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 this 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 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 injection, a composite safety endpoint (CSE) was defined for use in prospectively planned analyses which combined cardiovascular safety data from the four Phase 3 peginesatide injection 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 (IV) or subcutaneous (SC) injection once every 4 weeks. The starting dose was based on the participant's total weekly epoetin alfa or beta dose during the last week of the Screening Period; the first dose was administered one week after the last epoetin alfa or beta dose. Participants who received epoetin alfa or beta IV at the time of screening received peginesatide IV during the study, and participants who received epoetin alfa or beta SC at the time of screening received peginesatide SC during the study. 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.
DRUGEpoetin alfa or Epoetin beta
Participants continued to receive commercially available epoetin alfa or beta by intravenous or subcutaneous injection, at the same starting dose, frequency and route of administration as received during the last week of the Screening Period, with the first study dose of epoetin alfa or beta 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 IV epoetin alfa or beta 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 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 to 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
Bulgaria, France, Germany, Italy, Poland, Romania, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Peginesatide Participants received peginesatide by intravenous (IV) or subcutaneous (SC) injection once every 4 weeks. The starting dose was based on the participant's total weekly epoetin alfa or beta dose during the last week of the Screening Period; the first dose was administered one week after the last epoetin alfa or beta dose. Participants who received epoetin alfa or beta IV at the time of screening received peginesatide IV during the study, and participants who received epoetin alfa or beta SC at the time of screening received peginesatide SC during the study.
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. | 542 |
| Epoetin Participants continued to receive commercially available epoetin alfa or beta by intravenous or subcutaneous injection, at the same starting dose, frequency and route of administration as received during the last week of the Screening Period, with the first study dose of epoetin alfa or beta 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. | 273 |
| Total | 815 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | Death | 53 | 30 |
| Overall Study | Discontinued Dialysis | 0 | 1 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost ability to consent | 1 | 1 |
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | Never dosed | 1 | 0 |
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Pregnancy | 2 | 0 |
| Overall Study | Relocation | 8 | 6 |
| Overall Study | Renal transplant | 9 | 7 |
| Overall Study | Withdrawal by Subject | 44 | 12 |
Baseline characteristics
| Characteristic | Peginesatide | Epoetin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 192 Participants | 100 Participants | 292 Participants |
| Age, Categorical Between 18 and 65 years | 350 Participants | 173 Participants | 523 Participants |
| Age Continuous | 58.8 years STANDARD_DEVIATION 14.47 | 58.6 years STANDARD_DEVIATION 13.73 | 58.8 years STANDARD_DEVIATION 14.22 |
| Sex: Female, Male Female | 211 Participants | 120 Participants | 331 Participants |
| Sex: Female, Male Male | 331 Participants | 153 Participants | 484 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 445 / 542 | 222 / 273 |
| serious Total, serious adverse events | 268 / 542 | 141 / 273 |
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 to 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=542, 273] | 11.20 g/dL | Standard Deviation 0.553 |
| Peginesatide | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Evaluation Period [N=488, 237] | 11.13 g/dL | Standard Deviation 1.018 |
| Peginesatide | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Change from Baseline [N=488, 237] | -0.07 g/dL | Standard Deviation 1.009 |
| Epoetin | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Baseline [N=542, 273] | 11.21 g/dL | Standard Deviation 0.546 |
| Epoetin | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Evaluation Period [N=488, 237] | 11.05 g/dL | Standard Deviation 0.958 |
| Epoetin | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Change from Baseline [N=488, 237] | -0.17 g/dL | Standard Deviation 1 |
Comparison: The sample size for this study has been 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 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: [-0.05, 0.26]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 | 0.077 percentage of participants |
| Epoetin | Proportion of Participants Who Receive Red Blood Cell (RBC) Transfusions During the Titration and Evaluation Periods | 0.099 percentage of participants |
95% CI: [0.5, 1.24]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) | 0.635 percentage of participants |
| Epoetin | 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) | 0.659 percentage of participants |
95% CI: [0.87, 1.07]Cochran-Mantel-Haenszel