Anemia
Conditions
Keywords
Anemia, Drug Therapy, Peritoneal Dialysis.
Brief summary
The purpose of this study is to determine the efficacy and safety of peginesatide injection for maintenance treatment of anemia in participants on peritoneal dialysis.
Detailed description
According to the International Federation of Renal Registries, in 1999 the prevalence of peritoneal dialysis in the United States as approximately 9.5% of patients receiving dialysis (2005 United States Renal Data Systems data indicates a prevalence of around 7.5%). Data from Europe in 1999 to 2000 (not including the United Kingdom, France or Germany) indicated peritoneal dialysis was the mode of dialysis in approximately 11.1% of dialysis patients. 2006 data from the United Kingdom indicates that more than 20% of patients on dialysis are receiving peritoneal dialysis while French and German data indicate rates of 8.1% and 4.8% respectively. More than 90% of patients with chronic renal failure/chronic kidney disease Stage 5 (End Stage Renal Disease) are anemic. The vast majority of patients receiving hemodialysis or peritoneal dialysis receive erythropoiesis-stimulating agent therapy to treat their anemia. Anemia of chronic renal failure is due to several factors, primarily the inability of the diseased kidneys to produce adequate amounts of endogenous erythropoietin. Ancillary factors also include the shortened lifespan of red blood cells, iron and other nutritional deficiencies, infection, and inflammation. The prevalence of anemia increases with progressive deterioration of renal function, and affects more than 90% of patients with chronic kidney disease (CKD) Stage 5 (End Stage Renal Disease). Anemia is associated with increased mortality, increased likelihood of hospitalization, reduced cognitive function and exercise capacity, increased left ventricular hypertrophy and heart failure. Treatment of anemia reduces morbidity and mortality risks and may improve quality of life. Erythropoiesis stimulating agents have been established as a treatment for anemia in chronic renal failure participants, and have improved the management of anemia over alternatives such as transfusion. Peginesatide (hematide) is a parenteral formulation being developed for the correction of anemia in patients with chronic renal failure, and 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. Participants in this study received variable doses of peginesatide injection once every four weeks. Total commitment time for this study was about 29 weeks.
Interventions
DRUGPeginesatide
Peginesatide 0.04 to 0.16 mg/kg, subcutaneous injection, once every 4 weeks for up to 25 weeks. Initial dose based on patient's previous total weekly Epoetin dose, and thereafter could be adjusted to maintain hemoglobin values in the target range of 10 to 12 g/dL and ±1.5 g/dL from Baseline.
Sponsors
Affymax
Takeda
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. The patient was a man or woman and 18 to 90 years of age, inclusive. 2. The patient had CKD and had been on peritoneal dialysis for ≥3 months before enrollment. 3. The patient was on stable SC epoetin (alfa or beta) maintenance therapy continuously prescribed for a minimum of 8 weeks prior to enrollment. 4. The patient had 4 consecutive Hb values with a mean ≥10.0 and ≤12.0 g/dL during the screening period, with the difference between the mean of the first confirmed (2 consecutive) Hb values and the mean of the last confirmed (2 consecutive) Hb values being ≤1.0 g/dL. 5. The patient had 1 ferritin level ≥100 ng/mL within 4 weeks before enrollment.
Exclusion criteria
1. The patient had known bleeding or coagulation disorder. 2. The patient had known hematologic disease or cause of anemia other than renal disease (e.g., pure red cell aplasia, homozygous sickle-cell disease, thalassemia, multiple myeloma, hemolytic anemia, and myelodysplastic syndrome). 3. The patient had received a recent course of intensive iron replacement (i.e., more than 500 mg IV in the 28 days before enrollment). 4. The patient had advanced chronic congestive heart failure defined by New York Heart Association Class III or IV. 5. The patient had a known history of seizure disorder or received antiepileptic medication for a seizure disorder within 6 months before enrollment. 6. The patient had a scheduled kidney transplant. (Note: patients who were currently on a transplant waiting list were not excluded unless there was an identified donor).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Baseline and Week 20 to Week 25. | The primary efficacy endpoint was the mean change in Hemoglobin between Baseline (the mean of the 4 most recent hemoglobin values prior to Enrollment and the hemoglobin on the day of Enrollment) and the Evaluation Period (mean hemoglobin from Weeks 20 to 25). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Change in Hemoglobin From Baseline to the Evaluation Period Within 1 g/dL | Baseline and Week 20 to Week 25. | Percentage of participants with a mean change in Hemoglobin between Baseline (the mean of the 4 most recent hemoglobin values prior to enrollment and the hemoglobin on the day of enrollment) and the Evaluation Period (mean hemoglobin from measured at Weeks 20 to 25) of less than or equal ± 1 g/dL. The 95% confidence interval was calculated from the normal approximation with continuity correction. |
| Percentage of Participants With Red Blood Cell Transfusions | Up to 25 weeks. | The percentage of participants who received one or more red blood cell transfusions, including packed red blood cells and whole blood transfusions, during the Titration Period (Weeks 1 - 19) and Evaluation Period (Weeks 20 -25). 95% Confidence Intervals were calculated from the normal approximation with continuity correction. One patient had the last study visit during the titration period and the transfusion after the titration period. This patient is excluded from the summary of evaluation period. |
| Percentage of Participants With Hemoglobin Within the Target Range of 10.0 to 12.0 g/dL During the Evaluation Period | Week 20 to Week 25. | Mean hemoglobin was calculated from measurements taken during the Evaluation Period (Week 20 to Week 25). The target hemoglobin range was 10.0 to 12.0 g/dL. The 95% confidence interval was calculated from the normal approximation with continuity correction. |
| Percentage of Participants With Target Hemoglobin of 10.0 to 12.0 g/dL by 4-week Intervals | Up to 25 weeks. | Percentage of participants with mean hemoglobin levels falling between the target level of 10.0 to 12.0 g/dL during 4-week study intervals. Hemoglobin was measured every 2 weeks during the Titration Period (Weeks 1-19) and weekly during the Evaluation Period (Weeks 20-25). 95% Confidence Intervals were calculated from the normal approximation with continuity correction. |
| Percentage of Participants With Dose Adjustments During the Study | From Week 4 to Week 25 | The peginesatide dose was adjusted to maintain hemoglobin values in the target range of 10 to 12 g/dL and ±1.5 g/dL from Baseline during the Titration Period (Weeks 1-19) and Evaluation Period (Weeks 20-25). A dose was classified as adjusted if it was not within 20% of the previous dose. A dose was classified as increased or decreased if it was \>20% higher or \>20% lower respectively, than the previous dose. |
| Mean Hemoglobin During 4-week Intervals | Up to 25 weeks. | Hemoglobin was measured every 2 weeks during the Titration Period (Weeks 1-19) and weekly during the Evaluation Period (Weeks 20-25). One patient did not have central lab hemoglobin value during a regularly scheduled visit during weeks 2-5. |
Countries
Australia, Italy, New Zealand, United Kingdom, United States
Participant flow
Recruitment details
Participants enrolled at 26 sites in Australia, Italy, New Zealand, the United Kingdom and the United States from 31 October 2008 to 19 May 2010.
Pre-assignment details
Participants with chronic renal failure on peritoneal dialysis and receiving stable Epoetin (alfa or beta) maintenance therapy were enrolled into 1 treatment group (peginesatide injection).
Participants by arm
| Arm | Count |
|---|---|
| Peginesatide Peginesatide 0.04 to 0.16 mg/kg, subcutaneous injection, once every 4 weeks for up to 25 weeks. Initial dose based on patient's previous total weekly Epoetin dose, and thereafter could be adjusted to maintain hemoglobin values in the target range of 10 to 12 g/dL and ±1.5 g/dL from Baseline. | 59 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Death | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol deviation | 1 |
| Overall Study | Renal transplant | 3 |
| Overall Study | Switched to hemodialysis | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Peginesatide |
|---|---|
| Age Continuous | 54.0 years STANDARD_DEVIATION 15.99 |
| Age, Customized ≥65 to <75 years | 10 participants |
| Age, Customized <65 years | 42 participants |
| Age, Customized ≥75 years | 7 participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 59 |
| serious Total, serious adverse events | 27 / 59 |
Outcome results
Primary
Mean Change in Hemoglobin Between Baseline and the Evaluation Period
The primary efficacy endpoint was the mean change in Hemoglobin between Baseline (the mean of the 4 most recent hemoglobin values prior to Enrollment and the hemoglobin on the day of Enrollment) and the Evaluation Period (mean hemoglobin from Weeks 20 to 25).
