Anemia, Dialysis-Dependent Chronic Kidney Disease
Conditions
Keywords
Vadadustat, AKB-6548, anemia, chronic kidney disease, CKD, chronic renal insufficiency, renal impairment, erythropoietin, kidney, renal, oral anemia treatment, hemoglobin, hypoxia-inducible factor, HIF, efficacy, safety, phase 3, cardiovascular
Brief summary
A multicenter, randomized, open-label, active-controlled Phase 3 study for the correction or maintenance treatment of anemia in participants with incident dialysis-dependent chronic kidney disease (DD-CKD).
Detailed description
This is a multicenter, randomized, open-label, active-controlled Phase 3 study of the efficacy and safety of Vadadustat versus Darbepoetin alfa for the correction or maintenance treatment in participants with anemia secondary to chronic kidney disease who have recently initiated dialysis treatment for end-stage renal disease.
Interventions
DRUGVadadustat
Oral dose administered once daily for ≥36 weeks. Dose adjustment based on hemoglobin level as defined in the protocol.
DRUGDarbepoetin alfa
Subcutaneous or intravenous dose administered for ≥36 weeks. Initial dose based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics for all other investigational sites (non-US) for adult participants with chronic kidney disease not on dialysis. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.
Sponsors
Akebia Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Sponsor was blinded during the study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥18 years of age * Initiated chronic maintenance dialysis (either peritoneal or hemodialysis) for end-stage kidney disease within 16 weeks prior to Screening * Mean Screening hemoglobin between 8.0 and \<11.0 grams per deciliter (g/dL) (inclusive) * Serum ferritin ≥100 nanograms per deciliter (ng/mL) and TSAT ≥20% during Screening
Exclusion criteria
* Anemia due to a cause other than chronic kidney disease or participants with active bleeding or recent blood loss * Red blood cells transfusion within 8 weeks prior to randomization * Anticipated to recover adequate kidney function to no longer require dialysis * Uncontrolled hypertension * Severe heart failure at Screening (New York Heart Association Class IV) * Acute coronary syndrome (hospitalization for unstable angina, myocardial infarction); surgical or percutaneous intervention for coronary, cerebrovascular, or peripheral artery disease (aortic or lower extremity); surgical or percutaneous valvular replacement or repair; sustained ventricular tachycardia; hospitalization for congestive heart failure; or stroke within 12 weeks prior to or during Screening. * Participants meeting the criteria of erythropoiesis-stimulating agent resistance within 8 weeks prior to or during Screening defined as follows 1. epoetin: \> 7700 units/dose three times per week or \>23,000 units per week 2. Darbepoetin alfa: \>100 micrograms per week (mcg/week) 3. methoxy polyethylene glycol-epoetin beta: \>100 micrograms (mcg) every other week or \>200 mcg/month * Hypersensitivity to Vadadustat, Darbepoetin alfa or any of their excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin (Hb) to the Average Over the Primary Efficacy Period (Weeks 24 to 36) | Baseline; Weeks 24 to 36 | 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. |
| Median Time to First Major Adverse Cardiovascular Event (MACE) | Up to 176 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to First Cardiovascular MACE | Up to 176 weeks | 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. |
| Change From Baseline in Hb to the Average Over the Secondary Efficacy Period (Weeks 40 to 52) | Baseline; Weeks 40 to 52 | 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. |
| Median Time to First All-cause Mortality | Up to 176 weeks | 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. |
| Median Time to First Cardiovascular Death | Up to 176 weeks | 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. |
| Median Time to First MACE Plus Hospitalization for Heart Failure or Thromboembolic Event Excluding Vascular Access Thrombosis | Up to 176 weeks | 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. |
Other
| Measure | Time frame |
|---|---|
| Exploratory - Mean Monthly Dose of Intravenous (IV) Elemental Iron Administered in Participants Who Have Received IV Iron | Up to Week 52 |
| Exploratory - Proportion of Participants With Hb Values Within the Target Range During the Primary Evaluation Period (Weeks 24 to 36) | Weeks 24 to 36 |
| Exploratory - Proportion of Participants Receiving Red Blood Cells (RBCs) Transfusion(s) | Up to Week 52 |
