TITLE: A TRIAL OF DARBEPOETIN ALFA IN TYPE 2 DIABETES AND CHRONIC

KIDNEY DISEASE

ABSTRACT:

The study was done on 4038 patients with anemia, type 2 diabetes (T2D), and chronic
kidney disease (CKD) who were randomly assigned to treatment with darbepoetin alfa,
DA (n = 2012) or placebo (n = 2026). Primary composite endpoints were outcomes of
death or cardiovascular events (CVE) and death or end-stage renal disease (ESRD).
Compared with placebo, results with DA showed higher incidence of death or CVE (632
versus 602 patients; hazard ratio 1.05; 95% CI, 0.94 to 1.17; p = 0.41), death or ESRD
(652 versus 618 patients, hazard ratio 1.06; 95% CI, 0.95 to 1.19; p = 0.29), fatal or non-
fatal stroke (101 versus 53 patients, hazard ratio 1.92; 95% CI, .1.38-2.68; p <0.001) and
a slight improvement in the reported patient’s fatigue.

INTRODUCTION

T2D and CKD have been associated with high risk of CVE and ESRD. Erythropoiesis
stimulating agents (ESAs) increase hemoglobin (hgb) levels but whether this lowers the
associated risks is unknown. Previous studies have shown that the use of ESA in patients
with severe anemia and undergoing dialysis improves quality of life. However, no studies
have been done on ESA’s ability to reduce the associated risks in these patients. Hence
the Trial to Reduce CVE with Aranesp Therapy (TREAT) in patients with T2D, CKD not
undergoing dialysis and anemia, was undertaken.

METHODS

Participants, settings and locations

All patients with T2D, CKD (estimated glomerular filtration rate, GFR: 20-60
mL/min/1.73 m2 of body surface area, using the modification of diet in renal disease,
MDRD formula), anemia (hgb < 11 gram/deciliter, g/dL) and transferrin saturation of <
15% were eligible for enrollment. They were not admitted to study if the following
criteria were present: uncontrolled hypertension, kidney transplantation or scheduled
kidney transplantation, current use of intravenous antibiotics, chemotherapy or radiation
therapy, cancer (except skin cancer), diagnosed human immunodeficiency virus infection,
active bleeding, hematologic disease or pregnancy, pts who had a CVE or grand mal
seizure or had received an ESA in the 12 weeks before randomization.

The study was sponsored by AMGEN in collaboration with the University of Wisconsin
UW) in 24 countries at 623 sites. Data collection and management were undertaken by
the sponsor and the statistical data analysis were done by UW statistical center. The
principal investigators wrote and edited the manuscript.
Objectives

The objective of the study is to test the hypothesis that Aranesp therapy will reduce death
from any cause and the risk factors (CVE or ESRD) associated with T2D, CKD and
anemia.

Outcomes

The time to composite outcomes of death from any causes or CVE and death from any
cause or ESRD were the set primary endpoints. The secondary endpoints included the 1)
time to death and death from CV causes and components of primary endpoints, 2) GFR
decline rate, and 3) changes in patient’s outcome measured at week 25. Patient reported
outcome were measured by Functional Assessment of Cancer Therapy-Fatigue (FACT-
Fatigue) instrument (uses scale of 0-52 with high score reflecting less fatigue) and the 36-
item Short-Form General health Survey questionnaire (norm-based scale of 50 as the
average, high score indicates better quality of life).

Sample size, randomization, monitoring

The TREAT trial is a randomized, double-blind, placebo controlled study that involved
4038 participants of which 2012 patients were randomly assigned to darbepoetin alfa
(DA) to achieve a hgb level of 13 g/dL and 2026 patients to placebo using a computer
generated design 1:1 ratio. Randomization was stratified according to the following:
study site, patients baseline proteinuria level, and CVE history. Prefilled syringes of DA
and placebo were supplied as matching syringes. A point of care device was used to read
and enter the hgb levels, and using an algorithm, adjusted the dose to maintain a level of
13 g/dL. Patients in the placebo group were given DA if the hgb level fell below 9 g/dL
and returned to placebo group once hgb becomes > 9 g/dL. Site investigators were
notified if a patient had a 16g/dL < hgb < 7g/dL or a hgb decrease of 2 g/dL in a 4-week
period.

The hgb level and vital sign measurements were taken every two weeks during the drug
titration period and monthly thereafter, transferrin saturation and ferritin level were
measured quarterly while the other lab data were taken every 24 weeks. Patients were
assessed of any adverse events, hospitalization, transfusions and concomitant use of other
drugs on each visit at weeks 1, 13, 25 and every 24 weeks thereafter.

Monthly reports are reviewed by independent data and safety monitoring committee with
analyses scheduled when approximately 20, 40, 60 and 80% of CVE had occurred. With
a previous study on a different ESA showing that treatment with higher hgb level (13.5
g/dL versus 11.5 g/dL) is associated with higher rates of ADE, the consent form was
modified to include this information, with all participants asked to provide the form
again. The committee was requested to adopt a stopping rule at each assessment for either
CV component outcome or death.
Statistical methods

To draw meaningful conclusions, a statistical power of 80% is needed to detect a 20%

risk reduction for an event driven trial, requiring CV composite events of 1203.
Assumptions made during the enrollment of approximately 4000 patients included the
following: 12.5% annual event rate on placebo group, 15% loss to follow-up, attenuation
of treatment effect due to ESA anticipated use in ESRD patients. The study results were
analyzed according to the intention-to-treat principle using all patients whether they
completed study duration. Survival analysis was done using the Kaplan-Meier method
and the Cox hazard model hazard ratios and its 95% CI. All patients including dialysis
and transplantation patients were followed for study endpoints. T-test and p values were
used to compare treatments.