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

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions:	Kidney Disease Diabetes Mellitus Anemia
Interventions:	Drug: Placebo Drug: darbepoetin alfa

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
First Subject Enrolled: 25 Aug 2004 Last Subject Enrolled: 04 Dec 2007

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
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.
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.

Participant Flow: Overall Study

	Placebo	Darbepoetin Alfa
STARTED	2026	2012
Received Study Medication	2019	2004
COMPLETED	1361	1348
NOT COMPLETED	665	664
Withdrawal by Subject	194	171
Lost to Follow-up	96	108
Death	375	385

Baseline Characteristics

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Reporting Groups

	Description
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.
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.

Baseline Measures

	Darbepoetin Alfa	Placebo	Total
Number of Participants [units: participants]	2012	2026	4038
Age [units: Years] Mean ± Standard Deviation	67.2 ± 10.7	67.5 ± 10.6	67.4 ± 10.6
Gender [units: Participants]
Female	1178	1134	2312
Male	834	892	1726
Race/Ethnicity, Customized [units: Participants]
White or Caucasian	1270	1300	2570
Black or African American	414	401	815
Hispanic or Latino	273	265	538
Asian	35	43	78
Japanese	8	3	11
American Indian or Alaska Native	1	4	5
Native Hawaiian or Other Pacific Islander	4	5	9
Aborigine	2	1	3
Other	5	4	9
History of cardiovascular disease ^[1] [units: Participant]
With history of cardiovascular disease	1287	1355	2642
Without history of cardiovascular disease	725	671	1396
Baseline proteinuria level ^[2] [units: Participants]
>= 1 g/g creat	686	711	1397
< 1 g/g creat	1324	1315	2639

[1]	Cardiovascular disease history is based on the cardiovascular medical history case report form.
[2]	Baseline proteinuria level (g/g creat). Baseline proteinuria is defined as the last non-missing measurement prior or on the day of first investigational product.

Outcome Measures

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1. 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 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 ]

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2. Primary:

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 ]

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3. Secondary:

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 ]

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4. Secondary:

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 ]

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5. Secondary:

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 ]

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6. Secondary:

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 ]

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7. Secondary:

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 ]

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8. Secondary:

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 ]

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9. Secondary:

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 ]

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10. Secondary:

Change in Patient Reported Fatigue Relative to Baseline at Week 25 [ Time Frame: Baseline and week 25 ]

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11. Secondary:

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 ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multi-center studies, the investigator agrees not to publish any results before the first multi-center publication.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
4047 subjects were enrolled, but before unblinding, all information from 9 subjects was excluded from two sites (3 and 6 subjects, respectively) that did not adhere to Good Clinical Practice guidelines. 4038 subjects were analyzed and reported.

Results Point of Contact:

Name/Title: Study Director
Organization: Amgen Inc.
phone: 866-572-6436

Publications of Results:

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.

Publications automatically indexed to this study:

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.

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.

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.

Responsible Party:	Global Development Leader, Amgen Inc.
ClinicalTrials.gov Identifier:	NCT00093015 History of Changes
Other Study ID Numbers:	20010184, TREAT
Study First Received:	September 28, 2004
Results First Received:	August 6, 2010
Last Updated:	June 30, 2011
Health Authority:	United States: Food and Drug Administration