Anemia, Chronic Kidney Disease, Chronic Renal Failure
Conditions
Keywords
anemia, chronic kidney disease, CKD, chronic renal failure, CRF, dialysis, erythropoietin, EPO, erythropoiesis stimulating agent, ESA, Hematide™, hemodialysis, hemoglobin, Hb, Hgb, Omontys, peginesatide, red blood cell, red blood cell production
Brief summary
The purpose of the study was to evaluate the safety and efficacy of peginesatide in the maintenance treatment of anemia in participants on dialysis.
Detailed description
Anemia associated with chronic kidney disease is due to several factors, primarily the inability of the diseased kidneys to produce adequate amounts of endogenous erythropoietin. Ancillary factors include the shortened lifespan of red blood cells, iron and other nutritional deficiencies, infection, and inflammation. The presence and severity of anemia are related to the duration and extent of kidney failure. Anemia is associated with increased mortality, increased likelihood of hospitalization, reduced cognitive function, and increased left ventricular hypertrophy and heart failure. Erythropoiesis stimulating agents (ESAs) have been established as a treatment for anemia in chronic renal failure subjects, and have improved the management of anemia over alternatives such as transfusion. Peginesatide is a parenteral formulation developed for the treatment of anemia in patients with chronic kidney disease. Peginesatide binds to and activates the human erythropoietin receptor, and stimulates erythropoiesis in human red cell precursors in a manner similar to other known erythropoiesis-stimulating agents. Eligible participants were randomized in a 2:1 ratio to peginesatide administered once every 4 weeks or to continued treatment with epoetin alfa administered 1-3 times each week, respectively. Total commitment time for this study was 4 weeks of screening followed by a minimum of 52 weeks of study treatment. To evaluate the cardiovascular safety of peginesatide, a cardiovascular composite safety endpoint (CSE) was defined for use in prospectively planned analyses which combined cardiovascular safety data from the four Phase 3 peginesatide studies (NCT00598273, NCT00597753, NCT00598442, and NCT00597584). The CSE consisted of six events: death, stroke, myocardial infarction, and serious adverse events of congestive heart failure, unstable angina, and arrhythmia. An independent Event Review Committee (ERC) was used to provide blinded adjudication of potential CSE events.
Interventions
DRUGpeginesatide
Participants received peginesatide by intravenous injection once every 4 weeks. The starting dose was based on the participant's total weekly epoetin alfa dose during the last week of the Screening Period; the first dose was administered one week after the last epoetin alfa dose. The dose was adjusted to maintain hemoglobin levels in a target range of 10.0-12.0 grams per deciliter (g/dL) and ± 1.5 g/dL from baseline during the Titration and Evaluation Periods, and 10.0-12.0 g/dL during the Long-Term Safety and Efficacy Period.
DRUGEpoetin Alfa
Participants continued to receive commercially available epoetin alfa by intravenous injection, at the same starting dose and frequency as received during the last week of the Screening Period, with the first study dose of epoetin alfa administered after randomization at Week 0. The dose was adjusted to maintain hemoglobin levels in a target range of 10.0-12.0 g/dL and ± 1.5 g/dL from baseline during the Titration and Evaluation Periods, and 10.0-12.0 g/dL during the Long-Term Safety and Efficacy Period.
Sponsors
Takeda
Affymax
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
1. Participants with chronic renal failure on hemodialysis for ≥ 3 months prior to randomization. 2. On intravenous epoetin alfa maintenance therapy continuously prescribed for a minimum of 8 weeks prior to randomization. 3. Four consecutive hemoglobin values with a mean ≥ 10.0 and ≤ 12.0 g/dL during the screening period
Exclusion criteria
1. Females who are pregnant or breast-feeding. 2. Known intolerance to any erythropoiesis stimulating agent (ESA) or pegylated molecule or to all parenteral iron supplementation products. 3. Known bleeding or coagulation disorder. 4. Known hematologic disease or cause of anemia other than renal disease 5. Poorly controlled hypertension 6. Evidence of active malignancy within one year prior to randomization. 7. Temporary (untunneled) dialysis access catheter. 8. A scheduled kidney transplant 9. A scheduled surgery that may be expected to lead to significant blood loss.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Baseline and Weeks 29-36 | The baseline hemoglobin value is defined as the mean of five hemoglobin values: the four most recent hemoglobin values taken prior to the day of randomization and the value obtained on the day of randomization. The mean hemoglobin during the Evaluation Period for each participant is calculated as the mean of the available hemoglobin values during study Weeks 29 through 36. |
Secondary
| Measure | Time frame |
|---|---|
| Proportion of Participants Who Receive Red Blood Cell (RBC) Transfusions During the Titration and Evaluation Periods | Weeks 0 to 36 |
| Proportion of Participants Whose Mean Hemoglobin Level During the Evaluation Period is Within the Target Range of 10.0 - 12.0 Grams Per Deciliter (g/dL) | Weeks 29 to 36 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Peginesatide Participants received peginesatide by intravenous injection once every 4 weeks. The starting dose was based on the participant's total weekly epoetin alfa dose during the last week of the Screening Period; the first dose was administered one week after the last epoetin alfa dose. The dose was adjusted to maintain hemoglobin levels in a target range of 10.0-12.0 grams per deciliter (g/dL) and ± 1.5 g/dL from baseline during the Titration and Evaluation Periods, and 10.0-12.0 g/dL during the Long-Term Safety and Efficacy Period. | 524 |
