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)

Anemia Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02865850
• Other study ID #: AKB-6548-CI-0016
• Secondary ID: 2016-000838-21
• Status: Completed
• Phase: Phase 3
• Start date: July 2016
• Est. completion date: March 30, 2020

Study information

• Verified date: July 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 correction or maintenance treatment of anemia in participants with incident 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 correction or maintenance treatment in participants with anemia secondary to chronic kidney disease who have recently initiated dialysis treatment for end-stage renal disease.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 369
• Est. completion date: March 30, 2020
• Est. primary completion date: January 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

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	Bahia Blanca	Buenos Aires
Argentina	Research Site	Ciudad Autonoma Buenos Aires	Buenos Aires
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	Temperley	Buenos Aires
Brazil	Research Site	Belo Horizonte	Minas Gerais
Brazil	Research Site	Canoas	Rio Grande Do Sul
Brazil	Research Site	Curitiba	Paraná
Brazil	Research Site	Fortaleza	Ceará
Brazil	Research Site	Joinville	Santa Catarina
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	Santo André	Sao Paulo
Brazil	Research Site	São Bernardo do Campo	Sao Paulo
Brazil	Research Site	São Paulo	Sao Paulo
Germany	Research Site	Duesseldorf	Nordrhein Westfalen
Germany	Research Site	Rostock	Mecklenburg Vorpommern
Germany	Research Site	Villingen-Schwenningen	Baden Wuerttemberg
Italy	Research Site	Genova
Italy	Research Site	Lecco
Italy	Research Site	Napoli
Italy	Research Site	Pavia
Italy	Research Site	Roma
Italy	Research Site	San Giovanni Rotondo	Foggia
Italy	Research Site	Siena
Korea, Republic of	Research Site	Busan
Korea, Republic of	Research Site	Chuncheon	Gangwon-do
Korea, Republic of	Research Site	Seongnam-si,	Gyeonggi-do
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Mexico	Research Site	Culiacan	Sinaloa
Mexico	Research Site	Morelia	Michoacán
Mexico	Research Site	Zapopan	Jalisco
Poland	Research Site	Golub Dobrzyn
Poland	Research Site	Lodz
Poland	Research Site	Lodz
Portugal	Research Site	Leiria
Portugal	Research Site	Loures
Russian Federation	Research Site #2	Kemerovo
Russian Federation	Research Site	Krasnoyarsk
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	St. Petersburg
Russian Federation	Research Site	St. Petersburg
Ukraine	Research Site	Brovary
Ukraine	Research Site	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 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	Astoria	New York
United States	Research Site	Augusta	Georgia
United States	Research Site	Canyon Country	California
United States	Research Site #1	Chattanooga	Tennessee
United States	Research Site #2	Chattanooga	Tennessee
United States	Research Site	Columbus	Georgia
United States	Research Site	Coral Gables	Florida
United States	Research Site	Coral Springs	Florida
United States	Research Site	Downey	California
United States	Research Site	El Paso	Texas
United States	Research Site	Glendale	California
United States	Research Site	Granada Hills	California
United States	Research Site	Hampton	Virginia
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 Mesa	California
United States	Research Site	Lauderdale Lakes	Florida
United States	Research Site #2	Lawrenceville	Georgia
United States	Research Site	Long Beach	California
United States	Research Site	Los Angeles	California
United States	Research Site	Meridian	Idaho
United States	Research Site	Mesa	Arizona
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami Beach	Florida
United States	Research Site	Montebello	California
United States	Research Site	Monterey Park	California
United States	Research Site	Nashville	Tennessee
United States	Research Site	Newhall	California
United States	Research Site #1	Northridge	California
United States	Research Site #2	Northridge	California
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Riverside	California
United States	Research Site	Riverside	California
United States	Research Site	Roseville	Michigan
United States	Research Site	Sacramento	California
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	San Diego	California
United States	Research Site	San Dimas	California
United States	Research Site	Stamford	Connecticut
United States	Research Site	Statesboro	Georgia
United States	Research Site	Takoma Park	Maryland
United States	Research Site	Westminster	Colorado
United States	Research Site	Whittier	California
United States	Research Site	Winston-Salem	North Carolina
United States	Research Site	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Akebia Therapeutics

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Germany,  Italy,  Korea, Republic of,  Mexico,  Poland,  Portugal,  Russian Federation,  Ukraine, 

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 (<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
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-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	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
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-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	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
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-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	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