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 determine the dose ranges of peginesatide administered intravenously or subcutaneously that maintained hemoglobin in participants on dialysis whose hemoglobin values were stable on epoetin (alfa or beta).
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 subjects with chronic kidney disease, and have improved the management of anemia over alternatives such as transfusion. Peginesatide is a parenteral formulation developed for the treatment of anemia associated 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. Six dose cohorts of 15 participants each were evaluated in this study. Participants received peginesatide injection once every 4 weeks administered intravenously or subcutaneously for a total of 7 doses.
Interventions
DRUGpeginesatide
Tiered peginesatide starting doses of 0.05, 0.075, or 0.1 milligram per kilogram (mg/kg) for participants on an epoetin (alfa or beta) dose of ≤100 Units/kg/week, \>100 to 150 Units/kg/week, or \>150 Units/kg/week, respectively. Doses were administered subcutaneously (SC) once every 4 weeks (Q4W) for a total of 7 doses. No transition period between epoetin treatment and start of peginesatide treatment.
Sponsors
Affymax
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant is informed of the investigational nature of this study and has given written, witnessed informed consent in accordance with institutional, local, and national guidelines * Males or females ≥ 18 years of age. Pre-menopausal females (with the exception of those who are surgically sterile) must have a negative pregnancy test at screening; those who are sexually active must practice a highly effective method of birth control for at least 4 weeks prior to study start, and must be willing to continue contraception until at least 4 weeks after the last dose of study drug * Clinically stable on hemodialysis for ≥ 3 months prior to study start * Epoetin (alfa or beta) maintenance therapy, ≥ 50 and ≤ 200 Units/kg/week, at the same dosing frequency, continuously prescribed for 8 weeks prior to study start * Three mid- or end-of-week hemoglobin values of ≥ 10.0 and ≤ 12.5 grams per deciliter (g/dL) in the 4 weeks prior to study start, with ≤ 1.2 g/dL difference between any of the three values * One transferrin saturation (TSAT) \> 20% within 4 weeks prior to study start * One ferritin level ≥ 100 ng/mL within 4 weeks prior to study start * One serum or red cell folate level ≥ lower limit of normal during the 4 weeks prior to study start * One vitamin B12 level ≥ lower limit of normal during the 4 weeks prior to study start * One C-reactive protein (CRP) level ≤ 30 mg/L within 4 weeks prior to study start * Urea clearance/volume (Kt/V) ≥ 1.2 within 4 weeks prior to study start * One white blood cell count (WBC) ≥ 3.0 x 10\^9/L within 4 weeks prior to study start * One platelet count ≥ 100 x 10\^9/L and ≤ 500 x 10\^9/L within 4 weeks prior to study start
Exclusion criteria
* Pregnant or breast-feeding participants * Known intolerance to any erythropoiesis stimulating agent, parenteral iron supplementation or pegylated molecules * History of antibodies to any erythropoiesis stimulating agent or history of pure red cell aplasia (PRCA) * Known bleeding or coagulation disorder * Known hematologic disease (e.g., homozygous sickle-cell disease, thalassemia of all types, multiple myeloma, hemolytic anemia) * Uncontrolled or symptomatic inflammatory disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, etc.) * Known history of seizure disorder or received anti-epileptic medication within the previous 6 months * Uncontrolled or symptomatic secondary hyperparathyroidism, per Investigator's clinical judgment * Poorly controlled hypertension within 4 weeks prior to study start, per Investigator's clinical judgment * Chronic congestive heart failure of New York Heart Association class III or IV * High likelihood of early withdrawal or interruption of the study (e.g., myocardial infarction, severe or unstable coronary artery disease, stroke, respiratory, autoimmune, neuropsychiatric, or neurological abnormalities, liver disease including active hepatitis B or C, active HIV disease, or any other clinically significant medical diseases or conditions in the prior 6 months that may, in the Investigator's opinion, interfere with safety, assessment, or follow-up of the participant) * Evidence of malignancy within the past 5 years (except non-melanoma skin cancer which is not an exclusion criterion) * Life expectancy \< 12 months * Temporary (untunneled) dialysis access catheter * Anticipated elective surgery during the study period, that may be expected to lead to significant blood loss, including vascular access surgery such as an arteriovenous fistula or graft, or a scheduled kidney transplant * Red blood cell or whole blood transfusion within 12 weeks prior to study start * Received antibiotics for systemic infection within 2 weeks prior to study start * Previous exposure to any investigational agent within 6 weeks prior to study start, or planned receipt of an investigational agent, other than as specified by this protocol, during the study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Baseline and Weeks 2-29 | The Baseline hemoglobin was the mean of the four most recent mid- or end-of-week predialysis hemoglobin values collected prior to study start. Study start was the date of the first dose of peginesatide injection in participants who did not have a one-week transition period, or the date when Epoetin treatment was first withheld in participants who did have a one-week transition period. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Hemoglobin Within 1.0 g/dL Below Baseline to 1.5 g/dL Above Baseline Throughout the Trial (Weeks 2-29) | Weeks 2 to 29 | Hemoglobin relative to baseline: Hemoglobin at a given time point was considered to be not within the specified range (within 1 g/dL below to 1.5 g/dL above baseline) if the hemoglobin value at the time point was not within the range and the next available hemoglobin value within 14 days after the time point also was not within the specified range. These calculations were determined for all time points within a specified time period. |
| Proportion of Participants Who Maintained Hemoglobin Within 10 to 12.5 g/dL Throughout the Trial | Weeks 2 to 29 | Hemoglobin relative to baseline: Hemoglobin at a given time point was considered to be not within the specified range (within the range of 10 g/dL to 12.5 g/dL) if the hemoglobin value at the time point was not within the range and the next available hemoglobin value within 14 days after the time point also was not within the specified range. These calculations were determined for all time points within a specified time period. |
| Proportion of Participants Who Maintain Hemoglobin Within 9.5 to 13.0 g/dL Throughout the Trial | Weeks 2 to 29 | Hemoglobin relative to baseline: Hemoglobin at a given time point was considered to be not within the specified range (within the range of 9.5 g/dL to 13.0 g/dL) if the hemoglobin value at the time point was not within the range and the next available hemoglobin value within 14 days after the time point also was not within the specified range. These calculations were determined for all time points within a specified time period. |
Countries
Bulgaria, Romania, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1, Q4W, SC, No Transition Tiered peginesatide starting doses of 0.05, 0.075, or 0.1 milligram per kilogram (mg/kg) for participants on an epoetin (alfa or beta) dose of ≤100 Units/kg/week, \>100 to 150 Units/kg/week, or \>150 Units/kg/week, respectively. Doses were administered subcutaneously (SC) once every 4 weeks (Q4W) for a total of 7 doses. No transition period between epoetin treatment and start of peginesatide treatment. | 15 |