| Epoetin Alfa Participants continued to receive commercially available epoetin alfa by intravenous injection, at the same starting dose and frequency as received during the last week of the Screening Period, with the first study dose of epoetin alfa administered after randomization at Week 0. The dose was adjusted to maintain hemoglobin levels in a target range of 10.0-12.0 g/dL and ± 1.5 g/dL from baseline during the Titration and Evaluation Periods, and 10.0-12.0 g/dL during the Long-Term Safety and Efficacy Period. | 269 |
| Total | 793 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 2 |
| Overall Study | Death | 55 | 29 |
| Overall Study | Discontinued Dialysis | 0 | 1 |
| Overall Study | Lack of Efficacy | 2 | 0 |
| Overall Study | Lost to Follow-up | 10 | 3 |
| Overall Study | Never dosed | 2 | 0 |
| Overall Study | Noncompliance | 2 | 1 |
| Overall Study | Physician Decision | 5 | 1 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Relocation | 17 | 6 |
| Overall Study | Renal transplant | 10 | 3 |
| Overall Study | Site closed by sponsor | 19 | 7 |
| Overall Study | Site elected to close | 2 | 4 |
| Overall Study | Withdrawal by Subject | 35 | 12 |
Baseline characteristics
| Characteristic | Peginesatide | Epoetin Alfa | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 154 Participants | 79 Participants | 233 Participants |
| Age, Categorical Between 18 and 65 years | 370 Participants | 190 Participants | 560 Participants |
| Age Continuous | 57.3 years STANDARD_DEVIATION 13.96 | 57.5 years STANDARD_DEVIATION 13.68 | 57.4 years STANDARD_DEVIATION 13.86 |
| Sex: Female, Male Female | 231 Participants | 125 Participants | 356 Participants |
| Sex: Female, Male Male | 293 Participants | 144 Participants | 437 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 445 / 524 | 235 / 269 |
| serious Total, serious adverse events | 304 / 524 | 168 / 269 |
Outcome results
Primary
Mean Change in Hemoglobin Between Baseline and the Evaluation Period
The baseline hemoglobin value is defined as the mean of five hemoglobin values: the four most recent hemoglobin values taken prior to the day of randomization and the value obtained on the day of randomization. The mean hemoglobin during the Evaluation Period for each participant is calculated as the mean of the available hemoglobin values during study Weeks 29 through 36.
Time frame: Baseline and Weeks 29-36
Population: Full Analysis Population: All randomized participants who received at least one dose of study medication
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Peginesatide | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Baseline [N=524, 269] | 11.30 g/dL | Standard Deviation 0.523 |
| Peginesatide | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Evaluation Period [N=445, 248] | 11.06 g/dL | Standard Deviation 0.932 |
| Peginesatide | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Change from Baseline [N=445, 248] | -0.24 g/dL | Standard Deviation 0.956 |
| Epoetin Alfa | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Baseline [N=524, 269] | 11.32 g/dL | Standard Deviation 0.493 |
| Epoetin Alfa | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Evaluation Period [N=445, 248] | 11.25 g/dL | Standard Deviation 0.846 |
| Epoetin Alfa | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Change from Baseline [N=445, 248] | -0.09 g/dL | Standard Deviation 0.922 |
Comparison: The sample size for this study was determined based on a two group evaluation of non-inferiority using the t-distribution (one-sided significance level 0.025) with a non inferiority margin of -1.0 g/dL. A sample size of approximately 750 (peginesatide group of 500 and epoetin alfa group of 250) provided at least 99% power for the evaluation of non-inferiority, assuming an expected treatment difference of 0.0 g/dL and a standard deviation of 1.5 g/dL.95% CI: [-0.3, -0.01]ANOVA
Secondary
Proportion of Participants Who Receive Red Blood Cell (RBC) Transfusions During the Titration and Evaluation Periods
Time frame: Weeks 0 to 36
Population: Full Analysis Population: All randomized participants who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginesatide | Proportion of Participants Who Receive Red Blood Cell (RBC) Transfusions During the Titration and Evaluation Periods | 0.103 percentage of participants |
| Epoetin Alfa | Proportion of Participants Who Receive Red Blood Cell (RBC) Transfusions During the Titration and Evaluation Periods | 0.086 percentage of participants |
95% CI: [0.76, 1.92]Cochran-Mantel-Haenszel
Secondary
Proportion of Participants Whose Mean Hemoglobin Level During the Evaluation Period is Within the Target Range of 10.0 - 12.0 Grams Per Deciliter (g/dL)
Time frame: Weeks 29 to 36
Population: Full Analysis Population: All randomized participants who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginesatide | Proportion of Participants Whose Mean Hemoglobin Level During the Evaluation Period is Within the Target Range of 10.0 - 12.0 Grams Per Deciliter (g/dL) | 0.630 percentage of participants |
| Epoetin Alfa | Proportion of Participants Whose Mean Hemoglobin Level During the Evaluation Period is Within the Target Range of 10.0 - 12.0 Grams Per Deciliter (g/dL) | 0.717 percentage of participants |
95% CI: [0.79, 0.97]Cochran-Mantel-Haenszel