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)

Phase 3, Randomized, Open-Label, Active-Controlled Study Evaluating the Efficacy and Safety of Oral Vadadustat for the Correction or Maintenance Treatment of Anemia in Subjects With Incident Dialysis-Dependent Chronic Kidney Disease (DD-CKD) (INNO2VATE - CORRECTION/CONVERSION)

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).

Study Overview

• Status: Completed
• Conditions: Anemia; Dialysis-Dependent Chronic Kidney Disease
• Intervention / Treatment: Drug: Vadadustat; Drug: Darbepoetin alfa

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.

• Study Type: Interventional
• Enrollment (Actual): 369
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, 5000
    • Research Site
  • Corrientes, Argentina, 3400
    • Research Site
  • Salta, Argentina, A4400AXO
    • Research Site
  • San Luis, Argentina, 5700
    • Research Site
  • Buenos Aires
    • Bahia Blanca, Buenos Aires, Argentina, B8001HXM
      • Research Site
    • Ciudad Autonoma Buenos Aires, Buenos Aires, Argentina, C1181ACH
      • Research Site
    • Junin, Buenos Aires, Argentina, 6000
      • Research Site
    • Pergamino, Buenos Aires, Argentina, B2700CPM
      • Research Site
    • Temperley, Buenos Aires, Argentina, 1834
      • Research Site
• Brazil
  • Ceará
    • Fortaleza, Ceará, Brazil, 60430-370
      • Research Site
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150-221
      • Research Site
    • Juiz de Fora, Minas Gerais, Brazil, 36036-330
      • Research Site
  • Paraná
    • Curitiba, Paraná, Brazil, 80010-030
      • Research Site
    • Maringá, Paraná, Brazil, 87060-040
      • Research Site
  • Rio Grande Do Sul
    • Canoas, Rio Grande Do Sul, Brazil, 92425-900
      • Research Site
    • Passo Fundo, Rio Grande Do Sul, Brazil, 99010-080
      • Research Site
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-074
      • Research Site
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
      • Research Site
  • Santa Catarina
    • Joinville, Santa Catarina, Brazil, 89202-050
      • Research Site
  • Sao Paulo
    • Santo André, Sao Paulo, Brazil, 09090-790
      • Research Site
    • São Bernardo do Campo, Sao Paulo, Brazil, 09715-090
      • Research Site
    • São Paulo, Sao Paulo, Brazil, 04039-000
      • Research Site
• Germany
  • Baden Wuerttemberg
    • Villingen-Schwenningen, Baden Wuerttemberg, Germany, 78054
      • Research Site
  • Mecklenburg Vorpommern
    • Rostock, Mecklenburg Vorpommern, Germany, 18057
      • Research Site
  • Nordrhein Westfalen
    • Duesseldorf, Nordrhein Westfalen, Germany, 40210
      • Research Site
• Italy
  • Genova, Italy, 16132
    • Research Site
  • Lecco, Italy, 23900
    • Research Site
  • Napoli, Italy, 80138
    • Research Site
  • Pavia, Italy, 27100
    • Research Site
  • Roma, Italy, 168
    • Research Site
  • Siena, Italy, 53100
    • Research Site
  • Foggia
    • San Giovanni Rotondo, Foggia, Italy, 71013
      • Research Site
• Korea, Republic of
  • Busan, Korea, Republic of, 47392
    • Research Site
  • Seoul, Korea, Republic of, 6591
    • Research Site
  • Seoul, Korea, Republic of, 7345
    • Research Site
  • Gangwon-do
    • Chuncheon, Gangwon-do, Korea, Republic of, 200-702
      • Research Site
  • Gyeonggi-do
    • Seongnam-si,, Gyeonggi-do, Korea, Republic of, 13496
      • Research Site
• Mexico
  • Jalisco
    • Zapopan, Jalisco, Mexico, 45030
      • Research Site
  • Michoacán
    • Morelia, Michoacán, Mexico, 58260
      • Research Site
  • Sinaloa
    • Culiacan, Sinaloa, Mexico, 80230
      • Research Site
• Poland
  • Golub Dobrzyn, Poland, 87-400
    • Research Site
  • Lodz, Poland, 90-153
    • Research Site
  • Lodz, Poland, 92-213
    • Research Site
• Portugal
  • Leiria, Portugal, 2400-441
    • Research Site
  • Loures, Portugal, 2674-514
    • Research Site
• Russian Federation
  • Kemerovo, Russian Federation, 650066
    • Research Site #2
  • Krasnoyarsk, Russian Federation, 660022
    • Research Site
  • Moscow, Russian Federation, 125466
    • Research Site
  • Saint-Petersburg, Russian Federation, 197022
    • Research Site
  • Saint-Petersburg, Russian Federation, 197110
    • Research Site
  • St. Petersburg, Russian Federation, 198205
    • Research Site
  • St. Petersburg, Russian Federation, 199004
    • Research Site
• Ukraine
  • Brovary, Ukraine, 7400
    • Research Site
  • Cherkassy, Ukraine, 18009
    • Research Site
  • Dnipro, Ukraine, 49005
    • Research Site
  • Ivano-Frankivsk, Ukraine, 76008
    • Research Site
  • Kharkiv, Ukraine, 61037
    • Research Site
  • Kyiv, Ukraine, 2125
    • Research Site
  • Mykolaiv, Ukraine, 54058
    • Research Site
  • Ternopil, Ukraine, 46002
    • Research Site
  • Uzhgorod, Ukraine, 88018
    • Research Site
  • Vinnytsia, Ukraine, 21018
    • Research Site
  • Zaporizhzhia, Ukraine, 69600
    • Research Site
  • Zhytomyr, Ukraine, 10002
    • Research Site
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35805
      • Research Site
  • Arizona
    • Mesa, Arizona, United States, 85210
      • Research Site
  • California
    • Anaheim, California, United States, 92801
      • Research Site
    • Canyon Country, California, United States, 91387
      • Research Site
    • Downey, California, United States, 90240
      • Research Site
    • Glendale, California, United States, 91204
      • Research Site
    • Granada Hills, California, United States, 91344
      • Research Site
    • La Mesa, California, United States, 91942
      • Research Site
    • Long Beach, California, United States, 92886
      • Research Site
    • Los Angeles, California, United States, 90022
      • Research Site
    • Montebello, California, United States, 90640
      • Research Site
    • Monterey Park, California, United States, 91754
      • Research Site
    • Newhall, California, United States, 91321
      • Research Site
    • Northridge, California, United States, 91324
      • Research Site #1
    • Northridge, California, United States, 91324
      • Research Site #2
    • Riverside, California, United States, 92505
      • Research Site
    • Riverside, California, United States, 92503
      • Research Site
    • Sacramento, California, United States, 95825
      • Research Site
    • San Diego, California, United States, 92115
      • Research Site
    • San Dimas, California, United States, 91773
      • Research Site
    • Whittier, California, United States, 90603
      • Research Site
  • Colorado
    • Arvada, Colorado, United States, 80002
      • Research Site
    • Westminster, Colorado, United States, 80031
      • Research Site
  • Connecticut
    • Stamford, Connecticut, United States, 06902
      • Research Site
  • Florida
    • Coral Gables, Florida, United States, 33134
      • Research Site
    • Coral Springs, Florida, United States, 33071
      • Research Site
    • Lauderdale Lakes, Florida, United States, 33313
      • Research Site
    • Miami, Florida, United States, 33150
      • Research Site
    • Miami, Florida, United States, 33125
      • Research Site
    • Miami Beach, Florida, United States, 33140
      • Research Site
    • Winter Park, Florida, United States, 32789
      • Research Site
  • Georgia
    • Augusta, Georgia, United States, 30904
      • Research Site
    • Columbus, Georgia, United States, 31904
      • Research Site
    • Lawrenceville, Georgia, United States, 30046
      • Research Site #2
    • Statesboro, Georgia, United States, 30458
      • Research Site
  • Idaho
    • Meridian, Idaho, United States, 83642
      • Research Site
  • Maryland
    • Takoma Park, Maryland, United States, 20912
      • Research Site
  • Michigan
    • Roseville, Michigan, United States, 48066
      • Research Site
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Research Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Research Site
  • New York
    • Astoria, New York, United States, 11102
      • Research Site
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19106
      • Research Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37408
      • Research Site #1
    • Chattanooga, Tennessee, United States, 37408
      • Research Site #2
    • Knoxville, Tennessee, United States, 37923
      • Research Site
    • Nashville, Tennessee, United States, 37205
      • Research Site
  • Texas
    • Arlington, Texas, United States, 76015
      • Research Site
    • El Paso, Texas, United States, 79935
      • Research Site
    • Houston, Texas, United States, 77054
      • Research Site
    • Houston, Texas, United States, 77099
      • Research Site
    • San Antonio, Texas, United States, 78229
      • Research Site
    • San Antonio, Texas, United States, 78212-4740
      • Research Site
  • Virginia
    • Hampton, Virginia, United States, 23666
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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. For participants already on Darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.; Other Names: Aranesp
EXPERIMENTAL: Vadadustat	Drug: Vadadustat; Oral dose administered once daily for ≥36 weeks. Dose adjustment based on hemoglobin level as defined in the protocol.; Other Names: AKB-6548

