Efficacy and Safety Study to Evaluate Vadadustat for the Maintenance Treatment of Anemia in Participants With Dialysis-dependent Chronic Kidney Disease (DD-CKD)

• ClinicalTrials.gov Identifier: NCT02892149
• Recruitment Status: Completed
• First Posted: September 8, 2016
• Results First Posted: June 28, 2022
• Last Update Posted: June 28, 2022
• Sponsor: Akebia Therapeutics
• Information provided by (Responsible Party): Akebia Therapeutics

Tracking Information

• First Submitted Date: September 2, 2016
• First Posted Date: September 8, 2016
• Results First Submitted Date: April 25, 2022
• Results First Posted Date: June 28, 2022
• Last Update Posted Date: June 28, 2022
• Actual Study Start Date: August 2016
• Actual Primary Completion Date: January 16, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 7, 2022)

• Change From Baseline in Hemoglobin (Hb) to the Average Over the Primary Efficacy Period (Weeks 24 to 36) [ Time Frame: 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 (<10.0 versus ≥10.0 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) [ Time Frame: Up to 170 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-0017 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.

Original Primary Outcome Measures (submitted: September 2, 2016)

• Mean change in hemoglobin between Baseline and the primary evaluation period [ Time Frame: Baseline visit, Week 36 ]
• Major adverse cardiovascular events (MACE), defined as all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke [ Time Frame: from Baseline visit to end of study (event-driven, minimum 1 year) ]

Current Secondary Outcome Measures (submitted: June 7, 2022)

• Change From Baseline in Hb to the Average Over the Secondary Efficacy Period (Weeks 40 to 52) [ Time Frame: 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 (<10.0 versus ≥10.0 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 MACE Plus Hospitalization for Heart Failure or Thromboembolic Event Excluding Vascular Access Thrombosis [ Time Frame: Up to 170 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-0017 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 MACE [ Time Frame: Up to 170 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-0017 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 [ Time Frame: Up to 170 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-0017 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 All-cause Mortality [ Time Frame: Up to 170 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-0017 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.

Original Secondary Outcome Measures (submitted: September 2, 2016)

• Mean change in hemoglobin value between Baseline and the secondary evaluation period [ Time Frame: Baseline visit, Week 52 ]
• Proportion of subjects with mean HGB within the target range during the primary evaluation period [ Time Frame: Baseline visit, Week 36 ]
• AEs and SAEs [ Time Frame: from Baseline visit to end of study (event-driven, minimum 1 year) ]

Current Other Pre-specified Outcome Measures (submitted: June 7, 2022)

• 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 ]
• 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 ]
• 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 ]
• 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 ]
• Exploratory - Proportion of Participants With an Hb Increase of >1.0 g/dL From Baseline Visit [ Time Frame: Baseline; up to Week 52 ]
• Exploratory - Time to Achieve Hb Increase of >1.0 g/dL From Baseline Visit [ Time Frame: 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 [ Time Frame: Baseline; Weeks 24 to 36 ]
• Exploratory - Mean Monthly Dose of Intravenous (IV) Elemental Iron Administered in Participants Who Have Received IV Iron [ Time Frame: Up to Week 52 ]
• Exploratory - Proportion of Participants Receiving IV Iron Therapy [ Time Frame: Up to Week 52 ]
• Exploratory - Proportion of Participants Receiving Red Blood Cells (RBCs) Transfusion(s) [ Time Frame: Up to Week 52 ]

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety Study to Evaluate Vadadustat for the Maintenance Treatment of Anemia in Participants With Dialysis-dependent Chronic Kidney Disease (DD-CKD)
• Official Title: Phase 3, Randomized, Open-Label, Active-Controlled Study Evaluating the Efficacy and Safety of Oral Vadadustat for the Maintenance Treatment of Anemia in Subjects With Dialysis-Dependent Chronic Kidney Disease (DD-CKD) (INNO2VATE-CONVERSION)
• Brief Summary: A multicenter, randomized, open-label, active-controlled Phase 3 study for the maintenance treatment of anemia in participants with 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 maintenance treatment of anemia in participants with DD-CKD
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:

Sponsor was blinded during the study

Primary Purpose: Treatment

Condition

• Anemia
• Dialysis-Dependent Chronic Kidney Disease

Intervention

• Drug: Vadadustat
  Oral dose administered once daily for ≥36 weeks. Dose adjustment based on hemoglobin level as defined in the protocol.
  Other Name: AKB-6548
• Drug: Darbepoetin 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.
  Other Name: Aranesp

Study Arms

• Experimental: Vadadustat
  Intervention: Drug: Vadadustat
• Active Comparator: Darbepoetin alfa
  Intervention: Drug: Darbepoetin alfa

Publications *

• Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.
• Eckardt KU, Agarwal R, Aswad A, Awad A, Block GA, Bacci MR, Farag YMK, Fishbane S, Hubert H, Jardine A, Khawaja Z, Koury MJ, Maroni BJ, Matsushita K, McCullough PA, Lewis EF, Luo W, Parfrey PS, Pergola P, Sarnak MJ, Spinowitz B, Tumlin J, Vargo DL, Walters KA, Winkelmayer WC, Wittes J, Zwiech R, Chertow GM. Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021 Apr 29;384(17):1601-1612. doi: 10.1056/NEJMoa2025956.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 20, 2019): 3554
• Original Estimated Enrollment (submitted: September 2, 2016): 2200
• Actual Study Completion Date: March 30, 2020
• Actual Primary Completion Date: January 16, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• ≥18 years of age
• Receiving chronic maintenance dialysis (either peritoneal or hemodialysis) for end-stage kidney disease for at least 12 weeks prior to Screening
• Currently maintained on erythropoiesis-stimulating agent therapy, with a dose received within 6 weeks prior to or during Screening
• Mean Screening hemoglobin between 8.0 and 11.0 grams per deciliter (g/dL) (inclusive) in the US and between 9.0 and 12.0 g/dL (inclusive) outside of the US
• Serum ferritin ≥100 nanograms per milliliter (ng/mL) and transferrin saturation (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
• Uncontrolled hypertension
• Red blood cell transfusion within 8 weeks prior to randomization
• Anticipated to recover adequate kidney function to no longer require dialysis
• Severe heart failure at Screening (New York Heart Association Class IV)
• Acute coronary syndrome (hospitalization for unstable angina or 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 heart failure, or stroke within 12 weeks prior to or during Screening
• Hypersensitivity to Vadadustat, Darbepoetin alfa, or any of their excipients

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Brazil, Bulgaria, Canada, France, Germany, Israel, Italy, Korea, Republic of, Mexico, Poland, Portugal, Russian Federation, Serbia, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT02892149
• Other Study ID Numbers: AKB-6548-CI-0017; 2016-001360-11 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Akebia Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Akebia Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Chief Medical Officer; Akebia Therapeutics Inc.

• PRS Account: Akebia Therapeutics
• Verification Date: June 2022