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Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis (ALPS)

Primary Purpose

Anemia in Chronic Kidney Disease in Non-dialysis Patients

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Roxadustat

Placebo

About this trial

This is an interventional treatment trial for Anemia in Chronic Kidney Disease in Non-dialysis Patients focused on measuring anemia, chronic kidney disease (CKD), Hemoglobin (Hb), non-dialysis

Eligibility Criteria

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

Inclusion criteria:

Participant has a diagnosis of chronic kidney disease, with Kidney Disease Outcomes Quality Initiative (KDOQI) Stage 3, 4 or 5, not receiving 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 Participant's three most recent Hb values during the Screening period, obtained at least 4 days apart, must be less than or equal to 10.0 g/dL, with a difference of less than or equal to 1.0 g/dL between the highest and the lowest values. The last Hb value must be within 10 days prior to randomization.
Participant has a ferritin level greater than or equal to 30 ng/mL (greater than or equal to 67.4 pmol/L) at screening.
Participant has a transferrin saturation (TSAT) level greater than or equal to 5% at screening.
Participant has a serum folate level greater than or equal to lower limit of normal at screening.
Participant has a serum vitamin B12 level greater than or equal to lower limit of normal at screening.
Participant's alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels 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.
Participant's body weight is 45.0 kg up to a maximum of 160.0 kg.

Exclusion criteria:

Participant has received any ESA treatment within 12 weeks prior to randomization.
Participant has had more than one dose of IV iron within 12 weeks prior to randomization.
Participant has received a RBC transfusion within 8 weeks prior to randomization.
Participant has a known history of myelodysplastic syndrome or multiple myeloma.
Participant 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 CKD.
Participant has a known hemosiderosis, hemochromatosis, coagulation disorder, or hypercoagulable condition.
Participant has chronic inflammatory disease that could impact erythropoiesis (e.g., systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission.
Participant is anticipated to have elective surgery that is expected to lead to significant blood loss or anticipated elective coronary revascularization.
Participant has active or chronic gastrointestinal bleeding.
Participant has received any prior treatment with roxadustat or a hypoxia-inducible factor Prolyl Hydroxylase Inhibitor (HIF-PHI).
Participant has been treated with iron-chelating agents within 4 weeks prior to randomization.
Participant has a history of chronic liver disease (e.g., cirrhosis or fibrosis of the liver)
Participant has a known New York Heart Association Class III or Intravenous (IV) congestive heart failure.
Participant has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thromboembolic event (e.g., pulmonary embolism) within 12 weeks prior to randomization.
Uncontrolled hypertension or two or more blood pressure (BP) values of systolic BP (SBP) greater than or equal to 160 mmHg or diastolic BP (DBP) greater than or equal to 95 mmHg confirmed by repeat measurement within 2 weeks prior to randomization.
Participant has a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category 2F or higher) of renal cell carcinoma on renal ultrasound within 12 weeks prior to randomization.
Participant has a history of malignancy, except 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.
Participant 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).
Participant has an active clinically significant infection manifested by White Blood Count (WBC) > ULN, and/or fever, in conjunction with clinical signs or symptoms of infection within one week prior to randomization.
Participant has a known untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration and retinal vein occlusion.
Participant has had any prior organ transplant (that has not been explanted) or a scheduled organ transplantation.
Participant has participated in any interventional clinical study or has been treated with any investigational drugs within 30 days or 5 half lives or limit set by national law, whichever is longer, prior to the initiation of Screening.
Participant 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.
Participant 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

Placebo Comparator

Arm Label

Roxadustat

Placebo

Arm Description

Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg 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 and Hb increase from baseline (BL) 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 for at least 52 weeks up to a maximum of 104 weeks.

Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg 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 and Hb increase from baseline (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.

Outcomes

Primary Outcome Measures

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

Hemoglobin (Hb) response was measured as Yes or No. Response Yes (responders) 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 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, erythropoiesis-stimulating agent (ESA), or intravenous (IV) iron prior to Hb response. This was the primary efficacy endpoint for EU (EMA).

Hb Change From Baseline (BL) to the Average Hb in Weeks 28-52 Regardless of Rescue Therapy

The change from baseline to the average Hb values across weeks 28 to 52 without having received rescue therapy. The Hb values from visit windows at weeks 28, 32, 36, 40, 44, 48 and 52 were used for the calculation of the average of weeks 28 to 52. This was the primary efficacy endpoint for US (FDA).

Secondary Outcome Measures

Hb Change From BL to the Average Hb in Weeks 28-36 Without Having Received Rescue Therapy Within 6 Weeks Prior to and During 8-Week Evaluation Period

The Hb values from visit windows at weeks 28, 32 and 36 were used for the calculation of the average of weeks 28 to 36.

Change From BL in Low-Density Lipoprotein (LDL) Cholesterol (Regardless of Fasting Status) to the Average LDL Cholesterol of Weeks 12 to 28

Analysis was completed on all values collected on day 1 and weeks 12, 20 and 28.

Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron)

The time to first use of rescue therapy was calculated (in years) as: (First event date - Analysis date of first dose intake + 1) / 365.25. The First event date was defined as Date of first dose of rescue medication during the efficacy emergent period and Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1. The Efficacy Emergent Period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or the end of treatment (EOT) visit, whichever occurred first. Data reported was analysed by Kaplan-Meier estimate for cumulative proportion. Medication onset date was the date of the first use of rescue medication.

Change From BL in Short Form (SF)-36 Vitality (VT) Sub-score to the Average VT Sub-score of Weeks 12 to 28

Change from BL in SF-36 VT sub-score to the average value in weeks 12-28 was calculated using the physical component scores (PCS) of SF-36. The multi-purpose, short-form health survey has 36 questions with an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. The survey measures eight dimensions or scales: (1) physical functioning (PF) (10 items); (2) role limitations due to physical health problems (RP) (3 items); (3) bodily pain (BP) (2 items); (4) social functioning (SF) (2 items); (5) general health perceptions (GH) (5 items); (6) role limitations due to emotional problems (RE) (3 items); (7) vitality, energy or fatigue (VT) (4 items); and (8) mental health (MH) (5 items). The SF-36 scores ranged from 0-100 with higher scores indicating better health status.

Change From BL in SF-36 Physical Functioning (PF) Sub-score to the Average PF Sub-score of Weeks 12 to 28

Change from baseline in SF-36 PF normalized sub-score compared to the average PF sub-score of weeks 12 to 28. The multi-purpose, short-form health survey has 36 questions with an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. Change from baseline in PF sub score of SF-36 to the average of weeks 12-28 was compared by treatment arm for all participants (primary analysis) and in the subsets of participants with baseline PF sub score below 35 and equal or above 35. The SF-36 scores ranged from 0-100 with higher scores indicating better health status. All available SF-36 PF values were used i.e., both scheduled and unscheduled for the calculation of the average PF sub-score of weeks 12 to 28.

Change From BL in Mean Arterial Pressure (MAP) to the Average MAP of Weeks 20 to 28

The MAP was derived for each visit from the average systolic (SBP) and diastolic blood pressure (DBP) calculated for each visit using the three readings and the following equation: MAP = (2/3) * DBP + (1/3) * SBP. Baseline assessment was the assessment on day 1 (average of the three readings). If the baseline assessment was missing, then the latest available value prior to first drug administration was used.

Time to First Occurrence of Hypertension

Occurrence of hypertension was defined as SBP increase from BL ≥20 mmHg and SBP >170 mmHg or DBP increase from BL ≥15 mmHg and DBP ≥110 mmHg. Time to first occurrence of hypertension was defined as first date where SBP criterion or DBP criterion is met, whichever occurred first. Data was analysed using Kaplan-Meier estimate for cumulative proportion.

Rate of Progression of CKD Measured by Annualized Estimated Glomerular Filtration Rate (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 chronic dialysis (acute or chronic) are 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.

Average Level of Hb Over Weeks 28 to 36 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

All scheduled and unscheduled hemoglobin values from weeks 28 to 36 were taken into account for calculating the average values.

Average Level of Hb Over Weeks 44 to 52 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

All scheduled and unscheduled hemoglobin values from weeks 44 to 52 were taken into account for calculating the average values.

Average Level of Hb Over Weeks 96 to 104 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

All scheduled and unscheduled hemoglobin values from weeks 96 to 104 were taken into account for calculating the average values.

Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint

Hb response was measured as Yes or No; Yes 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. For a participant without rescue therapy before Hb response (defined in 1 primary outcome), the time to achieve Hb response was calculated (in weeks) as: (First event date - Analysis date of first dose intake + 1) / 7 where First event date was defined as First date of both values that met the criteria for response. Participants who discontinued or received rescue therapy prior to the first Hb response or before the second consecutive Hb value defined as a response were classified as non responders and were censored at week 24 or end of efficacy emergent period, whichever came first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Hb Change From BL to Each Post-Dosing Time Point

All scheduled and unscheduled hemoglobin values that belong to each visit window were taken into account using one value per analysis window. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose).

Hb Change From BL to the Average Hb Value of Weeks 28-36 Regardless of the Use of Rescue Therapy

The Hb values from visit windows from weeks 28 to 36 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing).

Hb Change From BL to the Average Hb Value of Weeks 44-52 Regardless of the Use of Rescue Therapy

The Hb values from visit windows from weeks 44 to 52 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing).

Hb Change From BL to the Average Hb Value of Weeks 96-104 Regardless of the Use of Rescue Therapy

The Hb values from visit windows from weeks 96 to 104 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing).

Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 28-36 Without Use of Rescue Therapy

The percentage of Hb values measured during weeks 28-36 within 10.0 -12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported.

Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 44-52 Without Use of Rescue Therapy

The percentage of Hb values measured during weeks 44-52 with values within 10.0 - 12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported.

Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 96-104 Without Use of Rescue Therapy

The percentage of Hb values measured during weeks 96-104 within 10.0 -12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported.

Time to First Hospitalization

Time to first hospitalization was defined in years as the First event date during the Efficacy Emergent Period - (Analysis date of first dose intake +1)/365.25. The first event date was defined as the Date of first admission. The Efficacy Emergent Period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. Analysis date of first dose intake was defined as the date of first study drug intake collected on day 1 visit. For participants who experienced more than one hospitalization, only their first event following study treatment was used. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Number of Days of Hospitalization Per Patient Exposure Year (PEY)

The sum of the durations of all hospitalizations in days was adjusted for the duration of exposure. Derived only for participants with at least one hospitalization. The number of days of hospitalization per PEY was calculated as the sum of the durations of all hospitalizations in days [Minimum (Date of discharge, End of Efficacy Emergent Period) - Date of admission + 1] / [Duration of Efficacy Emergent Period in days / 365.25]. Participants can have more than one hospitalization.

Time to First Use of Rescue Therapy (Composite of RBC, Transfusions, ESA Use, and IV Iron) in the First 24 Weeks of Treatment

Time to first use of rescue therapy in years. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Time to First Use of RBC Transfusions

Time to First Use of RBC Transfusions during efficacy emergent period. For participants who have experienced more than one RBC transfusion, only their first event following study treatment was used. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Mean Monthly Number of RBC Packs

During efficacy emergent period, the mean monthly number of RBC packs was calculated as the sum of units transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. In case of missing number of packs, values were estimated based on 1 unit for packed cells = 250 mL or 1 unit for whole blood = 500 mL. Participants without RBC transfusion were included with a value of zero. No estimation if values were missing.

Mean Monthly Volume of Blood Transfused

During efficacy emergent period, the mean monthly volume of blood transfused was calculated as the sum of blood volume transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occurred first. The mean monthly volume transfused was calculated as the sum of the volume transfused between the first dose and up to the last dose in the period divided by duration (in days) and multiplied by 28 days. Participants without RBC transfusion were included with a value of zero.

Time to First Use of ESA Rescue Therapy

Time to First Use of ESA Rescue Therapy during efficacy emergent period. For participants with use of ESA, the time to first use of ESA was calculated as (First event date - Analysis date of first dose intake + 1) / 365.25. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. Participants without ESA rescue were censored at the end of treatment.

Time to First Use of IV Iron

Time to first use of IV iron during efficacy emergent period in years. For participants with use of IV iron, the time to first use of IV iron was calculated as (First event date - Analysis date of first dose intake + 1) / 365.25. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occurred first.Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Change From BL to Each Post-Dosing Visit in Total Cholesterol

Change from baseline to each planned assessment for total cholesterol is reported. Baseline was defined as the value on day 1. If the value was missing, the latest value prior to first study drug administration was used.

Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio

Change from baseline to each planned assessment for LDL/HDL ratio is reported. Baseline was defined as the value on Day 1. If this value was missing, the latest value prior to first study drug administration was used.

Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol

Change from baseline to each planned assessment for non-HDL is reported. Baseline was defined as the value on day 1. If this value was missing, the latest value prior to first study drug administration was used.

Change From BL to Each Post-Dosing Visit in Apolipoproteins A1 (ApoA1)

Change from baseline to each planned assessment for apolipoproteins A1 is reported. Baseline was defined as the value on day 1. If this value was missing, the latest value prior to first study drug administration was used.

Change From BL to Each Post-Dosing Visit in Apolipoproteins B (ApoB)

Change from baseline to each planned assessment for apolipoproteins B is reported. Baseline was defined as the value on day 1. If this value was missing, the latest value prior to first study drug administration was used.

Change From BL to Each Post-Dosing Visit in Ratio ApoB/ApoA1

Change from baseline to each planned assessment for ratio of ApoB/ApoA1 is reported. Baseline was defined as the value on day 1. If this value was missing, the latest value prior to first study drug administration was used.

Percentage of Participants With Mean LDL Cholesterol <100 mg/dL Calculated Over Weeks 12 to 28

Mean LDL cholesterol <100 mg/dL over weeks 12 to 28 was defined as a binary variable (Yes/No), where Yes was defined as mean LDL cholesterol <100 mg/dL over weeks 12 to 28. Participants without any LDL value within this duration were excluded.

Percentage of Participants Who Have Achieved Antihypertensive Treatment Goal in CKD Participants Over Weeks 12-28

Occurrence of achieved antihypertensive treatment goal was defined as the average SBP < 130 mmHg and the average DBP < 80 mmHg over the period of weeks 12-28. Participants without any blood pressure measurement were excluded.

Change From BL to the Average Value of Weeks 12-28 in Quality of Life (QoL) SF-36 Physical Component Score (PCS)

The 36-Item short-form health survey (SF-36) is a multi-purpose survey with 36 questions. It provides an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. For each scale scores range from 0-100. The physical component score was calculated based on the results of the SF-36 scores. Higher scores indicate better health status.

Change From BL to the Average Value of Weeks 12-28 in Anemia Subscale (Ans) of Functional Assessment of Cancer Therapy (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 Anemia Subscale (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. For the above score, a higher score indicates better QoL.

Change From BL to the Average Value of Weeks 12-28 in Total FACT-An Score

Baseline FACT-An Total Score was defined as the FACT-An Total score 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 (PWB) - 7 items, functional (FWB) - 7 items, social/family (SWB) - 7 items, and emotional (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score is obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range is 0-188. A higher score indicates better QoL.

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

The Euroqol Questionnaire - 5 Dimensions 5 Levels (EQ-5D 5L) is a self-reported questionnaire. The EQ-5D 5L is used as a measure of respondents' Health Related Quality of Life (HRQoL). The EQ-5D 5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D 5L descriptive system comprises of 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 answers are labeled 'Best imaginable health state' and 'Worst imaginable health state' with higher scores for higher HRQoL.

Change From BL to the Average Value of Weeks 12-28 in Overall Work Impairment Due to Anaemic Symptoms

Work productivity and activity impairment: anemic symptoms (WPAI:ANS) questionnaire version 2 was used to measure work and activity impairment during the last seven days due to anemia. It is self-assessed questionnaire which consists of 6 questions covering work and daily activities. Questions include asking if participant is working, how many hours the person missed work due to anemic symptoms, how many hours the person missed work due to other reasons, how many hours participant actually worked and how the anemic symptoms impacted their productivity and ability to do daily activities. For the last 2 questions, they were scored from 0-10 with 0 identifying no effect on work and 10 completely prevented from working. Overall work impairment due to ANS was calculated as 100 x Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]. Scores were calculated with the formula to derive the overall work impairment on each timepoints in percentage, and then changes of the percentage from baseline are reported.

Percentage of Participants in Each Category in Patients' Global Impression of Change (PGIC)

The Patients' Global Impression of Change (PGIC) is a participant-rated instrument that measures change in participants overall status on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).

Change From BL to Each Study Visit in Serum Hepcidin

Baseline was assessed on 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 BL to Each Study Visit 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 BL to Each Study Visit in Serum Transferrin Saturation (TSAT)

Baseline was assessed on 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 BL to Each Study Visit in Serum HbA1c Level

HbA1c was measured at each timepoint and presented in 'fraction of 1' unit by dividing the values in percentage by 100, in order to fit for CDISC (Clinical Data Interchange Standards Consortium) standard terminology. Changes from baseline to each timepoint were reported in unit 'fraction of 1'. Baseline was assessed on 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 BL to Each Study Visit in Fasting Blood Glucose

Baseline was assessed on 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 BL to Each Study Visit in Albumin/Creatinine Ratio in Urine

Baseline assessment was the assessment from day 1 visit. If baseline value was missing, value from screening visit was used. In case of missing data, no imputation rules were applied. To compute the geometric mean of albumin/creatinine ratio in urine and associated 95% CI, the mean of log-transformed albumin/creatinine ratio in urine values (ratio) and associated 95% CI are back-transformed to the raw scale. All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis.

Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio

Baseline assessment was the 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. To compute the geometric mean of serum Cr (ratio) and associated 95% CI, the mean of log-transformed serum Cr (ratio) values and associated 95% CI are back-transformed to the raw scale. All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis.

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

The endpoint was defined as time to doubling serum creatinine or chronic dialysis or renal transplant what ever came first. Time to event was defined as (First event date - Analysis date of first dose intake + 1) / 365.25. First event date was defined as date of dialysis or date of renal transplant (whichever occurred first) and analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The data evaluated until the safety emergent period, which was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose, and results were presented for every 6 months up to 2 years.

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

CKD 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. The time to CKD progression was calculated (in years) as (First event date - Analysis date of first dose intake + 1) / 365.25. First event date was defined as first occurrence of serum creatinine being doubled compared with baseline, first occurrence of chronic dialysis or renal transplant, occurrence of participants who died (whichever occurred first). Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The data evaluated until the safety emergent period, which was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose, and results were presented for every 6 months up to 2 years.

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

All eGFR values collected during the safety emergent period are considered, excluding those collected on or after initiation of dialysis (acute or chronic). The First event date was defined as First occurrence of 40% decrease in eGFR from baseline, first occurrence of chronic dialysis or renal transplant (whichever occurred first and Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the analysis date of last dose or end of study (EOS), whichever occurred first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The data evaluated until the safety emergent period, which was defined as the evaluation period from analysis date of first drug intake up to 28 days after the analysis last dose, and results were presented for every 6 months up to 2 years.

Full Information

NCT ID

NCT01887600

First Posted

June 25, 2013

Last Updated

February 7, 2021

Sponsor

Astellas Pharma Europe B.V.

Collaborators

FibroGen

1. Study Identification

Unique Protocol Identification Number

NCT01887600

Brief Title

Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis

Acronym

ALPS

Official Title

A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy and Safety of Roxadustat for the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Completed

Study Start Date

September 3, 2013 (Actual)

Primary Completion Date

November 1, 2017 (Actual)

Study Completion Date

November 1, 2017 (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

This study was conducted to treat anemia in patients with chronic kidney disease. Anemia is a reduced number of red blood cells or hemoglobin. Hemoglobin is important for the transport of oxygen in your blood. The purpose of the study was to see if Roxadustat is both effective and safe as a treatment for anemia in patients with chronic kidney disease.

Detailed Description

The study consisted of three study periods as follows: Screening period: up to 6 weeks Treatment period: minimum 52 weeks (primary treatment period) up to a maximum of 104 weeks (extended treatment period) Post-Treatment Follow-Up period: 4 weeks

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

anemia, chronic kidney disease (CKD), Hemoglobin (Hb), non-dialysis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

594 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Roxadustat

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Roxadustat

Other Intervention Name(s)

ASP1517, FG-4592

Intervention Description

Roxadustat was administered initially according to the tiered weight-based dosing, where participants with weight from ≥ 45 to ≤ 70 kg received 70 mg and participants with > 70 to ≤ 160 kg received 100 mg of roxadustat. Dose-titration based upon regular measurement of Hb levels was performed until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) 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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo was administered initially according to the tiered weight-based dosing, where participants with weight from ≥ 45 to ≤ 70 kg received 70 mg and participants with > 70 to ≤ 160 kg received 100 mg of roxadustat. Dose-titration based upon regular measurement of Hb levels was performed until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) 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.

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Baseline to week 24

Title

Hb Change From Baseline (BL) to the Average Hb in Weeks 28-52 Regardless of Rescue Therapy

Description

Time Frame

Baseline and weeks 28 to 52

Secondary Outcome Measure Information:

Title

Hb Change From BL to the Average Hb in Weeks 28-36 Without Having Received Rescue Therapy Within 6 Weeks Prior to and During 8-Week Evaluation Period

Description

The Hb values from visit windows at weeks 28, 32 and 36 were used for the calculation of the average of weeks 28 to 36.

