Trial Outcomes & Findings for Efficacy and Safety Study to Evaluate Vadadustat for the Correction or Maintenance Treatment of Anemia in Participants With Incident Dialysis-dependent Chronic Kidney Disease (DD-CKD) (NCT NCT02865850)

Last Updated: 2022-07-18

Results Overview

The Baseline average was calculated as the average of the Hb values obtained at the screening visit closest to the date of randomization and the randomization visit. The average for the Primary Efficacy Period was calculated as the average Hb value over Weeks 24 to 36. Analysis was conducted using an analysis of covariance (ANCOVA) model with multiple imputation for missing data with Baseline hemoglobin concentration (\<9.5 versus ≥9.5 g/dL), geographic region (United States \[US\] versus European Union \[EU\] versus Rest of World \[ROW\]), and New York Heart Association congestive heart failure (NYHA CHF) class (Class 0 \[no CHF\] or I versus II or III) as covariates.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

369 participants

Primary outcome timeframe

Baseline; Weeks 24 to 36

Results posted on

2022-07-18

Participant Flow

A total of 652 participants were screened for entry into the study. Of these, 369 participants were enrolled and randomized in the study.

Participant milestones

Participant milestones
Measure	Vadadustat Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Overall Study STARTED	181	188
Overall Study COMPLETED	160	165
Overall Study NOT COMPLETED	21	23

Reasons for withdrawal

Reasons for withdrawal
Measure	Vadadustat Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Overall Study Death	15	19
Overall Study Withdrawal by Subject	3	2
Overall Study Lost to Follow-up	3	2

Baseline Characteristics

Dialysis assessment was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vadadustat n=181 Participants Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa n=188 Participants Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.	Total n=369 Participants Total of all reporting groups
Age, Continuous	56.5 Years STANDARD_DEVIATION 14.80 • n=181 Participants	55.6 Years STANDARD_DEVIATION 14.60 • n=188 Participants	56.0 Years STANDARD_DEVIATION 14.69 • n=369 Participants
Sex: Female, Male Female	74 Participants n=181 Participants	75 Participants n=188 Participants	149 Participants n=369 Participants
Sex: Female, Male Male	107 Participants n=181 Participants	113 Participants n=188 Participants	220 Participants n=369 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=181 Participants	0 Participants n=188 Participants	1 Participants n=369 Participants
Race/Ethnicity, Customized Asian	12 Participants n=181 Participants	8 Participants n=188 Participants	20 Participants n=369 Participants
Race/Ethnicity, Customized Black or African American	38 Participants n=181 Participants	35 Participants n=188 Participants	73 Participants n=369 Participants
Race/Ethnicity, Customized White	129 Participants n=181 Participants	143 Participants n=188 Participants	272 Participants n=369 Participants
Race/Ethnicity, Customized Not Reported	0 Participants n=181 Participants	1 Participants n=188 Participants	1 Participants n=369 Participants
Race/Ethnicity, Customized Reported as Other	0 Participants n=181 Participants	1 Participants n=188 Participants	1 Participants n=369 Participants
Race/Ethnicity, Customized Multiple	1 Participants n=181 Participants	0 Participants n=188 Participants	1 Participants n=369 Participants
Average hemoglobin	9.369 Grams per deciliter (g/dL) STANDARD_DEVIATION 1.0701 • n=181 Participants	9.190 Grams per deciliter (g/dL) STANDARD_DEVIATION 1.1381 • n=188 Participants	9.278 Grams per deciliter (g/dL) STANDARD_DEVIATION 1.1074 • n=369 Participants
Number of Participants on Different Types of Dialysis Peritoneal Dialysis	22 Participants n=179 Participants • Dialysis assessment was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.	16 Participants n=186 Participants • Dialysis assessment was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.	38 Participants n=365 Participants • Dialysis assessment was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.
Number of Participants on Different Types of Dialysis Hemodialysis	158 Participants n=179 Participants • Dialysis assessment was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.	169 Participants n=186 Participants • Dialysis assessment was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.	327 Participants n=365 Participants • Dialysis assessment was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.
Number of Participants on Different Types of Dialysis Chronic Dialysis Not Previously Initiated	1 Participants n=179 Participants • Dialysis assessment was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.	1 Participants n=186 Participants • Dialysis assessment was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.	2 Participants n=365 Participants • Dialysis assessment was summarized in the Safety Population (INNO2VATE) which included all participants from the INNO2VATE population who received 1 or more doses of study drug.
Mean Years Since Chronic Dialysis Initiated	0.138 Years STANDARD_DEVIATION 0.0883 • n=179 Participants • Participants with missing chronic dialysis initiation date were not included for the analysis.	0.151 Years STANDARD_DEVIATION 0.2848 • n=186 Participants • Participants with missing chronic dialysis initiation date were not included for the analysis.	0.145 Years STANDARD_DEVIATION 0.2123 • n=365 Participants • Participants with missing chronic dialysis initiation date were not included for the analysis.
Number of Participants with History of Diabetes	81 Participants n=181 Participants	82 Participants n=188 Participants	163 Participants n=369 Participants
Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class 0	129 Participants n=181 Participants	126 Participants n=188 Participants	255 Participants n=369 Participants
Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class I	30 Participants n=181 Participants	35 Participants n=188 Participants	65 Participants n=369 Participants
Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class II	18 Participants n=181 Participants	23 Participants n=188 Participants	41 Participants n=369 Participants
Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class III	3 Participants n=181 Participants	4 Participants n=188 Participants	7 Participants n=369 Participants
Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class IV	0 Participants n=181 Participants	0 Participants n=188 Participants	0 Participants n=369 Participants
Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class Missing	1 Participants n=181 Participants	0 Participants n=188 Participants	1 Participants n=369 Participants
Number of Participants with Any History of Heart Failure Yes	16 Participants n=181 Participants	15 Participants n=188 Participants	31 Participants n=369 Participants
Number of Participants with Any History of Heart Failure No	54 Participants n=181 Participants	62 Participants n=188 Participants	116 Participants n=369 Participants
Number of Participants with Any History of Heart Failure Missing	111 Participants n=181 Participants	111 Participants n=188 Participants	222 Participants n=369 Participants