| Exploratory - Proportion of Participants Receiving IV Iron Therapy | Up to Week 52 |
| Exploratory - Proportion of Time With Hb Values Within the Target Range During the Primary Evaluation Period (Weeks 24 to 36) | Weeks 24 to 36 |
| Exploratory - Proportion of Time With Hb Values Within the Target Range During the Secondary Evaluation Period (Weeks 40 to 52) | Weeks 40 to 52 |
| Exploratory - Proportion of Participants With Hb Values Within the Target Range During the Secondary Evaluation Period (Weeks 40 to 52) | Weeks 40 to 52 |
| Exploratory - Proportion of Participants With an Hb Increase of >1.0 g/dL From Baseline Visit | Baseline; up to Week 52 |
| Exploratory - Time to Achieve Hb Increase of >1.0 g/dL From Baseline Visit | Baseline; up to Week 52 |
| Exploratory - Mean Change in Hb Between Baseline (Mean Pretreatment Hb) and the Primary Evaluation Period (Mean Hb From Weeks 24 to 36) Stratified by Pre-baseline Erythropoiesis-stimulating Agent (ESA) Exposure | Baseline; Weeks 24 to 36 |
Countries
Argentina, Brazil, Germany, Italy, Mexico, Poland, Portugal, Russia, South Korea, Ukraine, United States
Participant flow
Pre-assignment details
A total of 652 participants were screened for entry into the study. Of these, 369 participants were enrolled and randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 181 |
| 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. | 188 |
| Total | 369 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 15 | 19 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Vadadustat | Darbepoetin Alfa | Total |
|---|---|---|---|
| Age, Continuous | 56.5 Years STANDARD_DEVIATION 14.8 | 55.6 Years STANDARD_DEVIATION 14.6 | 56.0 Years STANDARD_DEVIATION 14.69 |
| Average hemoglobin | 9.369 Grams per deciliter (g/dL) STANDARD_DEVIATION 1.0701 | 9.190 Grams per deciliter (g/dL) STANDARD_DEVIATION 1.1381 | 9.278 Grams per deciliter (g/dL) STANDARD_DEVIATION 1.1074 |
| Mean Years Since Chronic Dialysis Initiated | 0.138 Years STANDARD_DEVIATION 0.0883 | 0.151 Years STANDARD_DEVIATION 0.2848 | 0.145 Years STANDARD_DEVIATION 0.2123 |
| Number of Participants on Different Types of Dialysis Chronic Dialysis Not Previously Initiated | 1 Participants | 1 Participants | 2 Participants |
| Number of Participants on Different Types of Dialysis Hemodialysis | 158 Participants | 169 Participants | 327 Participants |
| Number of Participants on Different Types of Dialysis Peritoneal Dialysis | 22 Participants | 16 Participants | 38 Participants |
| Number of Participants with Any History of Heart Failure Missing | 111 Participants | 111 Participants | 222 Participants |
| Number of Participants with Any History of Heart Failure No | 54 Participants | 62 Participants | 116 Participants |
| Number of Participants with Any History of Heart Failure Yes | 16 Participants | 15 Participants | 31 Participants |
| Number of Participants with History of Diabetes | 81 Participants | 82 Participants | 163 Participants |
| Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class 0 | 129 Participants | 126 Participants | 255 Participants |
| Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class I | 30 Participants | 35 Participants | 65 Participants |
| Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class II | 18 Participants | 23 Participants | 41 Participants |
| Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class III | 3 Participants | 4 Participants | 7 Participants |
| Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class IV | 0 Participants | 0 Participants | 0 Participants |
| Number of Participants with NYHA Functional Classification of Heart Failure NYHA Class Missing | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 12 Participants | 8 Participants | 20 Participants |
| Race/Ethnicity, Customized Black or African American | 38 Participants | 35 Participants | 73 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Reported as Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 129 Participants | 143 Participants | 272 Participants |
| Sex: Female, Male Female | 74 Participants | 75 Participants | 149 Participants |
| Sex: Female, Male Male | 107 Participants | 113 Participants | 220 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 179 | 20 / 186 |
| other Total, other adverse events | 79 / 179 | 83 / 186 |
| serious Total, serious adverse events | 89 / 179 | 105 / 186 |
Outcome results
Primary
Change From Baseline in Hemoglobin (Hb) to the Average Over the Primary Efficacy Period (Weeks 24 to 36)
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.
