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

Anemia Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02892149
• Other study ID #: AKB-6548-CI-0017
• Secondary ID: 2016-001360-11
• Status: Completed
• Phase: Phase 3
• Start date: August 2016
• Est. completion date: March 30, 2020

Study information

• Verified date: June 2022
• Source: Akebia Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3554
• Est. completion date: March 30, 2020
• Est. primary completion date: January 16, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Anemia
• Dialysis-Dependent Chronic Kidney Disease
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• Vadadustat
Oral dose administered once daily for =36 weeks. Dose adjustment based on hemoglobin level as defined in the protocol.
• 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.

Locations

Country	Name	City	State
Argentina	Research Site	Ciudad Autonoma Buenos Aires	Buenos Aires
Argentina	Research Site	Cordoba
Argentina	Research Site	Cordoba
Argentina	Research Site	Corrientes
Argentina	Research Site	Junin	Buenos Aires
Argentina	Research Site	Pergamino	Buenos Aires
Argentina	Research Site	Salta
Argentina	Research Site	San Luis
Argentina	Research Site	Sarandi	Buenos Aires
Australia	Research Site	Box Hill	Victoria
Australia	Research Site	Cairns	Queensland
Australia	Research Site	Fitzroy	Victoria
Australia	Research Site	Launceston	Tasmania
Australia	Research Site	Liverpool	New South Wales
Australia	Research Site	Nedlands	Western Australia
Australia	Research Site	New Lambton Heights	New South Wales
Australia	Research Site	Wahroonga	New South Wales
Brazil	Research Site	Belo Horizonte	Minas Gerais
Brazil	Research Site	Belo Horizonte	Minas Gerais
Brazil	Research Site	Canoas	Rio Grande Do Sul
Brazil	Research Site	Criciúma	Santa Catarina
Brazil	Research Site	Curitiba	Paraná
Brazil	Research Site	Feira de Santana	Bahia
Brazil	Research Site	Fortaleza	Ceará
Brazil	Research Site	Itabuna	Bahia
Brazil	Research Site	Joinville	Santa Catarina
Brazil	Research Site	Juiz de Fora	Minas Gerais
Brazil	Research Site	Juiz de Fora	Minas Gerais
Brazil	Research Site	Maringá	Paraná
Brazil	Research Site	Passo Fundo	Rio Grande Do Sul
Brazil	Research Site	Porto Alegre	Rio Grande Do Sul
Brazil	Research Site	Porto Alegre	Rio Grande Do Sul
Brazil	Research Site	Porto Alegre	Rio Grande Do Sul
Brazil	Research Site	Porto Alegre	Rio Grande Do Sul
Brazil	Research Site	Santo André	Sao Paulo
Brazil	Research Site	Santo André	Sao Paulo
Brazil	Research Site	São Bernardo do Campo	Sao Paulo
Brazil	Research Site	São José do Rio Preto	Sao Paulo
Brazil	Research Site	São Paulo	Sao Paulo
Brazil	Research Site	São Paulo	Sao Paulo
Brazil	Research Site	São Paulo	Sao Paulo
Brazil	Research Site	Vitória	Espírito Santo
Bulgaria	Research Site	Byala
Bulgaria	Research Site	Cherven bryag
Bulgaria	Research Site	Dobrich
Bulgaria	Research Site	Dupnitsa
Bulgaria	Research Site	Haskovo
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Ruse
Bulgaria	Research Site	Shumen
Bulgaria	Research Site	Silistra
Bulgaria	Research Site	Sliven
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Varna
Bulgaria	Research Site	Veliko Tarnovo
Bulgaria	Research Site	Vidin
Bulgaria	Research Site	Vratsa
Canada	Research Site	Greenfield Park	Quebec
Canada	Research Site	Halifax	Nova Scotia
Canada	Research Site	Montréal	Quebec
Canada	Research Site	Oshawa	Ontario
Canada	Research Site	Sudbury	Ontario
Canada	Research Site	Sydney	Nova Scotia
France	Research Site	Bordeaux	Gironde
France	Research Site	Marseille	Bouches-du-Rhône
France	Research Site	Paris
France	Research Site	Paris
France	Research Site	Reims	Marne
France	Research Site	Saint-Priest-En-Jarez	Loire
Germany	Research Site	Berlin
Germany	Research Site	Duesseldorf	Nordrhein Westfalen
Germany	Research Site	Rostock	Mecklenburg Vorpommern
Germany	Research Site	Villingen-Schwenningen	Baden Wuerttemberg
Israel	Research Site	Ashkelon
Israel	Research Site	Haifa
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Israel	Research Site	Kfar- Saba
Israel	Research Site	Rishon Lezion
Italy	Research Site	Bari
Italy	Research Site	Genova
Italy	Research Site	Lecco
Italy	Research Site	Pavia
Italy	Research Site	Roma
Italy	Research Site	Siena
Korea, Republic of	Research Site	Bucheon-si	Gyeonggi-do
Korea, Republic of	Research Site	Busan
Korea, Republic of	Research Site	Busan
Korea, Republic of	Research Site	Chuncheon	Gangwon-do
Korea, Republic of	Research Site	Goyang-si	Gyeonggi-do
Korea, Republic of	Research Site	Goyang-si	Gyeonggi-do
Korea, Republic of	Research Site	Guri	Gyeonggi-do
Korea, Republic of	Research Site	Seongnam-si,	Gyeonggi-do
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Suwon-si	Gyeonggi-do
Mexico	Research Site	Culiacan	Sinaloa
Mexico	Research Site	Morelia	Michoacán
Mexico	Research Site	Pachuca	Hidalgo
Mexico	Research Site	Zapopan	Jalisco
Poland	Research Site	Biala Podlaska
Poland	Research Site	Golub Dobrzyn
Poland	Research Site	Kolobrzeg
Poland	Research Site	Lodz
Poland	Research Site	Lodz
Poland	Research Site	Lodz
Poland	Research Site	Warszawa
Portugal	Research Site	Beja
Portugal	Research Site	Leiria
Portugal	Research Site	Loures
Russian Federation	Research Site	Ekaterinburg
Russian Federation	Research Site #2	Kemerovo
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Nizhniy Novgorod
Russian Federation	Research Site	Nizhniy Novgorod
Russian Federation	Research Site	Novorossiysk
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	St. Petersburg
Russian Federation	Research Site	St. Petersburg
Serbia	Research Site #1	Belgrade
Serbia	Research Site #2	Belgrade
Serbia	Research Site #3	Belgrade
Serbia	Research Site #4	Belgrade
Serbia	Research Site	Kragujevac
Serbia	Research Site	Nis
Serbia	Research Site	Zajecar
Ukraine	Research Site	Brovary
Ukraine	Research Site #1	Cherkassy
Ukraine	Research Site	Dnipro
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Mykolaiv
Ukraine	Research Site	Ternopil
