GRADE: A Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes

Sponsor

GRADE Study Group (Other)

Overall Status

Completed

CT.gov ID

NCT01794143

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH), Becton, Dickinson and Company (Industry), Bristol-Myers Squibb (Industry), Merck Sharp & Dohme LLC (Industry), Novo Nordisk A/S (Industry), Roche Diagnostics (Industry), Sanofi (Industry), Centers for Disease Control and Prevention (U.S. Fed)

5,047

Enrollment

Locations

Arms

140.2

Patients Per Site

Study Details

Study Description

Brief Summary

The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Comparative Effectiveness of Glycemia-lowering Medications	Drug: Sulfonylurea (glimepiride) Drug: DPP-4 inhibitor (sitagliptin) Drug: GLP-1 receptor agonist (liraglutide) Drug: Insulin (glargine)	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

5047 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study

Study Start Date :

May 1, 2013

Actual Primary Completion Date :

Apr 30, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Sulfonylurea (glimepiride) Sulfonylurea	Drug: Sulfonylurea (glimepiride) Used in accordance with labeling and/or usual practice. Other Names: Glimepiride
Active Comparator: DPP-4 inhibitor DPP-4 inhibitor (sitagliptin)	Drug: DPP-4 inhibitor (sitagliptin) Used in accordance with labeling and/or usual practice Other Names: Sitagliptin
Active Comparator: GLP-1 receptor agonist GLP-1 receptor agonist (liraglutide)	Drug: GLP-1 receptor agonist (liraglutide) Used in accordance with labeling and/or usual practice. Other Names: Liraglutide
Active Comparator: Insulin (glargine) Insulin (glargine), Lantus	Drug: Insulin (glargine) Used in accordance with labeling and/or usual practice. Other Names: Lantus

Outcome Measures

Primary Outcome Measures

Time to HbA1c>=7%, while receiving metformin and the randomly assigned study medication [Quarterly for 4 to 7 years]
The primary metabolic outcome is the time to primary failure defined as an HbA1c>=7% (53mmol/mol), subsequently confirmed.

Secondary Outcome Measures

Time to HbA1c>7.5%, while receiving metformin and the randomly assigned study medication. [Quarterly for 4 to 7 years]
The secondary metabolic outcome is time to HbA1c>7.5% (58 mmol/mol), confirmed.

Other Outcome Measures

Time to HbA1c>7.5%, while receiving study medications and basal insulin [Quarterly for 4 to 7 years]
The tertially metabolic outcome is the time to a HbA1c>7.5% (58 mmol/mol), confirmed, while receiving metformin, the originally assigned medication and basal insulin.

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Men or women diagnosed with diabetes at age ≥ 30 years (≥ 20 for American Indians)
Duration of diagnosed diabetes < 10 years
HbA1c criteria (at final run-in visit, ~2 weeks prior to randomization): 6.8-8.5%
Taking a daily dose of ≥ 1000 mg metformin for a minimum of 8 weeks at final run-in
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, perform self-monitoring of blood glucose
Fluent in either English or Spanish
A negative pregnancy test for all females of childbearing potential (i.e. pre-menopausal, and not surgically sterile)
Provision of signed and dated informed consent prior to any study procedures

Exclusion Criteria:

