Anemia, Chronic Kidney Disease, Chronic Renal Failure
Conditions
Keywords
anemia, chronic kidney disease, CKD, chronic renal failure, CRF, erythropoietin, EPO, erythropoiesis stimulating agent, ESA, Hematide™, 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 for the treatment of anemia in participants with chronic kidney disease, who are not on dialysis and not on erythropoiesis stimulating agent (ESA) treatment.
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 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. Study participants received doses of peginesatide administered once every 4 weeks or darbepoetin alfa administered once every 2 weeks. Total commitment time for this study was a 4 week screening period followed by a minimum of 52 weeks of study treatment. Eligible participants were randomized in equal proportions to two peginesatide treatment regimens and one control, darbepoetin alfa, treatment regimen. 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 subcutaneous injection once every 4 weeks. The starting dose was 0.025 milligram per kilogram (mg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 grams per deciliter (g/dL).
DRUGDarbepoetin alfa
Participants received darbepoetin alfa by subcutaneous injection once every 2 weeks, as prescribed. The starting dose was 0.75 microgram per kilogram (mcg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL.
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. Chronic renal failure with an estimated glomerular filtration rate \< 60 milliliters per minute per 1.73 m\^2 and not expected to begin dialysis for at least 12 weeks. 2. Two consecutive hemoglobin values ≥ 8.0 g/dL and \< 11.0 g/dL within 4 weeks prior to randomization.
Exclusion criteria
1. Females who are pregnant or breast-feeding. 2. Treatment with an ESA in the 12 weeks prior to randomization. 3. Known intolerance to any ESA, parenteral iron supplementation, or pegylated molecule. 4. Prior chronic hemodialysis or chronic peritoneal dialysis treatment. 5. Known bleeding or coagulation disorder. 6. Known hematologic disease or cause of anemia other than renal disease. 7. Poorly controlled hypertension. 8. Evidence of active malignancy within one year prior to randomization 9. A scheduled kidney transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Baseline and Weeks 25-36 | The baseline hemoglobin value is defined as the mean of three hemoglobin values: the two 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 25 through 36. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Received Red Blood Cell (RBC) Transfusions During the Correction and Evaluation Periods | Weeks 0 to 36 | — |
| Proportion of Participants Achieving Hemoglobin Response During the Correction and Evaluation Periods | Weeks 0 to 36 | A hemoglobin response is defined as a hemoglobin increase of ≥ 1.0 gram per deciliter (g/dL) above baseline and a hemoglobin ≥ 11.0 g/dL without RBC transfusion during the previous 8 weeks. |
Countries
Bulgaria, Czechia, Germany, Hungary, Italy, Poland, Puerto Rico, Romania, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Peginesatide 0.025 mg/kg Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.025 milligram per kilogram (mg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 grams per deciliter (g/dL). | 167 |
| Peginesatide 0.04 mg/kg Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.04 mg/kg and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL. | 163 |
| Darbepoetin Alfa Participants received darbepoetin alfa by subcutaneous injection once every 2 weeks, as prescribed. The starting dose was 0.75 microgram per kilogram (mcg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL. | 163 |
| Total | 493 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 | 0 |
| Overall Study | Death | 19 | 11 | 11 |
| Overall Study | Lost to Follow-up | 4 | 3 | 3 |
| Overall Study | Noncompliance | 0 | 2 | 1 |
| Overall Study | Physician Decision | 2 | 1 | 1 |
| Overall Study | Relocation | 1 | 4 | 0 |
| Overall Study | Renal transplant | 0 | 0 | 1 |
| Overall Study | Site closed by sponsor | 5 | 2 | 1 |
| Overall Study | Started dialysis | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 16 | 6 |
Baseline characteristics
| Characteristic | Peginesatide 0.025 mg/kg | Peginesatide 0.04 mg/kg | Darbepoetin Alfa | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 104 Participants | 106 Participants | 101 Participants | 311 Participants |
| Age, Categorical Between 18 and 65 years | 63 Participants | 57 Participants | 62 Participants | 182 Participants |
| Age Continuous | 68.1 years STANDARD_DEVIATION 12.93 | 68.3 years STANDARD_DEVIATION 13.53 | 67.2 years STANDARD_DEVIATION 15.03 | 67.9 years STANDARD_DEVIATION 13.83 |
| Sex: Female, Male Female | 93 Participants | 96 Participants | 99 Participants | 288 Participants |
| Sex: Female, Male Male | 74 Participants | 67 Participants | 64 Participants | 205 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 142 / 167 | 134 / 163 | 134 / 163 |
| serious Total, serious adverse events | 86 / 167 | 80 / 163 | 70 / 163 |
Outcome results
Primary
Mean Change in Hemoglobin Between Baseline and the Evaluation Period
The baseline hemoglobin value is defined as the mean of three hemoglobin values: the two 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 25 through 36.