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	Up to 176 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	Up to 176 weeks

Other Outcome Measures

Outcome Measure	Time Frame
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 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
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 Receiving IV Iron Therapy	Up to Week 52
Exploratory - Proportion of Participants Receiving Red Blood Cells (RBCs) Transfusion(s)	Up to Week 52

Collaborators and Investigators

• Sponsor: Akebia Therapeutics

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2016
• Primary Completion (ACTUAL): January 31, 2020
• Study Completion (ACTUAL): March 30, 2020

Study Registration Dates

• First Submitted: August 8, 2016
• First Submitted That Met QC Criteria: August 10, 2016
• First Posted (ESTIMATE): August 15, 2016

Study Record Updates

• Last Update Posted (ACTUAL): July 18, 2022
• Last Update Submitted That Met QC Criteria: July 14, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: safety; renal; hemoglobin; anemia; chronic kidney disease; CKD; efficacy; erythropoietin; renal impairment; kidney; cardiovascular; chronic renal insufficiency; phase 3; HIF; Vadadustat; AKB-6548; oral anemia treatment; hypoxia-inducible factor
• Additional Relevant MeSH Terms: Urologic Diseases; Hematologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Anemia; Hematinics; Darbepoetin alfa
• Other Study ID Numbers: AKB-6548-CI-0016; 2016-000838-21 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes