Anemia Associated With Chronic Kidney Disease (CKD)
Conditions
Keywords
Anemia, Chronic Kidney Disease, CKD, Hemodialysis, Vadadustat, Erythropoiesis-stimulating agent (ESA)
Brief summary
This study will be conducted to demonstrate the efficacy and safety of vadadustat administered three times weekly (TIW) compared to a long-acting erythropoiesis-stimulating agent (ESA) (Mircera®) for the maintenance treatment of anemia in hemodialysis participants.
Detailed description
Following randomization, there will be 2 periods during the study: * Conversion and Maintenance Period (Weeks 0 to 52): There will be a primary efficacy evaluation period (Weeks 20 to 26) and a secondary efficacy evaluation period (Weeks 46 to 52). * Safety Follow-up Period (Early Termination \[ET\] and Follow-Up): post-treatment safety follow-up visit (ET/End of Treatment \[EOT\] +4 weeks) either in person or via telephone.
Interventions
DRUGVadadustat
oral tablets
DRUGMircera®
intravenous administration
Sponsors
Akebia Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥18 years of age * Receiving chronic, outpatient in-center hemodialysis three times weekly (TIW) for end-stage kidney disease for at least 12 weeks prior to Screening Visit 1 (SV1) * Currently maintained on Mircera® (≤250 μg/month) with at least 2 doses received within 8 weeks prior to Screening Visit 2 (SV2) * Mean Screening hemoglobin (Hb) between 8.5 and 11.0 grams per deciliter (g/dL) (inclusive), as determined by the average of 2 Hb values measured by the central laboratory at least 4 days apart between SV1 and SV2 * 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 (CKD). * Clinically meaningful bleeding event within 8 weeks prior to Baseline * Red blood cell (RBC) transfusion within 8 weeks prior to Baseline * Having received any doses of darbepoetin alfa (Aranesp®) within 4 weeks prior to Baseline * Having received any doses of epoetin alfa (Epogen®) within 1 week prior to Baseline. * 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, Mircera®, or any of their excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin (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 last 2 central laboratory Hb measurements of samples taken at or prior to the first dose. 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. 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. 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
United States
Participant flow
Recruitment details
This was a randomzied, open-label, active-controlled study of the efficacy and safety of conversion from long-acting Erythropoiesis-stimulating Agent (ESA) (Methoxy polyethylene glycol-epoetin beta \[Mircera®\]) to vadadustat Three Times Weekly (TIW) for the maintenance treatment of anemia in hemodialysis participants.
Pre-assignment details
A total of 456 participants were enrolled in the study. Participants were randomized 1:1:1 to Vadadustat 600 milligrams (mg) TIW Vadadustat 900 mg TIW or to remain on Mircera® according to the dialysis center's protocol.
Participants by arm
| Arm | Count |
|---|---|
| Vadadustat 600 mg TIW Participants were randomized to receive Vadadustat at an initial oral dose of 600 mg TIW. Up-and-down titration was allowed during the study based on Hb level measurements to maintain target Hb level | 152 |
| Vadadustat 900 mg TIW Participants were randomized to receive Vadadustat at an initial oral dose of 900 mg TIW. Up-and-down titration was allowed during the study based on Hb level measurements to maintain target Hb level | 152 |
| Mircera® Participants were randomized to Mircera® were already on Mircera®, the initial dosing regimen in the study was based on the prior dosing regimen | 152 |
| Total | 456 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 18 | 3 |
| Overall Study | Death | 13 | 11 | 13 |
| Overall Study | Investigator's Discretion | 8 | 4 | 3 |
| Overall Study | Lack of Efficacy | 1 | 3 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 3 |
| Overall Study | Non Compliance with Study Drug | 1 | 0 | 0 |
| Overall Study | Other | 9 | 5 | 2 |
| Overall Study | Protocol Violation | 2 | 1 | 0 |
| Overall Study | Transplant | 4 | 4 | 8 |
| Overall Study | Withdrawal by Subject | 6 | 8 | 2 |
Baseline characteristics
| Characteristic | Vadadustat 600 mg TIW | Vadadustat 900 mg TIW | Mircera® | Total |
|---|---|---|---|---|
| Age, Continuous | 59.4 Years STANDARD_DEVIATION 14.2 | 61.9 Years STANDARD_DEVIATION 13.27 | 61.6 Years STANDARD_DEVIATION 12.8 | 61.0 Years STANDARD_DEVIATION 13.45 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 42 Participants | 40 Participants | 56 Participants | 138 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 110 Participants | 109 Participants | 95 Participants | 314 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 3 Participants | 4 Participants | 12 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 56 Participants | 59 Participants | 53 Participants | 168 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 86 Participants | 87 Participants | 92 Participants | 265 Participants |
| Sex: Female, Male Female | 68 Participants | 60 Participants | 66 Participants | 194 Participants |
| Sex: Female, Male Male | 84 Participants | 92 Participants | 86 Participants | 262 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 14 / 151 | 12 / 150 | 17 / 150 |
| other Total, other adverse events | 61 / 151 | 67 / 150 | 64 / 150 |
| serious Total, serious adverse events | 68 / 151 | 66 / 150 | 67 / 150 |
Outcome results
Primary
Change From Baseline in Hemoglobin (Hb) to the Average Over the Primary Evaluation Period (PEP) (Weeks 20 to 26)
The Baseline Hb was defined as the average of last 2 central laboratory Hb measurements of samples taken at or prior to the first dose. 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. 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 600 mg TIW | Change From Baseline in Hemoglobin (Hb) to the Average Over the Primary Evaluation Period (PEP) (Weeks 20 to 26) | -0.07 Grams per deciliter (g/dL) | Standard Error 0.095 |
| Vadadustat 900 mg TIW | Change From Baseline in Hemoglobin (Hb) to the Average Over the Primary Evaluation Period (PEP) (Weeks 20 to 26) | 0.14 Grams per deciliter (g/dL) | Standard Error 0.095 |
| Mircera® | Change From Baseline in Hemoglobin (Hb) to the Average Over the Primary Evaluation Period (PEP) (Weeks 20 to 26) | 0.36 Grams per deciliter (g/dL) | Standard Error 0.092 |
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. 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 600 mg TIW | Change From Baseline in Hb to the Average Over the Secondary Evaluation Period (SEP) (Weeks 46 to 52) | -0.11 Grams per deciliter | Standard Error 0.11 |
| Vadadustat 900 mg TIW | Change From Baseline in Hb to the Average Over the Secondary Evaluation Period (SEP) (Weeks 46 to 52) | -0.22 Grams per deciliter | Standard Error 0.123 |
| Mircera® | Change From Baseline in Hb to the Average Over the Secondary Evaluation Period (SEP) (Weeks 46 to 52) | 0.16 Grams per deciliter | Standard Error 0.102 |