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)

Akebia Therapeutics369 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

369

Conditions

Anemia Dialysis-Dependent Chronic Kidney Disease

Interventions

VadadustatDRUG

Oral dose administered once daily for ≥36 weeks. Dose adjustment based on hemoglobin level as defined in the protocol.

Darbepoetin alfaDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (118)

Outcomes

Primary Outcomes

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

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

Secondary Outcomes

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.

Data from ClinicalTrials.gov

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Research Site

Huntsville, Alabama, United States

Research Site

Mesa, Arizona, United States

Research Site

Anaheim, California, United States

Research Site

Canyon Country, California, United States

Research Site

Downey, California, United States

Research Site

Glendale, California, United States

Research Site

Granada Hills, California, United States

Research Site

La Mesa, California, United States

Research Site

Long Beach, California, United States

Research Site

Los Angeles, California, United States

...and 108 more locations

Time frame: Baseline; Weeks 40 to 52

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

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

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

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