Time frame: Baseline; Weeks 24 to 36
Population: Randomized Population: All participants randomized. Analyses of this population were based on the randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat | 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 |
| Darbepoetin Alfa | Change From Baseline in Hemoglobin (Hb) to the Average Over the Primary Efficacy Period (Weeks 24 to 36) | 1.58 Grams per deciliter (g/dL) | Standard Error 0.108 |
Comparison: Treatment comparison: Vadadustat minus Darbepoetin Alfa95% CI: [-0.53, -0.1]
Primary
Median Time to First Major Adverse Cardiovascular Event (MACE)
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vadadustat | Median Time to First Major Adverse Cardiovascular Event (MACE) | 26.21 Weeks |
| Darbepoetin Alfa | Median Time to First Major Adverse Cardiovascular Event (MACE) | 46.64 Weeks |
Comparison: Statistical analysis from study AKB-6548-CI-0016 has been reported in this section.p-value: =0.99595% CI: [0.536, 1.761]Log Rank
Comparison: MACE analysis was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Time to first MACE for the Vadadustat and Darbepoetin alfa treatment groups was as follows: participants with events = 355 and 377 respectively; median time to first event (Q1, Q3) = 46.14 (24.71, 77.14) weeks versus 47.00 (22.43, 74.43) weeks, respectively. Statistical analysis from the pooled data has been reported in this section.p-value: =0.487795% CI: [0.833, 1.113]Log Rank
Secondary
Change From Baseline in Hb to the Average Over the Secondary Efficacy Period (Weeks 40 to 52)
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.
Time frame: Baseline; Weeks 40 to 52
Population: Randomized Population. Analyses of this population were based on the randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat | 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 |
| Darbepoetin Alfa | Change From Baseline in Hb to the Average Over the Secondary Efficacy Period (Weeks 40 to 52) | 1.50 g/dL | Standard Error 0.136 |
Comparison: Treatment comparison: Vadadustat minus Darbepoetin Alfa95% CI: [-0.34, 0.19]
Secondary
Median Time to First All-cause Mortality
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.
Time frame: Up to 176 weeks
Population: Safety Population (INNO2VATE). Only those participants with all-cause mortality were analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vadadustat | Median Time to First All-cause Mortality | 31.71 Weeks |
| Darbepoetin Alfa | Median Time to First All-cause Mortality | 45.36 Weeks |
Comparison: Statistical analysis from study AKB-6548-CI-0016 has been reported in this section.p-value: =0.511595% CI: [0.388, 1.555]Log Rank
Comparison: MACE analysis was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Time to first all-cause mortality for the Vadadustat and Darbepoetin alfa treatment groups was as follows: participants with events = 291 and 310 respectively; median time to first event (Q1, Q3) = 50.00 (29.71, 79.00) weeks versus 49.57 (25.86, 77.29) weeks, respectively. Statistical analysis from the pooled data has been reported in this section.p-value: =0.487895% CI: [0.812, 1.118]Log Rank
Secondary
Median Time to First Cardiovascular Death
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.
Time frame: Up to 176 weeks
Population: Safety Population (INNO2VATE). Only those participants with cardiovascular death were analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vadadustat | Median Time to First Cardiovascular Death | 22.00 Weeks |
| Darbepoetin Alfa | Median Time to First Cardiovascular Death | 58.14 Weeks |
Comparison: Statistical analysis from study AKB-6548-CI-0016 has been reported in this section.p-value: =0.952795% CI: [0.452, 2.666]Gray's test
Comparison: MACE analysis was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Time to first cardiovascular death for the Vadadustat and Darbepoetin alfa treatment groups was as follows: participants with events = 150 and 160 respectively; median time to first event (Q1, Q3) = 43.71 (27.43, 77.14) weeks versus 49.29 (24.43, 74.07) weeks, respectively. Statistical analysis from the pooled data has been reported in this section.p-value: =0.628495% CI: [0.766, 1.195]Gray's test
Secondary
Median Time to First Cardiovascular MACE
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.