Ukraine	Research Site	Uzhgorod
Ukraine	Research Site	Vinnytsia
Ukraine	Research Site	Zaporizhzhia
Ukraine	Research Site	Zhytomyr
United Kingdom	Research Site	Cambridge	Cambridgeshire
United Kingdom	Research Site	Doncaster	South Yorkshire
United Kingdom	Research Site	Kettering	Leicestershire
United Kingdom	Research Site	London	Greater London
United Kingdom	Research Site	Stevenage	Hertfordshire
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Anaheim	California
United States	Research Site	Arlington	Texas
United States	Research Site	Arvada	Colorado
United States	Research Site	Asheville	North Carolina
United States	Research Site	Astoria	New York
United States	Research Site	Augusta	Georgia
United States	Research Site	Austin	Texas
United States	Research Site	Austin	Texas
United States	Research Site	Austin	Texas
United States	Research Site #1	Bakersfield	California
United States	Research Site #2	Bakersfield	California
United States	Research Site	Bradenton	Florida
United States	Research Site	Bronx	New York
United States	Research Site	Canyon Country	California
United States	Research Site #1	Charlotte	North Carolina
United States	Research Site #2	Charlotte	North Carolina
United States	Research Site #1	Chattanooga	Tennessee
United States	Research Site #2	Chattanooga	Tennessee
United States	Research Site	Chula Vista	California
United States	Research Site	Columbus	Mississippi
United States	Research Site #1	Columbus	Georgia
United States	Research Site #2	Columbus	Georgia
United States	Research Site	Coral Gables	Florida
United States	Research Site	Coral Springs	Florida
United States	Research Site	Coral Springs	Florida
United States	Research Site	Dallas	Texas
United States	Research Site	Dallas	Texas
United States	Research Site	Denver	Colorado
United States	Research Site	Detroit	Michigan
United States	Research Site	Downey	California
United States	Research Site	Duncanville	Texas
United States	Research Site	Durham	North Carolina
United States	Research Site	El Centro	California
United States	Research Site	El Paso	Texas
United States	Research Site	Escondido	California
United States	Research Site	Fairfield	California
United States	Research Site	Flushing	New York
United States	Research Site	Fort Wayne	Indiana
United States	Research Site	Gallup	New Mexico
United States	Research Site	Glendale	California
United States	Research Site #1	Granada Hills	California
United States	Research Site #2	Granada Hills	California
United States	Research Site	Great Neck	New York
United States	Research Site	Greenville	North Carolina
United States	Research Site	Greenville	Texas
United States	Research Site	Hampton	Virginia
United States	Research Site	Hollywood	Florida
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Huntsville	Alabama
United States	Research Site	Kansas City	Missouri
United States	Research Site	Knoxville	Tennessee
United States	Research Site	La Habra	California
United States	Research Site	La Mesa	California
United States	Research Site	Lakewood	California
United States	Research Site #1	Lauderdale Lakes	Florida
United States	Research Site #1	Lawrenceville	Georgia
United States	Research Site #2	Lawrenceville	Georgia
United States	Research Site	Long Beach	California
United States	Research Site	Long Beach	California
United States	Research Site	Long Beach	California
United States	Research Site	Los Angeles	California
United States	Research Site	Manassas	Virginia
United States	Research Site	McAllen	Texas
United States	Research Site	Meridian	Idaho
United States	Research Site	Merrillville	Indiana
United States	Research Site	Mesa	Arizona
United States	AMPM Research Clinic	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami Beach	Florida
United States	Research Site	Monroe	Louisiana
United States	Research Site #1	Montebello	California
United States	Research Site	Monterey Park	California
United States	Research Site	Nashville	Tennessee
United States	Research Site #1	New Bern	North Carolina
United States	Research Site #2	New Bern	North Carolina
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	Newhall	California
United States	Research Site	Norfolk	Virginia
United States	Research Site #1	Northridge	California
United States	Research Site #2	Northridge	California
United States	Research Site	Ocala	Florida
United States	Research Site	Pembroke Pines	Florida
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Pine Bluff	Arkansas
United States	Research Site	Pontiac	Michigan
United States	Research Site	Port Huron	Michigan
United States	Research Site	Providence	Rhode Island
United States	Research Site	Riverside	California
United States	Research Site	Riverside	California
United States	Research Site	Roseville	California
United States	Research Site	Roseville	Michigan
United States	Research Site	Roswell	Georgia
United States	Research Site	Sacramento	California
United States	Research Site	Saint George	Utah
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site #2	San Antonio	Texas
United States	Research Site	San Diego	California
United States	Research Site	San Diego	California
United States	Research Site #1	San Dimas	California
United States	Research Site #2	San Dimas	California
United States	Research Site	Santa Fe	New Mexico
United States	Research Site	Shreveport	Louisiana
United States	Research Site	Simi Valley	California
United States	Research Site	South Burlington	Vermont
United States	Research Site	Springfield	Massachusetts
United States	Research Site	Stamford	Connecticut
United States	Research Site	Statesboro	Georgia
United States	Research Site	Takoma Park	Maryland
United States	Research Site	Tampa	Florida
United States	Research Site	Tarzana	California
United States	Research Site	Westminster	Colorado
United States	Research Site	Whittier	California
United States	Research Site	Whittier	California
United States	Research Site	Winston-Salem	North Carolina
United States	Research Site	Winter Park	Florida
United States	Research Site	Yonkers	New York

