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

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).

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).

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.

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

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 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 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.

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.

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.

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.

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

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

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

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.

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).

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).

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).

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).

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.

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.

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 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.

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 in years. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion.

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.

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.

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 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 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 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 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 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 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 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 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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.