5 and 2

Title

Time to Chronic Dialysis or Renal Transplant or Death

Description

Time Frame

Year 0.5, 1, 1.5 and 2

Title

Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant

Description

Time Frame

Year 0.5, 1, 1.5 and 2

Title

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Description

Time Frame

From first dose of study drug up to end of study (up to week 108)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subject has a diagnosis of CKD, with Kidney Disease Outcomes Quality Initiative (KDOQI) Stage 3, 4 or 5, not on dialysis; with an Estimated Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m^2 estimated using the abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) equation. The mean of the subject's two most recent (prior to randomization) Hb values during the screening period, obtained at least 4 days apart, must be less than or equal to 10.5 g/dL, with a difference of less than or equal to 1.0 g/dL. The last Hb value must be within 10 days prior to randomization. Subject is deemed suitable for treatment with Erythropoiesis Stimulating Agent (ESA) using the criteria specified in the Kidney Disease Improving Global Outcomes (KDIGO) 2012 recommendation considering the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anemia. Subject has a serum folate level greater than or equal to lower limit of normal (LLN) at screening. Subject has a serum vitamin B12 level greater than or equal to LLN at screening. Subject's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are less than or equal to 3 x upper limit of normal (ULN), and total bilirubin (TBL) is less than or equal to 1.5 x ULN. Subject's body weight is 45.0 kg to a maximum of 160.0 kg. Male subject must not donate sperm starting from screening, throughout the study period and up to 12 weeks after final study drug administration. Exclusion Criteria: Subject has received any Erythropoiesis Stimulating Agent (ESA) treatment within 12 weeks prior to randomization. Subject has received any dose of IV iron within 6 weeks prior to randomization. Subject has received a Red Blood Cell (RBC) transfusion within 8 weeks prior to randomization. Subject has a known history of myelodysplastic syndrome or multiple myeloma. Subject has a known hereditary hematologic disease such as thalassemia or sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than Chronic Kidney Disease (CKD). Subject has a known hemosiderosis, hemochromatosis, coagulation disorder, or hypercoagulable condition. Subject has a known chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission. Subject is anticipated to undergo elective surgery that is expected to lead to significant blood loss during the study period or anticipated elective coronary revascularization. Subject has active or chronic gastrointestinal bleeding. Subject has received any prior treatment with roxadustat or a Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Subject has been treated with iron-chelating agents within 4 weeks prior to randomization. Subject has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver). Subject has known New York Heart Association Class III or IV congestive heart failure. Subject has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization. Subject has one or more contraindications for treatment with darbepoetin alfa: Uncontrolled hypertension, or two or more blood pressure values of SBP greater than or equal to 160 mmHg or DBP greater than or equal to 95 mmHg (within 2 weeks prior to randomization). Known hypersensitivity to darbepoetin alfa, recombinant human erythropoietin, or any of the excipients. Subject has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or higher) of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to randomization. Subject has a history of malignancy, except for the following: cancers determined to be cured or in remission for greater than or equal to 5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps. Subject is positive for any of the following: human immunodeficiency virus (HIV). hepatitis B surface antigen (HBsAg). or anti-hepatitis C virus antibody (anti-HCV Ab). Subject has an active clinically significant infection that is manifested by White Blood Count (WBC) > Upper Limit of Normal (ULN), and/or fever, in conjunction with clinical signs or symptoms of infection within one week prior to randomization. Subject has a known untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration or retinal vein occlusion. Subject has had any prior organ transplant (that has not been explanted), subject is scheduled for organ transplantation, or subject is likely to initiate renal replacement therapy including dialysis within the first year of the study. Subject will be excluded from participation if any of the following apply: subject has received investigational therapy within 30 days or 5 half lives or limit set by national law, whichever is longer, prior to initiation of screening, or any condition which makes the subject unsuitable for study participation. Subject has an anticipated use of dapsone in any dose amount or chronic use of acetaminophen/paracetamol >2.0 g/day during the treatment or follow-up period of the study. Subject has a history of alcohol or drug abuse within 2 years prior to randomization

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Monitor

Organizational Affiliation

Astellas Pharma Europe B.V.