Time Frame

Baseline and weeks 28 to 36

Title

Change From BL in Low-Density Lipoprotein (LDL) Cholesterol (Regardless of Fasting Status) to the Average LDL Cholesterol of Weeks 12 to 28

Description

Analysis was completed on all values collected on day 1 and weeks 12, 20 and 28.

Time Frame

Baseline and weeks 12 to 28

Title

Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron)

Description

Time Frame

Baseline to week 104 (End of Treatment [EOT])

Title

Change From BL in Short Form (SF)-36 Vitality (VT) Sub-score to the Average VT Sub-score of Weeks 12 to 28

Description

Time Frame

Baseline and weeks 12 to 28

Title

Change From BL in SF-36 Physical Functioning (PF) Sub-score to the Average PF Sub-score of Weeks 12 to 28

Description

Time Frame

Baseline and weeks 12 to 28

Title

Change From BL in Mean Arterial Pressure (MAP) to the Average MAP of Weeks 20 to 28

Description

Time Frame

Baseline and weeks 20 to 28

Title

Time to First Occurrence of Hypertension

Description

Time Frame

Baseline and year 0.5, year 1, year 1.5 and year 2

Title

Rate of Progression of CKD Measured by Annualized Estimated Glomerular Filtration Rate (eGFR) Slope Over Time

Description

Time Frame

Baseline to week 108

Title

Average Level of Hb Over Weeks 28 to 36 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

Description

All scheduled and unscheduled hemoglobin values from weeks 28 to 36 were taken into account for calculating the average values.

Time Frame

Weeks 28 to 36

Title

Average Level of Hb Over Weeks 44 to 52 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

Description

All scheduled and unscheduled hemoglobin values from weeks 44 to 52 were taken into account for calculating the average values.

Time Frame

Weeks 44 to 52

Title

Average Level of Hb Over Weeks 96 to 104 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

Description

All scheduled and unscheduled hemoglobin values from weeks 96 to 104 were taken into account for calculating the average values.

Time Frame

Weeks 96 to 104

Title

Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint

Description

Time Frame

Baseline to week 24

Title

Hb Change From BL to Each Post-Dosing Time Point

Description

Time Frame

Baseline (day 1) 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, 104

Title

Hb Change From BL to the Average Hb Value of Weeks 28-36 Regardless of the Use of Rescue Therapy

Description

Time Frame

Baseline and weeks 28 to 36

Title

Hb Change From BL to the Average Hb Value of Weeks 44-52 Regardless of the Use of Rescue Therapy

Description

Time Frame

Baseline and weeks 44 to 52

Title

Hb Change From BL to the Average Hb Value of Weeks 96-104 Regardless of the Use of Rescue Therapy

Description

Time Frame

Baseline and weeks 96 to 104

Title

Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 28-36 Without Use of Rescue Therapy

Description

The percentage of Hb values measured during weeks 28-36 within 10.0 -12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported.

Time Frame

Baseline and weeks 28 to 36

Title

Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 44-52 Without Use of Rescue Therapy

Description

Time Frame

Baseline and weeks 44 to 52

Title

Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 96-104 Without Use of Rescue Therapy

Description

The percentage of Hb values measured during weeks 96-104 within 10.0 -12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported.

Time Frame

Baseline and weeks 96 to 104

Title

Time to First Hospitalization

Description

Time Frame

Baseline to week 104

Title

Number of Days of Hospitalization Per Patient Exposure Year (PEY)

Description

Time Frame

Baseline to week 104

Title

Time to First Use of Rescue Therapy (Composite of RBC, Transfusions, ESA Use, and IV Iron) in the First 24 Weeks of Treatment

Description

Time to first use of rescue therapy in years. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

Time Frame

Baseline to week 24

Title

Time to First Use of RBC Transfusions

Description

Time Frame

Baseline to week 104

Title

Mean Monthly Number of RBC Packs

Description

Time Frame

Baseline to week 104

Title

Mean Monthly Volume of Blood Transfused

Description

Time Frame

Baseline to week 104

Title

Time to First Use of ESA Rescue Therapy

Description

Time Frame

Baseline to week 104

Title

Time to First Use of IV Iron

Description

Time Frame

Baseline to week 104

Title

Change From BL to Each Post-Dosing Visit in Total Cholesterol

Description

Time Frame