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Study to Evaluate Vadadustat for the Correction of Anemia in Participants With Non-dialysis-dependent Chronic Kidney Disease

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ClinicalTrials.gov Identifier: NCT02648347
Recruitment Status : Completed
First Posted : January 7, 2016
Results First Posted : June 27, 2022
Last Update Posted : June 27, 2022
Sponsor:
Information provided by (Responsible Party):
Akebia Therapeutics

Study Description
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Brief Summary:
A multicenter, randomized, open-label, active-controlled Phase 3 study for the correction of anemia and maintenance of hemoglobin (Hb) in participants with Non-Dialysis-Dependent Chronic Kidney Disease (NDD-CKD)

Condition or disease Intervention/treatment Phase
Anemia Non-Dialysis-Dependent Chronic Kidney Disease Drug: Vadadustat Drug: Darbepoetin alfa Phase 3

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 of anemia and maintenance of Hb in participants with NDD-CKD
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1751 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Sponsor was blinded during the study
Primary Purpose: Treatment
Official Title: Phase 3, Randomized, Open-Label, Active-Controlled Study Evaluating the Efficacy and Safety of Oral Vadadustat for the Correction of Anemia in Subjects With Non-Dialysis-Dependent Chronic Kidney Disease (NDD-CKD) (PRO2TECT-CORRECTION)
Actual Study Start Date : December 2015
Actual Primary Completion Date : June 4, 2020
Actual Study Completion Date : July 31, 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Vadadustat 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
Active Comparator: Darbepoetin alfa 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.
Other Name: Aranesp


Outcome Measures
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Primary Outcome Measures :
  1. 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 Hb concentration (<9.5 versus ≥9.5 grams per deciliter [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.

  2. Median Time to First Major Adverse Cardiovascular Event (MACE) [ Time Frame: Up to Week 208 ]
    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. PROTECT MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0014 (NCT02648347) and AKB-6548-CI-0015 (NCT02680574). Results and statistical analysis from study AKB-6548-CI-0014 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-0014 and AKB-6548-CI-0015 has been reported under section "Statistical Analysis 2" of this outcome measure.


Secondary Outcome Measures :
  1. 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 Hb 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.

  2. Median Time to First MACE Plus Hospitalization for Heart Failure or Thromboembolic Event Excluding Vascular Access Thrombosis [ Time Frame: Up to Week 208 ]
    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. PROTECT MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0014 (NCT02648347) and AKB-6548-CI-0015 (NCT02680574). Results and statistical analysis from study AKB-6548-CI-0014 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-0014 and AKB-6548-CI-0015 has been reported under section "Statistical Analysis 2" of this outcome measure.

  3. Median Time to First Cardiovascular MACE [ Time Frame: Up to Week 208 ]
    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. PROTECT MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0014 (NCT02648347) and AKB-6548-CI-0015 (NCT02680574). Results and statistical analysis from study AKB-6548-CI-0014 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-0014 and AKB-6548-CI-0015 has been reported under section "Statistical Analysis 2" of this outcome measure.

  4. Median Time to First Cardiovascular Death [ Time Frame: Up to Week 208 ]
    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. PROTECT MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0014 (NCT02648347) and AKB-6548-CI-0015 (NCT02680574). Results and statistical analysis from study AKB-6548-CI-0014 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-0014 and AKB-6548-CI-0015 has been reported under section "Statistical Analysis 2" of this outcome measure.

  5. Median Time to First All-cause Mortality [ Time Frame: Up to Week 208 ]
    Only events that were positively adjudicated and confirmed by the EAC were included in the MACE analyses. PROTECT MACE results and analysis, by design, was performed on pooled data from studies AKB-6548-CI-0014 (NCT02648347) and AKB-6548-CI-0015 (NCT02680574). Results and statistical analysis from study AKB-6548-CI-0014 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-0014 and AKB-6548-CI-0015 has been reported under section "Statistical Analysis 2" of this outcome measure.


Other Outcome Measures:
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. Exploratory - Proportion of Participants With an Hb Increase of >1.0 g/dL From Baseline Visit [ Time Frame: Baseline; up to Week 52 ]
  6. Exploratory - Time to Achieve Hb Increase of >1.0 g/dL From Baseline Visit [ Time Frame: Baseline; up to Week 52 ]
  7. 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 ]
  8. Exploratory - Mean Monthly Dose of Intravenous (IV) Elemental Iron Administered in Participants Who Have Received IV Iron [ Time Frame: Up to Week 52 ]
  9. Exploratory - Proportion of Participants Receiving IV Iron Therapy [ Time Frame: Up to Week 52 ]
  10. Exploratory - Proportion of Participants Receiving Red Blood Cells (RBCs) Transfusion(s) [ Time Frame: Up to Week 52 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ≥18 years of age
  • Diagnosis of chronic kidney disease (CKD) with an estimated glomerular filtration rate ≤60 milliliters per minute per 1.73 square meter (mL/min/1.73 m^2) at Screening and not expected to start dialysis within 6 months of Screening
  • Mean Screening hemoglobin <10.0 grams per deciliter (g/dL)
  • Serum ferritin ≥100 nanograms per milliliter (ng/mL) and transferrin saturation (TSAT) ≥20% during Screening

Exclusion Criteria:

  • Anemia due to a cause other than CKD or participants with active bleeding or recent blood loss
  • Red blood cell transfusion within 8 weeks prior to randomization.
  • Any erythropoietic stimulating agent within 8 weeks prior to randomization
  • Uncontrolled hypertension
  • 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 Darbepoetin or Vadadustat or to any of their excipients
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02648347


Locations
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Sponsors and Collaborators
Akebia Therapeutics
Investigators
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Study Director: Chief Medical Officer Akebia Therapeutics Inc.
  Study Documents (Full-Text)

Documents provided by Akebia Therapeutics:
Study Protocol  [PDF] February 26, 2019
Statistical Analysis Plan  [PDF] January 29, 2020

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Akebia Therapeutics
ClinicalTrials.gov Identifier: NCT02648347    
Other Study ID Numbers: AKB-6548-CI-0014
2015-004265-81 ( EudraCT Number )
First Posted: January 7, 2016    Key Record Dates
Results First Posted: June 27, 2022
Last Update Posted: June 27, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Akebia Therapeutics:
Vadadustat
AKB-6548
Chronic kidney disease
anemia
CKD
chronic renal insufficiency
renal impairment
erythropoietin
kidney
renal
oral anemia treatment
 hemoglobin
hypoxia-inducible factor
HIF
hypoxia-inducible factor prolyl-hydroxylase inhibitor
HIF-PHI
efficacy
safety
Phase 3
cardiovascular
NDD-CKD
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Anemia
Hematologic Diseases
 Urologic Diseases
Renal Insufficiency
Darbepoetin alfa
Hematinics