Suspected type 1 diabetes (lean with polyuria, polydipsia, and weight loss with little response to metformin) or "secondary" diabetes due to specific causes (e.g. previously diagnosed monogenic syndromes, pancreatic surgery, pancreatitis)
Current or previous (within past 6 months) treatment with any diabetes drug/glucose-lowering medication other than metformin (limited use of no longer than seven days is allowed, for example during hospitalization)
More than 10 years of treatment with metformin at time of randomization screening
History of intolerance or allergy or other contraindications to any of the proposed study medications
Resides in the same household with another GRADE study participant
Current need for any specific glucose-lowering medications solely for other conditions, for example for polycystic ovary syndrome
Symptomatic hyperglycemia requiring immediate therapy during screening or run-in, in the judgment of the physician
A life-threatening event within 30 days prior to screening or currently planned major surgery
Any major cardiovascular event in previous year, including history of myocardial infarction, stroke, or vascular procedure such as coronary artery or peripheral bypass grafting, stent placements (peripheral or coronary) or angioplasty.
Plans for pregnancy during the course of the study for women of child-bearing potential
History of or planning bariatric surgery, including banding procedures or surgical gastric and/or intestinal bypass (if banding removed, may be considered eligible after 1 year)
History of congestive heart failure (NYHA 3 or greater)
History of pancreatitis
History of cancer, other than non-melanoma skin cancer, that required therapy in the 5 years prior to randomization
Personal or family history of MEN-2 or family history of medullary thyroid cancer
Estimated GFR (eGFR) <30 ml/min/1.73 m2 or end stage renal disease requiring renal replacement therapy
History of severe liver disease or acute hepatitis or ALT > 3 times upper limit of normal
Current alcoholism or excessive alcohol intake
Previous organ transplant
Treatment with oral or systemic glucocorticoids (other than short-term treatment, for example for poison ivy) or disease likely to require periodic or regular glucocorticoid therapy (inhaled steroids are allowed)
Treatment with atypical antipsychotics
History of hemolytic anemia, chronic transfusion requirement, or other condition rendering HbA1c results unreliable as indicator of chronic glucose levels, or hematocrit <35 for males and <33 for females
Clinically or medically unstable with expected survival <1 year
Unwillingness to permit sites to contact the PCP to communicate information about the study and the participant's data
No non-study PCP or inability to identify such a PCP (who will provide non-study care) by the time of final run-in
Participation in another interventional clinical trial
Previous randomization in the GRADE study
In the opinion of the principal investigator (PI), any other factor, including language barrier, likely to limit compliance with the protocol

Contacts and Locations

Locations

	Site	City	State	Country
1	University of Alabama-Birmingham	Birmingham	Alabama	United States
2	Southwestern American Indian Center	Phoenix	Arizona	United States
3	Veterans Medical Research Foundation, San Diego (San Diego VA)	San Diego	California	United States
4	University of Colorado	Denver	Colorado	United States
5	Yale University School of Medicine	New Haven	Connecticut	United States
6	South Florida VA Foundation (Miami VA)	Miami	Florida	United States
7	Atlanta VA Medical Center	Decatur	Georgia	United States
8	Kaiser Permanente of Georgia	Duluth	Georgia	United States
9	Pacific Health Research and Education Institute (VA Pacific Islands)	Honolulu	Hawaii	United States
10	Indiana University School of Medicine	Indianapolis	Indiana	United States
11	University of Iowa	Iowa City	Iowa	United States
12	Pennington Biomedical Research Center	Baton Rouge	Louisiana	United States
13	MedStar Health Research Institute	Hyattsville	Maryland	United States
14	Massachusetts General Hospital	Boston	Massachusetts	United States
15	University of Michigan	Ann Arbor	Michigan	United States
16	International Diabetes Center	Minneapolis	Minnesota	United States
17	University of Minnesota	Minneapolis	Minnesota	United States
18	Washington University School of Medicine	Saint Louis	Missouri	United States
19	University of Nebraska	Omaha	Nebraska	United States
20	University of New Mexico School of Medicine	Albuquerque	New Mexico	United States
21	Albert Einstein College of Medicine	Bronx	New York	United States
22	State University of New York (SUNY)-Downstate Medical Center	Brooklyn	New York	United States
23	Columbia University Naomi Berrie Diabetes Center	New York	New York	United States
24	Mount Sinai St. Luke's Hospital	New York	New York	United States
25	Duke University Medical Center	Durham	North Carolina	United States
26	University of North Carolina Diabetes Care Center	Durham	North Carolina	United States
27	University of Cincinnati	Cincinnati	Ohio	United States
28	Case Western Reserve University School of Medicine	Cleveland	Ohio	United States
29	Kaiser Permanente Northwest	Portland	Oregon	United States
30	Oregon Health and Science University	Portland	Oregon	United States
31	Vanderbilt University Medical Center	Nashville	Tennessee	United States
32	Baylor Endocrine Center	Dallas	Texas	United States
33	University of Texas-Southwestern Medical Center	Dallas	Texas	United States
34	Baylor College of Medicine	Houston	Texas	United States
35	University of Texas Health Science Center	San Antonio	Texas	United States
36	Seattle Institute for Biomedical and Clinical Research	Seattle	Washington	United States