Sponsors (1)

Lead Sponsor	Collaborator
Akebia Therapeutics

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Bulgaria,  Canada,  France,  Germany,  Israel,  Italy,  Korea, Republic of,  Mexico,  Poland,  Portugal,  Russian Federation,  Serbia,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory - Proportion of Participants With Hb Values Within the Target Range During the Primary Evaluation Period (Weeks 24 to 36)		Weeks 24 to 36
Other	Exploratory - Proportion of Time With Hb Values Within the Target Range During the Primary Evaluation Period (Weeks 24 to 36)		Weeks 24 to 36
Other	Exploratory - Proportion of Time With Hb Values Within the Target Range During the Secondary Evaluation Period (Weeks 40 to 52)		Weeks 40 to 52
Other	Exploratory - Proportion of Participants With Hb Values Within the Target Range During the Secondary Evaluation Period (Weeks 40 to 52)		Weeks 40 to 52
Other	Exploratory - Proportion of Participants With an Hb Increase of >1.0 g/dL From Baseline Visit		Baseline; up to Week 52
Other	Exploratory - Time to Achieve Hb Increase of >1.0 g/dL From Baseline Visit		Baseline; up to Week 52
Other	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
Other	Exploratory - Mean Monthly Dose of Intravenous (IV) Elemental Iron Administered in Participants Who Have Received IV Iron		Up to Week 52
Other	Exploratory - Proportion of Participants Receiving IV Iron Therapy		Up to Week 52
Other	Exploratory - Proportion of Participants Receiving Red Blood Cells (RBCs) Transfusion(s)		Up to Week 52
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 (<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.	Baseline; Weeks 24 to 36
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-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.	Up to 170 weeks
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 (<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.	Baseline; Weeks 40 to 52
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-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.	Up to 170 weeks
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-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.	Up to 170 weeks
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-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.	Up to 170 weeks
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-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.	Up to 170 weeks