Anemia, Diabetes Mellitus, Kidney Disease
Conditions
Brief summary
The purpose of this study is to assess the impact of treatment of anemia with darbepoetin alfa to a hemoglobin target of 13 g/dL on (1) all-cause mortality and nonfatal cardiovascular events, and (2) progression to end-stage renal disease or death, in subjects with chronic kidney disease and type 2 diabetes mellitus. Academic PI/Executive Committee Chairman: Marc Pfeffer, MD, PhD
Interventions
DRUGPlacebo
Volume and dose frequency changes resembling dosing in the active treatment group
DRUGdarbepoetin alfa
Starting dose : 0.75 mcg/kg subcutaneous (SC) every two weeks (Q2W); subsequent doses titrated to achieve hemoglobin (Hb) target of 13.0 g/dL
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Hemoglobin less than or equal to 11 g/dL * History of Chronic Kidney Disease * eGFR (estimated glomerular filtration rate) greater than or equal to 20 mL/min/1.73 m2 and less than or equal to 60 mL/min/1.73 m2 * Tsat (transferrin saturation) greater than 15%
Exclusion criteria
* Uncontrolled hypertension * Erythropoietic protein use within 12 weeks of randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to All-cause Mortality or Cardiovascular (CV) Events Including Hospitalization Due to Acute Myocardial Ischemia, Congestive Heart Failure (CHF), Myocardial Infarction (MI), and Cerebrovascular Accident (CVA) | Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first | Time from randomization to the first confirmed composite event. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized. |
| Time to All-cause Mortality or End Stage Renal Disease (ESRD) | Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first | Time from randomization to first event of all-cause mortality or ESRD. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Myocardial Infarction | Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first | Time from randomization to fatal or non-fatal myocardial infarction (MI). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized. |
| Time to Cerebrovascular Accident | Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first | Time from randomization to fatal or non-fatal cerebrovascular accident (CVA). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized. |
| Time to Congestive Heart Failure | Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first | Time from randomization to fatal or non-fatal congestive heart failure(CHF). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized. |
| Time to All-cause Mortality | Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first | Time from randomization to all-cause mortality. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized. |
| Rate of Decline in Estimated Glomerular Filtration Rate (eGFR) Relative to Baseline | Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first | GFR was estimated using the following MDRD formula: 186 x \[Serum creatinine\]\^(-1.154) x \[Age\]\^(-0.203) x \[0.742 if subject is female\] x \[1.210 if subject is black\]. Change from baseline in eGFR at week 49 for each treatment group are presented. The treatment effect of the rate of decline in eGFR per year was estimated using the mixed model. |
| Change in Patient Reported Fatigue Relative to Baseline at Week 25 | Baseline and week 25 | Change in patient reported fatigue measured by the Functional Assessment of Cancer Therapy (FACT) - Fatigue scale from baseline to week 25. Range and direction of scale: 0 = most fatigue; 52 = least fatigue |
| Time to Hospitalization Due to Acute Myocardial Ischemia | Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first | Time from randomization to hospitalization due to acute myocardial ischemia. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized. |
| Time to End Stage Renal Disease | Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first | Time from randomization to end stage renal disease (ESRD). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized. |
| Time to Cardiovascular Mortality | Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first | Time from randomization to cardiovascular (CV) mortality. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized. |
Participant flow
Recruitment details
First Subject Enrolled: 25 Aug 2004 Last Subject Enrolled: 04 Dec 2007
Participants by arm
| Arm | Count |
|---|---|
| Darbepoetin Alfa Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed. | 2,012 |
| Placebo Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was \<9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL. | 2,026 |
| Total | 4,038 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 375 | 385 |
| Overall Study | Lost to Follow-up | 96 | 108 |
| Overall Study | Withdrawal by Subject | 194 | 171 |
Baseline characteristics
| Characteristic | Darbepoetin Alfa | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 67.2 Years STANDARD_DEVIATION 10.7 | 67.4 Years STANDARD_DEVIATION 10.6 | 67.5 Years STANDARD_DEVIATION 10.6 |
| Baseline proteinuria level < 1 g/g creat | 1324 Participants | 2639 Participants | 1315 Participants |
| Baseline proteinuria level >= 1 g/g creat | 686 Participants | 1397 Participants | 711 Participants |
| History of cardiovascular disease With history of cardiovascular disease | 1287 Participant | 2642 Participant | 1355 Participant |
| History of cardiovascular disease Without history of cardiovascular disease | 725 Participant | 1396 Participant | 671 Participant |
| Race/Ethnicity, Customized Aborigine | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 35 Participants | 78 Participants | 43 Participants |
| Race/Ethnicity, Customized Black or African American | 414 Participants | 815 Participants | 401 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 273 Participants | 538 Participants | 265 Participants |
| Race/Ethnicity, Customized Japanese | 8 Participants | 11 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 4 Participants | 9 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 9 Participants | 4 Participants |
| Race/Ethnicity, Customized White or Caucasian | 1270 Participants | 2570 Participants | 1300 Participants |
| Sex: Female, Male Female | 1178 Participants | 2312 Participants | 1134 Participants |
| Sex: Female, Male Male | 834 Participants | 1726 Participants | 892 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,547 / 2,019 | 1,571 / 2,004 |
| serious Total, serious adverse events | 1,219 / 2,019 | 1,235 / 2,004 |
Outcome results
Primary
Time to All-cause Mortality or Cardiovascular (CV) Events Including Hospitalization Due to Acute Myocardial Ischemia, Congestive Heart Failure (CHF), Myocardial Infarction (MI), and Cerebrovascular Accident (CVA)
Time from randomization to the first confirmed composite event. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time frame: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to All-cause Mortality or Cardiovascular (CV) Events Including Hospitalization Due to Acute Myocardial Ischemia, Congestive Heart Failure (CHF), Myocardial Infarction (MI), and Cerebrovascular Accident (CVA) | 602 Participants |
| Darbepoetin Alfa | Time to All-cause Mortality or Cardiovascular (CV) Events Including Hospitalization Due to Acute Myocardial Ischemia, Congestive Heart Failure (CHF), Myocardial Infarction (MI), and Cerebrovascular Accident (CVA) | 632 Participants |
p-value: 0.4195% CI: [0.94, 1.17]Log Rank
Primary
Time to All-cause Mortality or End Stage Renal Disease (ESRD)
Time from randomization to first event of all-cause mortality or ESRD. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time frame: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to All-cause Mortality or End Stage Renal Disease (ESRD) | 618 Participants |
| Darbepoetin Alfa | Time to All-cause Mortality or End Stage Renal Disease (ESRD) | 652 Participants |
p-value: 0.2995% CI: [0.95, 1.19]Log Rank
Secondary
Change in Patient Reported Fatigue Relative to Baseline at Week 25
Change in patient reported fatigue measured by the Functional Assessment of Cancer Therapy (FACT) - Fatigue scale from baseline to week 25. Range and direction of scale: 0 = most fatigue; 52 = least fatigue
Time frame: Baseline and week 25
Population: Subjects with both the baseline and at least post-baseline measurement at week 25 for FACT-fatigue were included in the analysis and were analyzed as randomized. Last observation carried forward (LOCF) using last non-missing post-baseline value was used for missing post-baseline data for subjects who were still on study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Patient Reported Fatigue Relative to Baseline at Week 25 | 2.8 Units on a scale | Standard Deviation 10.3 |
| Darbepoetin Alfa | Change in Patient Reported Fatigue Relative to Baseline at Week 25 | 4.2 Units on a scale | Standard Deviation 10.5 |
p-value: <0.00195% CI: [0.64, 2.02]t-test, 2 sided
Secondary
Rate of Decline in Estimated Glomerular Filtration Rate (eGFR) Relative to Baseline
GFR was estimated using the following MDRD formula: 186 x \[Serum creatinine\]\^(-1.154) x \[Age\]\^(-0.203) x \[0.742 if subject is female\] x \[1.210 if subject is black\]. Change from baseline in eGFR at week 49 for each treatment group are presented. The treatment effect of the rate of decline in eGFR per year was estimated using the mixed model.
Time frame: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Population: Subjects were analyzed as randomized using all available eGFR measurements, except eGFR measurements measured after subjects develop ESRD since creatinine measurements were no longer reliable or meaningful for eGFR calculation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Rate of Decline in Estimated Glomerular Filtration Rate (eGFR) Relative to Baseline | -1.89 mL/min/1.73m^2 | Standard Deviation 10.6 |
| Darbepoetin Alfa | Rate of Decline in Estimated Glomerular Filtration Rate (eGFR) Relative to Baseline | -1.30 mL/min/1.73m^2 | Standard Deviation 10.81 |
p-value: 0.5495% CI: [-0.51, 0.26]Mixed Models Analysis
Secondary
Time to All-cause Mortality
Time from randomization to all-cause mortality. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time frame: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to All-cause Mortality | 395 Participants |
| Darbepoetin Alfa | Time to All-cause Mortality | 412 Participants |
p-value: 0.4895% CI: [0.92, 1.21]Log Rank
Secondary
Time to Cardiovascular Mortality
Time from randomization to cardiovascular (CV) mortality. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time frame: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Cardiovascular Mortality | 250 Participants |
| Darbepoetin Alfa | Time to Cardiovascular Mortality | 259 Participants |
p-value: 0.6195% CI: [0.88, 1.25]Log Rank
Secondary
Time to Cerebrovascular Accident
Time from randomization to fatal or non-fatal cerebrovascular accident (CVA). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time frame: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Cerebrovascular Accident | 53 Participants |
| Darbepoetin Alfa | Time to Cerebrovascular Accident | 101 Participants |
p-value: <0.00195% CI: [1.38, 2.68]Log Rank
Secondary
Time to Congestive Heart Failure
Time from randomization to fatal or non-fatal congestive heart failure(CHF). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time frame: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Congestive Heart Failure | 229 Participants |
| Darbepoetin Alfa | Time to Congestive Heart Failure | 205 Participants |
p-value: 0.2495% CI: [0.74, 1.08]Log Rank
Secondary
Time to End Stage Renal Disease
Time from randomization to end stage renal disease (ESRD). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time frame: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to End Stage Renal Disease | 330 Participants |
| Darbepoetin Alfa | Time to End Stage Renal Disease | 338 Participants |
p-value: 0.8395% CI: [0.87, 1.18]Log Rank
Secondary
Time to Hospitalization Due to Acute Myocardial Ischemia
Time from randomization to hospitalization due to acute myocardial ischemia. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time frame: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Hospitalization Due to Acute Myocardial Ischemia | 49 Participants |
| Darbepoetin Alfa | Time to Hospitalization Due to Acute Myocardial Ischemia | 41 Participants |
p-value: 0.495% CI: [0.55, 1.27]Log Rank
Secondary
Time to Myocardial Infarction
Time from randomization to fatal or non-fatal myocardial infarction (MI). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time frame: Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Population: The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Myocardial Infarction | 129 Participants |
| Darbepoetin Alfa | Time to Myocardial Infarction | 124 Participants |
p-value: 0.7395% CI: [0.75, 1.23]Log Rank