PRIMARY outcome

Timeframe: Baseline; Weeks 24 to 36

Population: Randomized Population: All participants randomized. Analyses of this population were based on the randomized treatment.

Outcome measures

Outcome measures
Measure	Vadadustat n=181 Participants Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa n=188 Participants Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Change From Baseline in Hemoglobin (Hb) to the Average Over the Primary Efficacy Period (Weeks 24 to 36)	1.26 Grams per deciliter (g/dL) Standard Error 0.109	1.58 Grams per deciliter (g/dL) Standard Error 0.108

PRIMARY outcome

Timeframe: Up to 176 weeks

Population: Safety Population (INNO2VATE): All participants from the INNO2VATE population who received 1 or more doses of study drug. Only those participants with MACE events were analyzed for this outcome measure.

MACE was defined as all-cause mortality, non-fatal myocardial infarction (MI), or non-fatal stroke. The primary safety outcome was positively adjudicated first MACE, which was defined as any death, Endpoint Adjudication Committee (EAC)-confirmed non-fatal MI, or EAC-confirmed non-fatal stroke occurring between the first dose date and each participant's last participation date. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0016 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.

Outcome measures

Outcome measures
Measure	Vadadustat n=22 Participants Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa n=24 Participants Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Median Time to First Major Adverse Cardiovascular Event (MACE)	26.21 Weeks Interval 13.71 to 50.0	46.64 Weeks Interval 22.86 to 58.14

SECONDARY outcome

Timeframe: Baseline; Weeks 40 to 52

Population: Randomized Population. Analyses of this population were based on the randomized treatment.

The Baseline average was calculated as the average of the Hb values obtained at the screening visit closest to the date of randomization and the randomization visit. The average for the Secondary Efficacy Period was calculated as the average Hb value over Weeks 40 to 52. Analysis was conducted using an ANCOVA model with multiple imputation for missing data with Baseline hemoglobin concentration (\<9.5 versus ≥9.5 g/dL), geographic region (US versus EU versus ROW), and NYHA CHF class (Class 0 \[no CHF\] or I versus II or III) as covariates.

Outcome measures

Outcome measures
Measure	Vadadustat n=181 Participants Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa n=188 Participants Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Change From Baseline in Hb to the Average Over the Secondary Efficacy Period (Weeks 40 to 52)	1.42 g/dL Standard Error 0.132	1.50 g/dL Standard Error 0.136

SECONDARY outcome

Timeframe: Up to 176 weeks

Population: Safety Population (INNO2VATE). Only those participants with MACE plus hospitalization for heart failure or thromboembolic event excluding vascular access thrombosis were analyzed for this outcome measure.

MACE was defined as all-cause mortality, non-fatal MI, or non-fatal stroke. Hospitalization for EAC adjudicated heart failure included presentation of participants to an acute care facility requiring an overnight hospitalization (change in calendar day) with an exacerbation of heart failure requiring treatment. EAC confirmed thromboembolic events for this secondary outcome measure included arterial thrombosis, deep vein thrombosis, and pulmonary embolism. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0016 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.

Outcome measures

Outcome measures
Measure	Vadadustat n=29 Participants Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa n=31 Participants Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Median Time to First MACE Plus Hospitalization for Heart Failure or Thromboembolic Event Excluding Vascular Access Thrombosis	27.14 Weeks Interval 14.14 to 46.14	47.00 Weeks Interval 21.86 to 61.57

SECONDARY outcome

Timeframe: Up to 176 weeks

Population: Safety Population (INNO2VATE). Only those participants with cardiovascular MACE events were analyzed for this outcome measure.

MACE was defined as all-cause mortality, non-fatal MI, or non-fatal stroke. Cardiovascular MACE analysis differed from the primary MACE endpoint as it included only deaths adjudicated by the EAC as cardiovascular deaths (i.e, only EAC-confirmed cardiovascular deaths) in addition to first events of non-fatal MI or non-fatal stroke. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0016 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.

Outcome measures

Outcome measures
Measure	Vadadustat n=16 Participants Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa n=14 Participants Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Median Time to First Cardiovascular MACE	18.50 Weeks Interval 11.29 to 34.43	54.07 Weeks Interval 35.29 to 67.0

SECONDARY outcome

Timeframe: Up to 176 weeks

Population: Safety Population (INNO2VATE). Only those participants with cardiovascular death were analyzed for this outcome measure.

Cardiovascular death included EAC adjudicated fatal MI, pump failure, sudden death, presumed sudden death, fatal stroke, fatal pulmonary embolism, cardiovascular procedure-related death, other cardiovascular death, and presumed cardiovascular death. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0016 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.

Outcome measures

Outcome measures
Measure	Vadadustat n=9 Participants Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa n=10 Participants Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Median Time to First Cardiovascular Death	22.00 Weeks Interval 12.71 to 33.14	58.14 Weeks Interval 21.86 to 67.57

SECONDARY outcome

Timeframe: Up to 176 weeks

Population: Safety Population (INNO2VATE). Only those participants with all-cause mortality were analyzed for this outcome measure.

Only events that were positively adjudicated and confirmed by the EAC were included in the MACE analyses. INNOVATE MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Results and statistical analysis from study AKB-6548-CI-0016 has been reported in below table and under section "Statistical Analysis 1". Results and statistical analysis of the pooled data from studies AKB-6548-CI-0016 and AKB-6548-CI-0017 has been reported under section "Statistical Analysis 2" of this outcome measure.

Outcome measures

Outcome measures
Measure	Vadadustat n=15 Participants Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa n=20 Participants Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Median Time to First All-cause Mortality	31.71 Weeks Interval 13.71 to 62.0	45.36 Weeks Interval 21.57 to 58.14

Serious events: 89 serious events

Other events: 79 other events

Deaths: 15 deaths

Darbepoetin Alfa

Serious events: 105 serious events

Other events: 83 other events

Deaths: 20 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trial Information Desk

Akebia Therapeutics, Inc.

Phone: +1 617-844-6128

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Vadadustat n=179 participants at risk Participants were randomized to receive Vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, Vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements to maintain target Hb levels.	Darbepoetin Alfa n=186 participants at risk Participants were randomized to Darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult participants with chronic kidney disease on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Vascular disorders Hypertension	15.1% 27/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	12.9% 24/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Gastrointestinal disorders Diarrhoea	10.1% 18/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	9.1% 17/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Gastrointestinal disorders Nausea	7.8% 14/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	7.0% 13/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Infections and infestations Urinary tract infection	5.0% 9/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	8.6% 16/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Injury, poisoning and procedural complications Procedural hypotension	6.1% 11/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	6.5% 12/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.3% 13/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	5.4% 10/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Gastrointestinal disorders Vomiting	7.3% 13/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	4.8% 9/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Vascular disorders Hypotension	2.8% 5/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	8.6% 16/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Injury, poisoning and procedural complications Dialysis related complication	4.5% 8/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	5.9% 11/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Nervous system disorders Headache	4.5% 8/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	5.9% 11/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Infections and infestations Nasopharyngitis	5.6% 10/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	4.3% 8/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Injury, poisoning and procedural complications Fall	5.6% 10/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	4.3% 8/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Gastrointestinal disorders Constipation	1.7% 3/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	7.0% 13/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Respiratory, thoracic and mediastinal disorders Cough	6.1% 11/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	2.7% 5/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.
Skin and subcutaneous tissue disorders Pruritus	1.1% 2/179 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.	5.4% 10/186 • Up to 176 weeks Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported in study AKB-6548-CI-0016 (NCT02865850). Of the participants randomized, 365 participants were included in the Safety population (179 and 186 participants in the Vadadustat and Darbepoetin alfa treatment groups, respectively). Four randomized participants did not receive treatment.