Time frame: Up to 176 weeks
Population: Safety Population (INNO2VATE). Only those participants with cardiovascular MACE events were analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vadadustat | Median Time to First Cardiovascular MACE | 18.50 Weeks |
| Darbepoetin Alfa | Median Time to First Cardiovascular MACE | 54.07 Weeks |
Comparison: Statistical analysis from study AKB-6548-CI-0016 has been reported in this section.p-value: =0.52195% CI: [0.67, 2.771]Gray's test
Comparison: MACE analysis was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Time to first cardiovascular MACE for the Vadadustat and Darbepoetin alfa treatment groups was as follows: participants with events = 225 and 242 respectively; median time to first event (Q1, Q3) = 43.29 (21.71, 77.14) weeks versus 45.79 (21.14, 73.86) weeks, respectively. Statistical analysis from the pooled data has been reported in this section.p-value: =0.500795% CI: [0.795, 1.144]Gray's test
Secondary
Median Time to First MACE Plus Hospitalization for Heart Failure or Thromboembolic Event Excluding Vascular Access Thrombosis
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vadadustat | Median Time to First MACE Plus Hospitalization for Heart Failure or Thromboembolic Event Excluding Vascular Access Thrombosis | 27.14 Weeks |
| Darbepoetin Alfa | Median Time to First MACE Plus Hospitalization for Heart Failure or Thromboembolic Event Excluding Vascular Access Thrombosis | 47.00 Weeks |
Comparison: Statistical analysis from study AKB-6548-CI-0016 has been reported in this section.p-value: =0.887195% CI: [0.618, 1.743]Log Rank
Comparison: MACE analysis was performed on pooled data from studies AKB-6548-CI-0016 (NCT02865850) and AKB-6548-CI-0017 (NCT02892149). Time to first MACE plus hospitalization for heart failure or thromboembolic event Excluding vascular access thrombosis for the Vadadustat and Darbepoetin alfa treatment groups was as follows: participants with events = 420 and 449 respectively; median time to first event (Q1, Q3) = 42.07 (21.50, 71.14) weeks versus 45.29 (22.29, 72.43) weeks, respectively.p-value: =0.409695% CI: [0.84, 1.096]Log Rank
Other Pre-specified
Exploratory - Mean Change in Hb Between Baseline (Mean Pretreatment Hb) and the Primary Evaluation Period (Mean Hb From Weeks 24 to 36) Stratified by Pre-baseline Erythropoiesis-stimulating Agent (ESA) Exposure
Time frame: Baseline; Weeks 24 to 36
Other Pre-specified
Exploratory - Mean Monthly Dose of Intravenous (IV) Elemental Iron Administered in Participants Who Have Received IV Iron
Time frame: Up to Week 52
Other Pre-specified
Exploratory - Proportion of Participants Receiving IV Iron Therapy
Time frame: Up to Week 52
Other Pre-specified
Exploratory - Proportion of Participants Receiving Red Blood Cells (RBCs) Transfusion(s)
Time frame: Up to Week 52
Other Pre-specified
Exploratory - Proportion of Participants With an Hb Increase of >1.0 g/dL From Baseline Visit
Time frame: Baseline; up to Week 52
Other Pre-specified
Exploratory - Proportion of Participants With Hb Values Within the Target Range During the Primary Evaluation Period (Weeks 24 to 36)
Time frame: Weeks 24 to 36
Other Pre-specified
Exploratory - Proportion of Participants With Hb Values Within the Target Range During the Secondary Evaluation Period (Weeks 40 to 52)
Time frame: Weeks 40 to 52
Other Pre-specified
Exploratory - Proportion of Time With Hb Values Within the Target Range During the Primary Evaluation Period (Weeks 24 to 36)
Time frame: Weeks 24 to 36
Other Pre-specified
Exploratory - Proportion of Time With Hb Values Within the Target Range During the Secondary Evaluation Period (Weeks 40 to 52)
Time frame: Weeks 40 to 52
Other Pre-specified
Exploratory - Time to Achieve Hb Increase of >1.0 g/dL From Baseline Visit
Time frame: Baseline; up to Week 52