Official's Role

Study Director

Facility Information:

Facility Name

Site AT43009

City

Vienna

Country

Austria

Facility Name

Site BY37503

City

Brest

ZIP/Postal Code

224027

Country

Belarus

Facility Name

Site BY37501

City

Grodno

ZIP/Postal Code

230017

Country

Belarus

Facility Name

Site BY37506

City

Minsk

ZIP/Postal Code

220036

Country

Belarus

Facility Name

Site BY37507

City

Minsk

ZIP/Postal Code

220116

Country

Belarus

Facility Name

Site BY37505

City

Minsk

ZIP/Postal Code

223040

Country

Belarus

Facility Name

Site BY37502

City

Vitebsk

ZIP/Postal Code

210037

Country

Belarus

Facility Name

Site BG35907

City

Sofia

ZIP/Postal Code

1113

Country

Bulgaria

Facility Name

Site BG35927

City

Sofia

ZIP/Postal Code

1709

Country

Bulgaria

Facility Name

Site BG35916

City

Varna

ZIP/Postal Code

9000

Country

Bulgaria

Facility Name

Site HR38505

City

Karlovac

ZIP/Postal Code

47000

Country

Croatia

Facility Name

Site HR38504

City

Slavonski Brod

ZIP/Postal Code

35000

Country

Croatia

Facility Name

Site HR38510

City

Zagreb

ZIP/Postal Code

10 000

Country

Croatia

Facility Name

Site HR38502

City

Zagreb

ZIP/Postal Code

10000

Country

Croatia

Facility Name

Site HR38509

City

Zagreb

ZIP/Postal Code

10000

Country

Croatia

Facility Name

Site CZ42018

City

Novy Jicin

State/Province

ZIP/Postal Code

741 01

Country

Czechia

Facility Name

Site CZ42008

City

Liberec

ZIP/Postal Code

46063

Country

Czechia

Facility Name

Site CZ42021

City

Prague

Country

Czechia

Facility Name

Site FI35810

City

Helsinki

ZIP/Postal Code

290

Country

Finland

Facility Name

Site FR33004

City

Avignon

ZIP/Postal Code

84900

Country

France

Facility Name

Site FR33009

City

Colmar

ZIP/Postal Code

68024

Country

France

Facility Name

Site FR33010

City

Grenoble

Country

France

Facility Name

Site FR33062

City

Limoges

ZIP/Postal Code

87042

Country

France

Facility Name

Site FR33012

City

Lyon

ZIP/Postal Code

69437

Country

France

Facility Name

Site FR33007

City

Saint-Priest-en-Jarez

ZIP/Postal Code

42270

Country

France

Facility Name

Site GE99503

City

Tbilisi

ZIP/Postal Code

144

Country

Georgia

Facility Name

Site GE99504

City

Tbilisi

ZIP/Postal Code

144

Country

Georgia

Facility Name

Site GE99502

City

Tbilisi

ZIP/Postal Code

159

Country

Georgia

Facility Name

Site DE49073

City

Cloppenburg

ZIP/Postal Code

49661

Country

Germany

Facility Name

Site DE49054

City

Düsseldorf

ZIP/Postal Code

40210

Country

Germany

Facility Name

Site DE49065

City

Hamburg

ZIP/Postal Code

23397

Country

Germany

Facility Name

Site DE49075

City

Heilbronn

ZIP/Postal Code

74076

Country

Germany

Facility Name

Site DE49057

City

Hoyerswerda

ZIP/Postal Code

02977

Country

Germany

Facility Name

Site HU36028

City

Budapest

ZIP/Postal Code

1097

Country

Hungary

Facility Name

Site HU36029

City

Budapest

Country

Hungary

Facility Name

Site HU36027

City

Kistarcsa

ZIP/Postal Code

2143

Country

Hungary

Facility Name

Site HU36008

City

Pecs

ZIP/Postal Code

H 7624

Country

Hungary

Facility Name

Site HU36046

City

Velence

Country

Hungary

Facility Name

Site IE35301

City

Cork

Country

Ireland

Facility Name

Site IL97202

City

Be'er Ya'akov

ZIP/Postal Code

70300

Country

Israel

Facility Name

Site IL97215

City

Haifa

ZIP/Postal Code

34362

Country

Israel

Facility Name

Site LV37101

City

Riga

ZIP/Postal Code

LV-1002

Country

Latvia

Facility Name

Site LV37104

City

Ventspils

ZIP/Postal Code

LV-3601

Country

Latvia

Facility Name

Site ME38202

City

Niksic

ZIP/Postal Code

81400

Country

Montenegro

Facility Name

Site ME38201

City

Podgorica

ZIP/Postal Code

81000

Country

Montenegro

Facility Name

Site NL31005

City

Utrecht

ZIP/Postal Code

3584 CX

Country

Netherlands

Facility Name

Site MK38901

City

Skopje

ZIP/Postal Code

1000

Country

North Macedonia

Facility Name

Site MK38903

City

Struga