Time frame: Baseline and Weeks 25-36
Population: Full Analysis Population: All randomized participants who received at least one dose of study medication
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Peginesatide 0.025 mg/kg | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Evaluation Period [N=151, 145, 150] | 11.55 g/dL | Standard Deviation 0.741 |
| Peginesatide 0.025 mg/kg | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Baseline [N=167, 163, 163] | 10.02 g/dL | Standard Deviation 0.626 |
| Peginesatide 0.025 mg/kg | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Change from Baseline [N=151, 145, 150] | 1.50 g/dL | Standard Deviation 0.898 |
| Peginesatide 0.04 mg/kg | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Evaluation Period [N=151, 145, 150] | 11.71 g/dL | Standard Deviation 0.855 |
| Peginesatide 0.04 mg/kg | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Baseline [N=167, 163, 163] | 10.03 g/dL | Standard Deviation 0.618 |
| Peginesatide 0.04 mg/kg | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Change from Baseline [N=151, 145, 150] | 1.68 g/dL | Standard Deviation 0.962 |
| Darbepoetin Alfa | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Baseline [N=167, 163, 163] | 10.03 g/dL | Standard Deviation 0.654 |
| Darbepoetin Alfa | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Change from Baseline [N=151, 145, 150] | 1.35 g/dL | Standard Deviation 1.004 |
| Darbepoetin Alfa | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Evaluation Period [N=151, 145, 150] | 11.40 g/dL | Standard Deviation 0.728 |
Comparison: The sample size for this study was determined based on a two-group evaluation of non-inferiority in means with a non-inferiority margin (Δ) of -1.0 g/dL (one-sided significance level of 0.0125, or, comparably, a two-sided significance level of 0.025). A sample size of 450 (150 per treatment group) provided power greater than 99% for the evaluation of non-inferiority, assuming an expected treatment difference of 0.0 g/dL and a pooled standard deviation of 1.5 g/dL.97.5% CI: [-0.09, 0.36]ANOVA
Comparison: The sample size for this study was determined based on a two-group evaluation of non-inferiority in means with a non-inferiority margin (Δ) of -1.0 g/dL (one-sided significance level of 0.0125, or, comparably, a two-sided significance level of 0.025). A sample size of 450 (150 per treatment group) provided power greater than 99% for the evaluation of non-inferiority, assuming an expected treatment difference of 0.0 g/dL and a pooled standard deviation of 1.5 g/dL.97.5% CI: [0.08, 0.54]ANOVA
Secondary
Proportion of Participants Achieving Hemoglobin Response During the Correction and Evaluation Periods
A hemoglobin response is defined as a hemoglobin increase of ≥ 1.0 gram per deciliter (g/dL) above baseline and a hemoglobin ≥ 11.0 g/dL without RBC transfusion during the previous 8 weeks.
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 0.025 mg/kg | Proportion of Participants Achieving Hemoglobin Response During the Correction and Evaluation Periods | 0.910 percentage of participants |
| Peginesatide 0.04 mg/kg | Proportion of Participants Achieving Hemoglobin Response During the Correction and Evaluation Periods | 0.933 percentage of participants |
| Darbepoetin Alfa | Proportion of Participants Achieving Hemoglobin Response During the Correction and Evaluation Periods | 0.951 percentage of participants |
95% CI: [0.9, 1.01]Cochran-Mantel-Haenszel
95% CI: [0.93, 1.04]Cochran-Mantel-Haenszel
Secondary
Proportion of Participants Who Received Red Blood Cell (RBC) Transfusions During the Correction 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 0.025 mg/kg | Proportion of Participants Who Received Red Blood Cell (RBC) Transfusions During the Correction and Evaluation Periods | 0.114 percentage of participants |
| Peginesatide 0.04 mg/kg | Proportion of Participants Who Received Red Blood Cell (RBC) Transfusions During the Correction and Evaluation Periods | 0.104 percentage of participants |
| Darbepoetin Alfa | Proportion of Participants Who Received Red Blood Cell (RBC) Transfusions During the Correction and Evaluation Periods | 0.049 percentage of participants |
95% CI: [1.04, 5.01]Cochran-Mantel-Haenszel
95% CI: [0.94, 4.69]Cochran-Mantel-Haenszel