| Cohort 2, Q4W, IV, No Transition Tiered peginesatide starting doses of 0.05, 0.075, or 0.1 mg/kg for participants on an epoetin (alfa or beta) dose of ≤100 Units/kg/week, \>100 to 150 Units/kg/week, or \>150 Units/kg/week, respectively. Doses were administered intravenously (IV) once every 4 weeks for a total of 7 doses. No transition period between epoetin treatment and start of peginesatide treatment. | 15 |
| Cohort 3, Q4W, SC, Transition Tiered peginesatide starting doses of 0.05, 0.075, or 0.1 mg/kg for participants on an epoetin (alfa or beta) dose of ≤100 Units/kg/week, \>100 to 150 Units/kg/week, or \>150 Units/kg/week, respectively. Doses were administered subcutaneously once every 4 weeks for a total of 7 doses. With transition period between epoetin treatment and start of peginesatide treatment. | 16 |
| Cohort 4, Q4W, IV, Transition Tiered peginesatide starting doses of 0.05, 0.075, or 0.1 mg/kg for participants on an epoetin (alfa or beta) dose of ≤100 Units/kg/week, \>100 to 150 Units/kg/week, or \>150 Units/kg/week, respectively. Doses were administered intravenously once every 4 weeks for a total of 7 doses. With transition period between epoetin treatment and start of peginesatide treatment. | 15 |
| Cohort 5, Q4W, SC, Transition Tiered peginesatide starting doses of 0.04 mg/kg or 0.075 mg/kg for participants with an epoetin (alfa or beta) dose of ≤100 Units/kg/week or 100 to 150 Units/kg/week, respectively. Doses were administered subcutaneously once every 4 weeks for a total of 7 doses. With transition period between epoetin treatment and start of peginesatide treatment. | 15 |
| Cohort 6, Q4W, IV, Transition Tiered peginesatide starting doses of 0.04 mg/kg or 0.075 mg/kg for participants with an epoetin (alfa or beta) dose of ≤100 Units/kg/week or 100 to 150 Units/kg/week, respectively. Doses were administered intravenously once every 4 weeks for a total of 7 doses. With transition period between epoetin treatment and start of peginesatide treatment. | 15 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Renal transplant | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Subject Not Compliant With Study | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 2, Q4W, IV, No Transition | Cohort 3, Q4W, SC, Transition | Cohort 4, Q4W, IV, Transition | Cohort 5, Q4W, SC, Transition | Cohort 6, Q4W, IV, Transition | Cohort 1, Q4W, SC, No Transition | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 4 Participants | 2 Participants | 3 Participants | 3 Participants | 4 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 12 Participants | 13 Participants | 12 Participants | 12 Participants | 11 Participants | 70 Participants |
| Age Continuous | 58.1 years STANDARD_DEVIATION 13.91 | 46.1 years STANDARD_DEVIATION 17.22 | 50.4 years STANDARD_DEVIATION 12.47 | 51.1 years STANDARD_DEVIATION 11.43 | 53 years STANDARD_DEVIATION 13.22 | 53.4 years STANDARD_DEVIATION 12.42 | 51.9 years STANDARD_DEVIATION 13.74 |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 4 Participants | 6 Participants | 4 Participants | 9 Participants | 34 Participants |
| Sex: Female, Male Male | 9 Participants | 11 Participants | 11 Participants | 9 Participants | 11 Participants | 6 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 15 | 8 / 15 | 7 / 16 | 8 / 15 | 10 / 15 | 9 / 15 |
| serious Total, serious adverse events | 2 / 15 | 1 / 15 | 3 / 16 | 1 / 15 | 3 / 15 | 2 / 15 |
Outcome results
Primary
Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial.
The Baseline hemoglobin was the mean of the four most recent mid- or end-of-week predialysis hemoglobin values collected prior to study start. Study start was the date of the first dose of peginesatide injection in participants who did not have a one-week transition period, or the date when Epoetin treatment was first withheld in participants who did have a one-week transition period.
Time frame: Baseline and Weeks 2-29
Population: Modified intent-to-treat (mITT) population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1, Q4W, SC, No Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Weeks 2-29 [N=15, 15, 15, 15, 15, 15] | 11.64 g/dL | Standard Deviation 0.722 |
| Cohort 1, Q4W, SC, No Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Baseline [N=15, 15, 14, 15, 15, 15] | 11.10 g/dL | Standard Deviation 0.6 |
| Cohort 1, Q4W, SC, No Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Change from Baseline [N=15, 15, 14, 15, 15, 15] | 0.53 g/dL | Standard Deviation 0.6 |
| Cohort 2, Q4W, IV, No Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Weeks 2-29 [N=15, 15, 15, 15, 15, 15] | 11.57 g/dL | Standard Deviation 0.771 |
| Cohort 2, Q4W, IV, No Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Baseline [N=15, 15, 14, 15, 15, 15] | 11.34 g/dL | Standard Deviation 0.596 |
| Cohort 2, Q4W, IV, No Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Change from Baseline [N=15, 15, 14, 15, 15, 15] | 0.23 g/dL | Standard Deviation 0.776 |
| Cohort 3, Q4W, SC, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Weeks 2-29 [N=15, 15, 15, 15, 15, 15] | 11.98 g/dL | Standard Deviation 0.858 |
| Cohort 3, Q4W, SC, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Baseline [N=15, 15, 14, 15, 15, 15] | 11.42 g/dL | Standard Deviation 0.448 |
| Cohort 3, Q4W, SC, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Change from Baseline [N=15, 15, 14, 15, 15, 15] | 0.57 g/dL | Standard Deviation 0.793 |
| Cohort 4, Q4W, IV, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Weeks 2-29 [N=15, 15, 15, 15, 15, 15] | 11.86 g/dL | Standard Deviation 0.538 |
| Cohort 4, Q4W, IV, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Baseline [N=15, 15, 14, 15, 15, 15] | 11.19 g/dL | Standard Deviation 0.628 |
| Cohort 4, Q4W, IV, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Change from Baseline [N=15, 15, 14, 15, 15, 15] | 0.67 g/dL | Standard Deviation 0.752 |
| Cohort 5, Q4W, SC, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Weeks 2-29 [N=15, 15, 15, 15, 15, 15] | 11.92 g/dL | Standard Deviation 0.699 |
| Cohort 5, Q4W, SC, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Baseline [N=15, 15, 14, 15, 15, 15] | 11.11 g/dL | Standard Deviation 0.81 |
| Cohort 5, Q4W, SC, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Change from Baseline [N=15, 15, 14, 15, 15, 15] | 0.82 g/dL | Standard Deviation 0.935 |
| Cohort 6, Q4W, IV, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Baseline [N=15, 15, 14, 15, 15, 15] | 11.24 g/dL | Standard Deviation 0.742 |
| Cohort 6, Q4W, IV, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Change from Baseline [N=15, 15, 14, 15, 15, 15] | -0.05 g/dL | Standard Deviation 1 |
| Cohort 6, Q4W, IV, Transition | Mean Hemoglobin Throughout the Trial and Mean Hemoglobin Change From Baseline Throughout the Trial. | Weeks 2-29 [N=15, 15, 15, 15, 15, 15] | 11.19 g/dL | Standard Deviation 1.114 |
Other Pre-specified
Proportion of Participants Who Maintained Hemoglobin Within 10 to 12.5 g/dL Throughout the Trial
Hemoglobin relative to baseline: Hemoglobin at a given time point was considered to be not within the specified range (within the range of 10 g/dL to 12.5 g/dL) if the hemoglobin value at the time point was not within the range and the next available hemoglobin value within 14 days after the time point also was not within the specified range. These calculations were determined for all time points within a specified time period.
Time frame: Weeks 2 to 29
Population: mITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1, Q4W, SC, No Transition | Proportion of Participants Who Maintained Hemoglobin Within 10 to 12.5 g/dL Throughout the Trial | 0.333 percentage of participants |
| Cohort 2, Q4W, IV, No Transition | Proportion of Participants Who Maintained Hemoglobin Within 10 to 12.5 g/dL Throughout the Trial | 0.200 percentage of participants |
| Cohort 3, Q4W, SC, Transition | Proportion of Participants Who Maintained Hemoglobin Within 10 to 12.5 g/dL Throughout the Trial | 0.200 percentage of participants |
| Cohort 4, Q4W, IV, Transition | Proportion of Participants Who Maintained Hemoglobin Within 10 to 12.5 g/dL Throughout the Trial | 0.200 percentage of participants |
| Cohort 5, Q4W, SC, Transition | Proportion of Participants Who Maintained Hemoglobin Within 10 to 12.5 g/dL Throughout the Trial | 0.200 percentage of participants |
| Cohort 6, Q4W, IV, Transition | Proportion of Participants Who Maintained Hemoglobin Within 10 to 12.5 g/dL Throughout the Trial | 0.067 percentage of participants |
Other Pre-specified
Proportion of Participants Who Maintain Hemoglobin Within 9.5 to 13.0 g/dL Throughout the Trial
Hemoglobin relative to baseline: Hemoglobin at a given time point was considered to be not within the specified range (within the range of 9.5 g/dL to 13.0 g/dL) if the hemoglobin value at the time point was not within the range and the next available hemoglobin value within 14 days after the time point also was not within the specified range. These calculations were determined for all time points within a specified time period.
Time frame: Weeks 2 to 29
Population: mITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1, Q4W, SC, No Transition | Proportion of Participants Who Maintain Hemoglobin Within 9.5 to 13.0 g/dL Throughout the Trial | 0.800 percentage of participants |
| Cohort 2, Q4W, IV, No Transition | Proportion of Participants Who Maintain Hemoglobin Within 9.5 to 13.0 g/dL Throughout the Trial | 0.667 percentage of participants |
| Cohort 3, Q4W, SC, Transition | Proportion of Participants Who Maintain Hemoglobin Within 9.5 to 13.0 g/dL Throughout the Trial | 0.533 percentage of participants |
| Cohort 4, Q4W, IV, Transition | Proportion of Participants Who Maintain Hemoglobin Within 9.5 to 13.0 g/dL Throughout the Trial | 0.533 percentage of participants |
| Cohort 5, Q4W, SC, Transition | Proportion of Participants Who Maintain Hemoglobin Within 9.5 to 13.0 g/dL Throughout the Trial | 0.600 percentage of participants |
| Cohort 6, Q4W, IV, Transition | Proportion of Participants Who Maintain Hemoglobin Within 9.5 to 13.0 g/dL Throughout the Trial | 0.600 percentage of participants |
Other Pre-specified
Proportion of Participants With Hemoglobin Within 1.0 g/dL Below Baseline to 1.5 g/dL Above Baseline Throughout the Trial (Weeks 2-29)
Hemoglobin relative to baseline: Hemoglobin at a given time point was considered to be not within the specified range (within 1 g/dL below to 1.5 g/dL above baseline) if the hemoglobin value at the time point was not within the range and the next available hemoglobin value within 14 days after the time point also was not within the specified range. These calculations were determined for all time points within a specified time period.
Time frame: Weeks 2 to 29
Population: mITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1, Q4W, SC, No Transition | Proportion of Participants With Hemoglobin Within 1.0 g/dL Below Baseline to 1.5 g/dL Above Baseline Throughout the Trial (Weeks 2-29) | 0.267 percentage of participants |
| Cohort 2, Q4W, IV, No Transition | Proportion of Participants With Hemoglobin Within 1.0 g/dL Below Baseline to 1.5 g/dL Above Baseline Throughout the Trial (Weeks 2-29) | 0.133 percentage of participants |
| Cohort 3, Q4W, SC, Transition | Proportion of Participants With Hemoglobin Within 1.0 g/dL Below Baseline to 1.5 g/dL Above Baseline Throughout the Trial (Weeks 2-29) | 0.200 percentage of participants |
| Cohort 4, Q4W, IV, Transition | Proportion of Participants With Hemoglobin Within 1.0 g/dL Below Baseline to 1.5 g/dL Above Baseline Throughout the Trial (Weeks 2-29) | 0.333 percentage of participants |
| Cohort 5, Q4W, SC, Transition | Proportion of Participants With Hemoglobin Within 1.0 g/dL Below Baseline to 1.5 g/dL Above Baseline Throughout the Trial (Weeks 2-29) | 0.400 percentage of participants |
| Cohort 6, Q4W, IV, Transition | Proportion of Participants With Hemoglobin Within 1.0 g/dL Below Baseline to 1.5 g/dL Above Baseline Throughout the Trial (Weeks 2-29) | 0.267 percentage of participants |