ZIP/Postal Code

6330

Country

North Macedonia

Facility Name

Site PL48001

City

Krakow

ZIP/Postal Code

31-559

Country

Poland

Facility Name

Site PL48066

City

Pulawy

ZIP/Postal Code

24-100

Country

Poland

Facility Name

Site PL48013

City

Szczecin

ZIP/Postal Code

70-111

Country

Poland

Facility Name

Site PL48007

City

Tarnow

ZIP/Postal Code

33-100

Country

Poland

Facility Name

Site PL48004

City

Warszawa

ZIP/Postal Code

04-749

Country

Poland

Facility Name

Site PL48009

City

Wroclaw

Country

Poland

Facility Name

Site PL48059

City

Zamosc

ZIP/Postal Code

22-400

Country

Poland

Facility Name

Site PT35120

City

Almada

ZIP/Postal Code

2801-951

Country

Portugal

Facility Name

Site PT35131

City

Braga

ZIP/Postal Code

4710-243

Country

Portugal

Facility Name

Site PT35112

City

Carnaxide

ZIP/Postal Code

2795-523

Country

Portugal

Facility Name

Site PT35119

City

Evora

ZIP/Postal Code

7000-811

Country

Portugal

Facility Name

Site PT35118

City

Lisboa

ZIP/Postal Code

1069-166

Country

Portugal

Facility Name

Site PT35133

City

Matosinhos

ZIP/Postal Code

4464-513

Country

Portugal

Facility Name

Site PT35122

City

Setubal

ZIP/Postal Code

2910-446

Country

Portugal

Facility Name

Site PT35132

City

Vila Nova de Gaia

ZIP/Postal Code

4434-502

Country

Portugal

Facility Name

Site RO40003

City

Bucharest

ZIP/Postal Code

11234

Country

Romania

Facility Name

Site RO40021

City

Bucharest

ZIP/Postal Code

22328

Country

Romania

Facility Name

Site RO40012

City

Bucuresti

ZIP/Postal Code

10825

Country

Romania

Facility Name

Site RO40004

City

Oradea

ZIP/Postal Code

410469

Country

Romania

Facility Name

Site RU70024

City

Chelyabinsk

ZIP/Postal Code

454047

Country

Russian Federation

Facility Name

Site RU70054

City

Irkutsk

ZIP/Postal Code

664079

Country

Russian Federation

Facility Name

Site RU70047

City

Moscow

ZIP/Postal Code

119992

Country

Russian Federation

Facility Name

Site RU70006

City

Moscow

ZIP/Postal Code

125284

Country

Russian Federation

Facility Name

Site RU70003

City

Nizhny Novgorod

ZIP/Postal Code

603032

Country

Russian Federation

Facility Name

Site RU70004

City

Omsk

ZIP/Postal Code

644112

Country

Russian Federation

Facility Name

Site RU70014

City

Rostov-on-Don

ZIP/Postal Code

344029

Country

Russian Federation

Facility Name

Site RU70011

City

Saint Petersburg

ZIP/Postal Code

196247

Country

Russian Federation

Facility Name

Site RU70002

City

Saint Petersburg

ZIP/Postal Code

197089

Country

Russian Federation

Facility Name

Site RU70060

City

Saratov

ZIP/Postal Code

410039

Country

Russian Federation

Facility Name

Site RU70057

City

Yaroslavl

ZIP/Postal Code

150000

Country

Russian Federation

Facility Name

Site RU70001

City

Yaroslavl

ZIP/Postal Code

150062

Country

Russian Federation

Facility Name

Site RS38102

City

Belgrade

ZIP/Postal Code

11000

Country

Serbia

Facility Name

Site RS38105

City

Belgrade

ZIP/Postal Code

11000

Country

Serbia

Facility Name

Site RS38103

City

Belgrade

ZIP/Postal Code

11080

Country

Serbia

Facility Name

Site RS38104

City

Belgrade

Country

Serbia

Facility Name

Site RS38117

City

Krusevac

ZIP/Postal Code

37000

Country

Serbia

Facility Name

Site RS38101

City

Nis

ZIP/Postal Code

11070

Country

Serbia

Facility Name

Site SK42109

City

Kosice

ZIP/Postal Code

04001

Country

Slovakia

Facility Name

Site SK42102

City

Košice

ZIP/Postal Code

04001

Country

Slovakia

Facility Name

Site SK42113

City

Puchov

ZIP/Postal Code

02001

Country

Slovakia

Facility Name

Site SK42116

City

Senica

ZIP/Postal Code

905 01

Country

Slovakia

Facility Name

Site SI38615

City

Jesenice

ZIP/Postal Code

SI-4270

Country

Slovenia

Facility Name

Site SI38603

City

Maribor

ZIP/Postal Code

2000

Country

Slovenia

Facility Name

Site SI38619

City

Slovenj Gradec

ZIP/Postal Code

SI 2380

Country

Slovenia

Facility Name

