Trial to Reduce Cardiovascular Events With Aranesp® Therapy (TREAT)

• 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 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 ] [ Designated as safety issue: No ]
  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) [ 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 ] [ Designated as safety issue: No ]
  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 to All-cause Mortality [ 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 ] [ Designated as safety issue: No ]
  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 to Cardiovascular Mortality [ 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 ] [ Designated as safety issue: No ]
  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 to Myocardial Infarction [ 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 ] [ Designated as safety issue: No ]
  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 [ 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 ] [ Designated as safety issue: No ]
  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 [ 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 ] [ Designated as safety issue: No ]
  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 End Stage Renal Disease [ 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 ] [ Designated as safety issue: No ]
  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.
• Rate of Decline in Estimated Glomerular Filtration Rate (eGFR) Relative to Baseline [ 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 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Baseline and week 25 ] [ Designated as safety issue: No ]
  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 [ 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 ] [ Designated as safety issue: No ]
  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.

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

• Kidney Disease
• Diabetes Mellitus
• Anemia

• Drug: Placebo
  Volume and dose frequency changes resembling dosing in the active treatment group
• Drug: darbepoetin 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

• Active Comparator: Active
  Intervention: Drug: darbepoetin alfa
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

• McMurray JJ, Uno H, Jarolim P, Desai AS, de Zeeuw D, Eckardt KU, Ivanovich P, Levey AS, Lewis EF, McGill JB, Parfrey P, Parving HH, Toto RM, Solomon SD, Pfeffer MA. Predictors of fatal and nonfatal cardiovascular events in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia: an analysis of the Trial to Reduce cardiovascular Events with Aranesp (darbepoetin-alfa) Therapy (TREAT). Am Heart J. 2011 Oct;162(4):748-755.e3.
• Mix TC, Brenner RM, Cooper ME, de Zeeuw D, Ivanovich P, Levey AS, McGill JB, McMurray JJ, Parfrey PS, Parving HH, Pereira BJ, Remuzzi G, Singh AK, Solomon SD, Stehman-Breen C, Toto RD, Pfeffer MA. Rationale--Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease. Am Heart J. 2005 Mar;149(3):408-13.
• Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009 Nov 19;361(21):2019-32. Epub 2009 Oct 30.
• Skali H, Parving HH, Parfrey PS, Burdmann EA, Lewis EF, Ivanovich P, Keithi-Reddy SR, McGill JB, McMurray JJ, Singh AK, Solomon SD, Uno H, Pfeffer MA; TREAT Investigators. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with Darbepoetin Alfa: the trial to reduce cardiovascular events with Aranesp therapy (TREAT) experience. Circulation. 2011 Dec 20;124(25):2903-8. Epub 2011 Nov 21.
• Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, de Zeeuw D, Ivanovich P, Levey AS, Parfrey P, Remuzzi G, Singh AK, Toto R, Huang F, Rossert J, McMurray JJ, Pfeffer MA; Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010 Sep 16;363(12):1146-55.
• Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill J, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R, Uno H; TREAT Investigators. Baseline characteristics in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). Am J Kidney Dis. 2009 Jul;54(1):59-69. Epub 2009 Jun 5.
• Pfeffer MA; TREAT Executive Committee. An ongoing study of anemia correction in chronic kidney disease. N Engl J Med. 2007 Mar 1;356(9):959-61. No abstract available.

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