THOUSAND OAKS, Calif., Oct. 30 /PRNewswire-FirstCall/ -- Amgen (Nasdaq: AMGN) today announced the publication of results from TREAT (the Trial to Reduce Cardiovascular Events with Aranesp® Therapy), a large, randomized, double-blind, placebo-controlled, Phase 3 pivotal study of patients with chronic kidney disease (CKD) not on dialysis, moderate anemia and type-2 diabetes. The study, published online today in the New England Journal of Medicine and presented at the annual meeting of the American Society of Nephrology (ASN), failed to meet its primary objectives of demonstrating a reduction in all-cause mortality, cardiovascular morbidity, including heart failure, heart attack, stroke, or hospitalization for myocardial ischemia, or end-stage renal disease (ESRD).
The primary endpoints of the study were a composite of time to all-cause mortality or cardiovascular morbidity (including heart failure, heart attack, stroke, or hospitalization for myocardial ischemia) and a composite of time to all-cause mortality or ESRD. Among the components of the primary cardiovascular composite endpoint, the risk of stroke increased by almost two-fold in patients in the Aranesp arm (101 patients [5.0 percent] vs. 53 patients [2.6 percent]; hazard ratio, 1.92; 95 percent confidence interval, 1.38 to 2.68; P<0.001). Although stroke is a recognized risk with erythropoiesis-stimulating agent (ESA) therapy, and has been identified in warnings in United States (U.S.) labeling since 2001, the risk observed in TREAT is of higher magnitude than that seen in previous clinical trials in CKD patients not on dialysis.
A post hoc analysis indicates that there were no significant differences between treatment arms in the incidence of cancer or of all-cause deaths in patients who developed cancer during the trial. However, this analysis also showed an excess in overall mortality among patients in the Aranesp arm with a history of cancer. This finding requires further investigation.
"ESAs were originally approved to raise red blood cell levels and to reduce the need for transfusions. In the TREAT study, we sought to demonstrate that, beyond these benefits, ESA therapy reduces cardiovascular morbidity and mortality. This hypothesis is not supported by the data," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "As the first, large-scale placebo-controlled study to examine the use of anemia therapy in diabetic CKD patients not on dialysis, the TREAT results demonstrated that in many diabetic CKD patients not on dialysis with moderate anemia, the risk of treatment to a target hemoglobin level of 13 g/dL will exceed the benefit of reducing the need for transfusions."
Amgen has shared this information with global regulatory authorities and anticipates that the TREAT results will be included in labeling once discussions are complete.
TREAT Study Design
TREAT was an international, Phase 3, randomized, double-blind, placebo-controlled study of 4,038 CKD patients with type-2 diabetes and anemia. Designed as a superiority study to demonstrate improved cardiovascular outcomes, it is the largest study of ESA use in CKD patients to date. Patients enrolled in the study were randomized in a one-to-one ratio to receive either treatment with Aranesp to a target hemoglobin of 13 g/dL or placebo. Due to the increased risk of negative outcomes associated with low hemoglobin levels, patients in the control arm whose hemoglobin fell below 9 g/dL were given Aranesp as a rescue medication until their hemoglobin level reached 9 g/dL. Investigators were blinded to this intervention.
TREAT had two primary endpoints. The first evaluated the time to all-cause mortality or cardiovascular morbidity including heart attack (myocardial infarction), congestive heart failure, hospitalization for angina (myocardial ischemia), or stroke (cerebrovascular accident). The second primary endpoint evaluated the time to all-cause mortality or chronic dialysis. TREAT was not designed to determine the appropriate hemoglobin target in this patient population.
For patients randomized to the Aranesp group, the starting dose was 0.75 mcg/kg administered subcutaneously every two weeks; subsequent doses were titrated to achieve a hemoglobin target of 13.0 g/dL. Once the target hemoglobin was reached, the frequency of administration was extended to once-monthly. From 3 months to the end of treatment, the median achieved hemoglobin level was 12.5 g/dL (interquartile range, 12.0 to 12.8) in the Aranesp group and 10.6 g/dL (interquartile range, 9.9 to 11.3) in the placebo group. The average achieved hemoglobin level in the Aranesp-treated group exceeded current recommendations for anemia treatment as described in FDA-approved labeling.
Chronic Kidney Disease: Impact and Prevalence
CKD affects more than 26 million Americans and millions more worldwide. The disease is characterized by progressive kidney damage and impaired kidney function and is most often caused by type-2 diabetes or high blood pressure. When CKD progresses to kidney failure, chronic dialysis or a kidney transplant are required to sustain life. Anemia is a common complication of CKD that may begin in the early stages of the disease and becomes more common and severe as kidney function declines. Studies have shown that anemia is associated with an increased risk of mortality and cardiovascular morbidity in CKD patients.
Aranesp was approved by the FDA in 2001 for the treatment of anemia associated with CRF for patients on dialysis and patients not on dialysis. The European Commission granted marketing authorization for the same indication in 2001 and subsequently updated it for CRF patients with symptomatic anemia in 2008.
In 2002, the FDA approved Aranesp for the treatment of anemia caused by concomitantly administered chemotherapy in patients with nonmyeloid malignancies. The European Commission authorized the treatment of anemia caused by concomitantly administered chemotherapy in patients with non-haematological malignancies in 2002 and extended it to include non-myeloid malignancies in patients receiving chemotherapy in 2003.
Important Aranesp Safety Information
WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and TUMOR PROGRESSION
Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL.
-- ESAs shortened overall survival and/or time-to-tumor progression in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers when dosed to target a hemoglobin of greater than or equal to 12 g/dL.
-- The risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to target a hemoglobin of less than 12 g/dL.
-- To minimize these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusions.
-- Use only for treatment of anemia due to concomitant myelosuppressive chemotherapy.
-- ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. (This information is specific to the U.S. prescribing information)
-- Discontinue following the completion of a chemotherapy course.
Aranesp is contraindicated in patients with uncontrolled hypertension.
All patients, including patients with cancer or chronic kidney failure:
-- You may get serious heart problems such as heart attack, stroke, heart failure, and may die sooner if you are treated with Aranesp to a hemoglobin level above 12 g/dL.
-- You may get blood clots at any time while taking Aranesp. If you are receiving Aranesp and you are going to have surgery, talk to your healthcare provider about whether or not you need to take a blood thinner to lessen the chance of blood clots during or following surgery. Clots can form in blood vessels (veins), especially in your leg (deep venous thrombosis or DVT). Pieces of a blood clot may travel to the lungs and block the blood circulation in the lungs (pulmonary embolus).
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