Site SI38609

City

Šempeter pri Gorici

ZIP/Postal Code

5290

Country

Slovenia

Facility Name

Site ES34049

City

Ferrol

State/Province

A Coruna

ZIP/Postal Code

15405

Country

Spain

Facility Name

Site ES34026

City

Barcelona

ZIP/Postal Code

08907

Country

Spain

Facility Name

Site ES34039

City

Cordoba

ZIP/Postal Code

14004

Country

Spain

Facility Name

Site ES34054

City

Girona

ZIP/Postal Code

17007

Country

Spain

Facility Name

Site ES34017

City

Jaen

ZIP/Postal Code

23007

Country

Spain

Facility Name

Site ES34037

City

Madrid

ZIP/Postal Code

28046

Country

Spain

Facility Name

Site ES34010

City

Madrid

ZIP/Postal Code

28922

Country

Spain

Facility Name

Site ES34030

City

Majadahonda

ZIP/Postal Code

28222

Country

Spain

Facility Name

Site ES34041

City

Santiago de Compostela

ZIP/Postal Code

15706

Country

Spain

Facility Name

Site UA38009

City

Lviv

State/Province

Lvivska

ZIP/Postal Code

79010

Country

Ukraine

Facility Name

Site UA38021

City

Cherkasy

ZIP/Postal Code

18009

Country

Ukraine

Facility Name

Site UA38006

City

Dnipropetrovsk

ZIP/Postal Code

49005

Country

Ukraine

Facility Name

Site UA38016

City

Ivano-Frankivsk

ZIP/Postal Code

76018

Country

Ukraine

Facility Name

Site UA38011

City

Kharkiv

ZIP/Postal Code

61103

Country

Ukraine

Facility Name

Site UA38017

City

Kiev

ZIP/Postal Code

4053

Country

Ukraine

Facility Name

Site UA38007

City

Mykolaiv

Country

Ukraine

Facility Name

Site UA38008

City

Odessa

ZIP/Postal Code

6500

Country

Ukraine

Facility Name

Site UA38001

City

Ternopil

ZIP/Postal Code

46002

Country

Ukraine

Facility Name

Site UA38018

City

Uzhgorod

ZIP/Postal Code

88018

Country

Ukraine

Facility Name

Site GB44098

City

Dorchester

State/Province

Dorset

ZIP/Postal Code

DT1 2JY

Country

United Kingdom

Facility Name

Site GB44064

City

Birmingham

ZIP/Postal Code

B9 5SS

Country

United Kingdom

Facility Name

Site GB44099

City

Dartford

ZIP/Postal Code

DA2 8DA

Country

United Kingdom

Facility Name

Site GB44102

City

Kings Lynn

ZIP/Postal Code

PE30 4ET

Country

United Kingdom

Facility Name

Site GB44081

City

Leicester

ZIP/Postal Code

LE5 4PW

Country

United Kingdom

Facility Name

Site GB44086

City

London

ZIP/Postal Code

E1 1BB

Country

United Kingdom

Facility Name

Site GB44006

City

London

ZIP/Postal Code

SE5 9RS

Country

United Kingdom

Facility Name

Site GB44082

City

London

ZIP/Postal Code

SW17 0QT

Country

United Kingdom

Facility Name

Site GB44097

City

Nottingham

ZIP/Postal Code

NG5 1PB

Country

United Kingdom

Facility Name

Site GB44100

City

Orpington

ZIP/Postal Code

BR6 8ND

Country

United Kingdom

Facility Name

Site GB44101

City

Preston

ZIP/Postal Code

PR2 9HT

Country

United Kingdom

Facility Name

Site GB44080

City

Stoke-on-Trent

ZIP/Postal Code

ST4 6QG

Country

United Kingdom

Facility Name

Site GB44001

City

Swansea

ZIP/Postal Code

SA6 6NL

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

IPD Sharing Time Frame

Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.

IPD Sharing Access Criteria

Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.

IPD Sharing URL

https://www.clinicalstudydatarequest.com/

Citations:

PubMed Identifier

36005278

Citation

Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.

Results Reference

derived

Links:

URL

https://astellasclinicalstudyresults.com/hcp/study.aspx?ID=401

Description

Link to results on the Astellas Clinical Study Results website.

Learn more about this trial

Roxadustat in the Treatment of Anemia in Chronic Kidney Disease (CKD) Patients, Not on Dialysis, in Comparison to Darbepoetin Alfa

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Roxadustat in the Treatment of Anemia in Chronic Kidney Disease (CKD) Patients, Not on Dialysis, in Comparison to Darbepoetin Alfa (Dolomites)

Anemia in Chronic Kidney Disease in Non-dialysis Patients

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial