Anemia
Conditions
Keywords
vadadustat, hemodialysis, erythropoiesis-stimulating agents, darbepoetin alfa, CKD, Anemia
Brief summary
This trial will be conducted to demonstrate the efficacy and safety of vadadustat compared to darbepoetin alfa for the maintenance treatment of anemia in hemodialysis participants after conversion from current erythropoiesis-stimulating agent (ESA) therapy.
Detailed description
This study consists of three periods: 1. Screening Period 2. Conversion and Maintenance Treatment Period 3. Safety Follow-up Period Individual participants will participate in total trial duration of approximately 64 weeks.
Interventions
DRUGVadadustat
oral tablets
DRUGDarbepoetin alfa
intravenous or subcutaneous solution
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Akebia Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
This is an open-label, Sponsor-blind study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Receiving chronic, outpatient three times weekly (TIW) in-center hemodialysis for end-stage renal disease for at least 12 weeks prior to Screening * Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥ 1.2 using the most recent historical measurement within 8 weeks prior to or during Screening * Use of any approved erythropoiesis-stimulating agents (ESAs) for at least the 8 weeks prior to Screening Visit 2 * Two hemoglobin (Hb) values, at least 4 days apart, measured by the central laboratory during Screening within the following prespecified ranges: 1. Hb values between 8.0 and 11.0 grams per deciliter (g/dL) (inclusive) in the United States; 2. Hb values between 9.0 and 12.0 g/dL (inclusive) in Europe * Serum ferritin ≥ 100 nanograms per milliliter (ng/mL) and transferrin saturation (TSAT) ≥ 20% during Screening * Folate and vitamin B12 measurements ≥ lower limit of normal during Screening
Exclusion criteria
* Anemia due to a cause other than chronic kidney disease (e.g., sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia) * Participants meeting cut-off of the following equivalent mean weekly doses calculated over 8 weeks prior to Screening Visit 2 1. Methoxy polyethylene glycol-epoetin beta \> 50 micrograms (µg)/week; 2. Darbepoetin alfa \> 100 µg/week; 3. Epoetin analogues \> 23000 International Units (IU)/week * Active bleeding or recent blood loss within 8 weeks prior to randomization * Red blood cell transfusion within 8 weeks prior to randomization * Current uncontrolled hypertension. * 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 (HF) or New York Heart Association Class IV HF, or stroke within 12 weeks prior to or during Screening. * Known hypersensitivity to vadadustat, darbepoetin alfa, or any of their excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hb to the Average Over the Primary Evaluation Period (PEP) (Weeks 20 to 26) | Baseline; Weeks 20 to 26 | The Baseline Hb was defined as the average of the last 2 central laboratory Hb values taken on or prior to the first dose date. The average for the PEP was calculated as the average of all Hb measurements from the central laboratory within the three visit windows during Weeks 20 through 26, regardless of intercurrent events. Analysis was conducted using an analysis of covariance (ANCOVA) model with multiple imputation for missing data with randomization stratification factors and Baseline Hb as covariates. Change from Baseline was calculated as PEP value minus the Baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hb to the Average Over the Secondary Evaluation Period (SEP) (Weeks 46 to 52) | Baseline; Weeks 46 to 52 | The Baseline Hb was defined as the average of the last 2 central laboratory Hb values taken on or prior to the first dose date. The average for the SEP was calculated as the average of all Hb measurements from the central laboratory within the three visit windows during Weeks 46 through 52, regardless of intercurrent events. Analysis was conducted using an ANCOVA model with multiple imputation for missing data with randomization stratification factors and Baseline Hb as covariates. Change from Baseline was calculated as SEP value minus the Baseline value. |
Countries
Czechia, Hungary, Italy, Poland, Spain, United States
Participant flow
Recruitment details
This was a randomized, open-label, active-controlled study of vadadustat versus darbepoetin alfa for the maintenance treatment of anemia in hemodialysis participants, after conversion from erythropoiesis-stimulating agent (ESA therapy).
Pre-assignment details
A total of 319 participants were enrolled in the study. Data was collected by the arm to which participants were randomized and not by dose received in vadadustat QD or vadadustat TIW arms.
Participants by arm
| Arm | Count |
|---|---|
| Vadadustat QD Participants were randomized to receive vadadustat QD orally. Vadadustat starting daily dose was determined by pre-Baseline mean weekly darbepoetin alfa dose (or ESA equivalent). In the low darbepoetin alfa dose group (less than or equal to \[\<=\] 0.45 micrograms per kilograms per week \[mcg/kg/week\]), participants received an initial vadadustat daily dose of 300 milligrams (mg) daily. In the high darbepoetin alfa dose group (\> 0.45 and \<= 1.5 mcg/kg/week), participants received an initial vadadustat daily dose of 450 mg daily. Vadadustat was titrated to achieve and maintain target hemoglobin (Hb) levels. The dose range for titration was 150 to 900 mg vadadustat QD. | 105 |
| Vadadustat TIW Participants were randomized to receive vadadustat TIW orally. Vadadustat starting daily dose was determined by pre-Baseline mean weekly darbepoetin alfa dose (or ESA equivalent). In the low darbepoetin alfa dose group (\<= 0.45 mcg/kg/week), participants received an initial vadadustat dose of 600 mg TIW. In the high darbepoetin alfa dose group (\> 0.45 and \<= 1.5 mcg/kg/week), participants received an initial vadadustat dose of 750 mg TIW. Vadadustat was titrated to achieve and maintain target Hb levels. The dose range for titration was 150 to 1200 mg vadadustat TIW. | 106 |
| Darbepoetin Alfa Participants were randomized to receive darbepoetin alfa as a solution in single-dose prefilled syringes via intravenous (IV) injection through dialysis vascular access. For participants who had received darbepoetin alfa during screening, the initial dosing regimen was approximately the same weekly dose that they were receiving prior to randomization. For participants who had received darbepoetin alfa for the first time, the initial dosing regimen was determined by the United States Package Insert (USPI) or European Union Summary of product characteristics (EU SmPC), per the medical judgment of the investigator. | 108 |
| Total | 319 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event (includes Death) | 14 | 19 | 10 |
| Overall Study | Change in Dialysis Modality | 0 | 1 | 2 |
| Overall Study | Lack of Efficacy | 3 | 3 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 2 |
| Overall Study | Meeting Criteria for Trial Medication Stopping Rules | 16 | 20 | 19 |
| Overall Study | Other | 5 | 3 | 2 |
| Overall Study | Permanent Change in Frequency of In-center Hemodialysis from TIW | 1 | 0 | 0 |
| Overall Study | Physician Decision | 4 | 2 | 1 |
| Overall Study | Receipt of a Solid Organ, Hematopoietic Stem Cell, or Bone Marrow Transplantation | 0 | 2 | 3 |
| Overall Study | Withdrawal by Subject | 7 | 6 | 2 |
Baseline characteristics
| Characteristic | Darbepoetin Alfa | Total | Vadadustat QD | Vadadustat TIW |
|---|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 12.8 | 61.0 years STANDARD_DEVIATION 12.9 | 60.9 years STANDARD_DEVIATION 13.4 | 61.2 years STANDARD_DEVIATION 12.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 85 Participants | 23 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 82 Participants | 234 Participants | 82 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 8 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Black Or African American | 33 Participants | 94 Participants | 31 Participants | 30 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 4 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Reported as Other | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 71 Participants | 206 Participants | 68 Participants | 67 Participants |
| Sex: Female, Male Female | 43 Participants | 136 Participants | 47 Participants | 46 Participants |
| Sex: Female, Male Male | 65 Participants | 183 Participants | 58 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 12 / 105 | 9 / 104 | 7 / 108 |
| other Total, other adverse events | 46 / 105 | 49 / 104 | 46 / 108 |
| serious Total, serious adverse events | 47 / 105 | 47 / 104 | 47 / 108 |
Outcome results
Primary
Change From Baseline in Hb to the Average Over the Primary Evaluation Period (PEP) (Weeks 20 to 26)
The Baseline Hb was defined as the average of the last 2 central laboratory Hb values taken on or prior to the first dose date. The average for the PEP was calculated as the average of all Hb measurements from the central laboratory within the three visit windows during Weeks 20 through 26, regardless of intercurrent events. Analysis was conducted using an analysis of covariance (ANCOVA) model with multiple imputation for missing data with randomization stratification factors and Baseline Hb as covariates. Change from Baseline was calculated as PEP value minus the Baseline value.
Time frame: Baseline; Weeks 20 to 26
Population: Randomized Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat QD | Change From Baseline in Hb to the Average Over the Primary Evaluation Period (PEP) (Weeks 20 to 26) | 0.07 Grams per deciliter (g/dL) | Standard Error 0.12 |
| Vadadustat TIW | Change From Baseline in Hb to the Average Over the Primary Evaluation Period (PEP) (Weeks 20 to 26) | -0.19 Grams per deciliter (g/dL) | Standard Error 0.12 |
| Darbepoetin Alfa | Change From Baseline in Hb to the Average Over the Primary Evaluation Period (PEP) (Weeks 20 to 26) | 0.34 Grams per deciliter (g/dL) | Standard Error 0.12 |
Secondary
Change From Baseline in Hb to the Average Over the Secondary Evaluation Period (SEP) (Weeks 46 to 52)
The Baseline Hb was defined as the average of the last 2 central laboratory Hb values taken on or prior to the first dose date. The average for the SEP was calculated as the average of all Hb measurements from the central laboratory within the three visit windows during Weeks 46 through 52, regardless of intercurrent events. Analysis was conducted using an ANCOVA model with multiple imputation for missing data with randomization stratification factors and Baseline Hb as covariates. Change from Baseline was calculated as SEP value minus the Baseline value.
Time frame: Baseline; Weeks 46 to 52
Population: Randomized Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat QD | Change From Baseline in Hb to the Average Over the Secondary Evaluation Period (SEP) (Weeks 46 to 52) | 0.04 g/dL | Standard Error 0.15 |
| Vadadustat TIW | Change From Baseline in Hb to the Average Over the Secondary Evaluation Period (SEP) (Weeks 46 to 52) | 0.03 g/dL | Standard Error 0.15 |
| Darbepoetin Alfa | Change From Baseline in Hb to the Average Over the Secondary Evaluation Period (SEP) (Weeks 46 to 52) | 0.44 g/dL | Standard Error 0.15 |