The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE Study)
This parallel group, unmasked clinical trial will randomize 5000 consenting subjects with
[Less Than]5 years duration of diagnosed type 2 diabetes, Hba1c from 6.8-8.5%, and who have been
treated with metformin alone. Subjects will adjust metformin during run-in, as
necessary, aiming for 2000 mg per day and those unable to tolerate at least 1000 mg/day will
eligible participants will be randomly assigned to one of four diabetes medications in combination with metformin. The principal comparisons will be among the four drug groups starting from the time of randomization.
Briefly, the primary outcome is the time to the observation of a Hba1c [Greater Than]7%, subsequently confirmed while
receiving the maximally tolerated dose of the assigned regimen (intention-to-treat principle).
The secondary outcome is the time to the observation of a Hba1c [Greater Than]7.5%, subsequently
confirmed, and the tertiary outcome is defined as the time to another Hba1c [Greater Than]7.5%, confirmed,
after treatment with basal insulin, at which time an intensive basal/bolus insulin regimen is
initiated. each of these outcomes is counted while receiving the maximally tolerated dose of the
assigned regimen and regardless of adherence to assigned medications at the time of the
Hba1c test according to principles of intention-to-treat analysis.
The study design and recruitment plan will allow a practical head-to-head
comparison among four different therapy combinations. The trial is designed to be pragmatic
(i.e. with immediate potential for translation) since we will be using approved medications and
their combinations according to labeling.
The trial will be conducted under an intent-to-treat design such that all randomized
subjects will continue follow-up and complete all outcome assessments until the planned
conclusion of the study (planned follow-up of 4 to 7 years, depending on the time of entry),
including those who have reached the primary outcome. otherwise, analyses of all outcomes
would be susceptible to a healthy survivor effect where the only subjects evaluated at out years
would be those who have not yet experienced primary failure of the assigned regimen.
in order to encourage retention in the study over time and ensure a longer exposure to
the study drug combination for the purposes of intention-to-treat analyses of other outcomes,
such as microalbuminuria, assigned study medications will be continued until the need for
intensification of insulin therapy with basal plus rapid-acting insulin. at the time that
the secondary metabolic outcome occurs, participants who were assigned to study medications
other than insulin will have basal insulin added to continued metformin and the original
randomly-assigned second medications.
The basal insulin will be adjusted according to the study insulin protocol. any subject whose Hba1c again reaches [Greater Than]7.5%, confirmed, while treated with basal insulin (after secondary metabolic outcome) will be considered to have reached the tertiary metabolic outcome. These subjects will continue their metformin and basal insulin therapy
regimen, intensify the insulin regimen with the addition of rapid-acting insulin, according to study
guidelines, and discontinue the original randomly assigned medications.
among subjects assigned to basal insulin plus metformin, when the secondary metabolic
outcome occurs, the insulin regimen (with metformin) will likewise be intensified.
on august 2013 Minor change in wording of specific aims regarding cardiovascular disease, which now includes electrocardiograms were added,
all subjects will be followed in GRaDe until study end. Metformin, the randomly
assigned drugs, and insulin and other supplies required for study insulin initiation, adjustment,
and intensification will be supplied free-of-charge throughout the study.
1. Men or women >=30 years of age at time of diabetes diagnosis; for American Indians, age
is >20 years at time of diagnosis
2. Duration of diagnosed diabetes <5 years determined as accurately as possible based on
available records at screening
3. HbA1c criteria (at final run-in visit, ~2 weeks prior to randomization): 6.8-8.5%
4. Taking a daily dose of >1000 mg metformin for a minimum of 8 weeks at final run-in
5. Willingness to administer daily subcutaneous injections, take a second diabetes drug
after randomization, potentially initiate insulin and intensify insulin therapy if study
metabolic goals are not met, and perform self-monitoring of blood glucose
6. Fluent in either English or Spanish
7. A negative pregnancy test for all females of childbearing potential (i.e. pre-menopausal,
and not surgically sterile)
8. Provision of signed and dated informed consent prior to any study procedures