Time frame: Baseline and Week 20 to Week 25.
Population: The Full Analysis Set included all patients who received at least 1 dose of peginesatide injection and where data was available at both time points (indicated by N).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Peginesatide | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Baseline [N=59] | 11.22 g/dL | Standard Deviation 0.495 |
| Peginesatide | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Evaluation Period [N=46] | 11.33 g/dL | Standard Deviation 1.066 |
| Peginesatide | Mean Change in Hemoglobin Between Baseline and the Evaluation Period | Change from Baseline [N=46] | 0.10 g/dL | Standard Deviation 1.154 |
95% CI: [-0.24, 0.44]
Secondary
Mean Hemoglobin During 4-week Intervals
Hemoglobin was measured every 2 weeks during the Titration Period (Weeks 1-19) and weekly during the Evaluation Period (Weeks 20-25). One patient did not have central lab hemoglobin value during a regularly scheduled visit during weeks 2-5.
Time frame: Up to 25 weeks.
Population: Full Analysis Set where data was available for each time interval (indicated by N).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Peginesatide | Mean Hemoglobin During 4-week Intervals | Week 2-5 [N=58] | 11.57 g/dL | Standard Deviation 0.741 |
| Peginesatide | Mean Hemoglobin During 4-week Intervals | Week 6-9 [N=56] | 11.65 g/dL | Standard Deviation 1.044 |
| Peginesatide | Mean Hemoglobin During 4-week Intervals | Week 10-13 [N=54] | 11.53 g/dL | Standard Deviation 1.119 |
| Peginesatide | Mean Hemoglobin During 4-week Intervals | Week 14-17 [N=52] | 11.33 g/dL | Standard Deviation 1.037 |
| Peginesatide | Mean Hemoglobin During 4-week Intervals | Week 18-21 [N=45] | 11.46 g/dL | Standard Deviation 1.004 |
| Peginesatide | Mean Hemoglobin During 4-week Intervals | Week 22-25 [N=46] | 11.25 g/dL | Standard Deviation 1.122 |
Secondary
Percentage of Participants With a Change in Hemoglobin From Baseline to the Evaluation Period Within 1 g/dL
Percentage of participants with a mean change in Hemoglobin between Baseline (the mean of the 4 most recent hemoglobin values prior to enrollment and the hemoglobin on the day of enrollment) and the Evaluation Period (mean hemoglobin from measured at Weeks 20 to 25) of less than or equal ± 1 g/dL. The 95% confidence interval was calculated from the normal approximation with continuity correction.
Time frame: Baseline and Week 20 to Week 25.
Population: Full analysis set where data was available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginesatide | Percentage of Participants With a Change in Hemoglobin From Baseline to the Evaluation Period Within 1 g/dL | 60.9 percentage of participants |
Secondary
Percentage of Participants With Dose Adjustments During the Study
The peginesatide dose was adjusted to maintain hemoglobin values in the target range of 10 to 12 g/dL and ±1.5 g/dL from Baseline during the Titration Period (Weeks 1-19) and Evaluation Period (Weeks 20-25). A dose was classified as adjusted if it was not within 20% of the previous dose. A dose was classified as increased or decreased if it was \>20% higher or \>20% lower respectively, than the previous dose.
Time frame: From Week 4 to Week 25
Population: Safety Analysis Set. N indicates the number of patients with study drug administered during the period after excluding the initial dose of study drug and excluding the first dose after a restart of study drug and is the denominator for percentage calculations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peginesatide | Percentage of Participants With Dose Adjustments During the Study | Any adjustment in Titration Period [N=57] | 80.7 percentage of participants |
| Peginesatide | Percentage of Participants With Dose Adjustments During the Study | Any adjustment in Evaluation Period [N=42] | 52.4 percentage of participants |
| Peginesatide | Percentage of Participants With Dose Adjustments During the Study | Dose increased in Titration Period [N=57] | 28.1 percentage of participants |
| Peginesatide | Percentage of Participants With Dose Adjustments During the Study | Dose increased in Evaluation Period [N=42] | 16.7 percentage of participants |
| Peginesatide | Percentage of Participants With Dose Adjustments During the Study | Dose decreased in Titration Period [N=57] | 66.7 percentage of participants |
| Peginesatide | Percentage of Participants With Dose Adjustments During the Study | Dose decreased in Evaluation Period [N=42] | 35.7 percentage of participants |
Secondary
Percentage of Participants With Hemoglobin Within the Target Range of 10.0 to 12.0 g/dL During the Evaluation Period
Mean hemoglobin was calculated from measurements taken during the Evaluation Period (Week 20 to Week 25). The target hemoglobin range was 10.0 to 12.0 g/dL. The 95% confidence interval was calculated from the normal approximation with continuity correction.
Time frame: Week 20 to Week 25.
Population: Full analysis set where data was available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginesatide | Percentage of Participants With Hemoglobin Within the Target Range of 10.0 to 12.0 g/dL During the Evaluation Period | 63.0 percentage of participants |
Secondary
Percentage of Participants With Red Blood Cell Transfusions
The percentage of participants who received one or more red blood cell transfusions, including packed red blood cells and whole blood transfusions, during the Titration Period (Weeks 1 - 19) and Evaluation Period (Weeks 20 -25). 95% Confidence Intervals were calculated from the normal approximation with continuity correction. One patient had the last study visit during the titration period and the transfusion after the titration period. This patient is excluded from the summary of evaluation period.
Time frame: Up to 25 weeks.
Population: Full Analysis Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peginesatide | Percentage of Participants With Red Blood Cell Transfusions | Entire study (n=59) | 10.2 percentage of participants |
| Peginesatide | Percentage of Participants With Red Blood Cell Transfusions | Titration Period (n=59) | 5.1 percentage of participants |
| Peginesatide | Percentage of Participants With Red Blood Cell Transfusions | Evaluation period (n=47) | 4.3 percentage of participants |
Secondary
Percentage of Participants With Target Hemoglobin of 10.0 to 12.0 g/dL by 4-week Intervals
Percentage of participants with mean hemoglobin levels falling between the target level of 10.0 to 12.0 g/dL during 4-week study intervals. Hemoglobin was measured every 2 weeks during the Titration Period (Weeks 1-19) and weekly during the Evaluation Period (Weeks 20-25). 95% Confidence Intervals were calculated from the normal approximation with continuity correction.
Time frame: Up to 25 weeks.
Population: Full analysis set where data was available for each time interval (indicated by N).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peginesatide | Percentage of Participants With Target Hemoglobin of 10.0 to 12.0 g/dL by 4-week Intervals | Week 22-25 [N=46] | 63.0 percentage of participants |
| Peginesatide | Percentage of Participants With Target Hemoglobin of 10.0 to 12.0 g/dL by 4-week Intervals | Week 2-5 [N=58] | 67.2 percentage of participants |
| Peginesatide | Percentage of Participants With Target Hemoglobin of 10.0 to 12.0 g/dL by 4-week Intervals | Week 6-9 [N=56] | 53.6 percentage of participants |
| Peginesatide | Percentage of Participants With Target Hemoglobin of 10.0 to 12.0 g/dL by 4-week Intervals | Week 10-13 [N=54] | 59.3 percentage of participants |
| Peginesatide | Percentage of Participants With Target Hemoglobin of 10.0 to 12.0 g/dL by 4-week Intervals | Week 14-17 [N=52] | 61.5 percentage of participants |
| Peginesatide | Percentage of Participants With Target Hemoglobin of 10.0 to 12.0 g/dL by 4-week Intervals | Week 18-21 [N=45] | 64.4 percentage of participants |