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

Type 2 Diabetes Clinical Trial

— GRADE  

Official title:

Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01794143
• Other study ID #: GRADE
• Secondary ID: 1U01DK098246-01
• Status: Completed
• Phase: Phase 3
• Start date: May 2013

Study information

• Verified date: April 2022
• Source: GRADE Study Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5047
• Est. primary completion date: April 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years and older

Eligibility

Inclusion Criteria:

1. Men or women diagnosed with diabetes at age = 30 years (= 20 for American Indians)

2. Duration of diagnosed diabetes < 10 years

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, 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

Exclusion Criteria:

1. 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)

2. 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)

3. More than 10 years of treatment with metformin at time of randomization screening

4. History of intolerance or allergy or other contraindications to any of the proposed study medications

5. Resides in the same household with another GRADE study participant

6. Current need for any specific glucose-lowering medications solely for other conditions, for example for polycystic ovary syndrome

7. Symptomatic hyperglycemia requiring immediate therapy during screening or run-in, in the judgment of the physician

8. A life-threatening event within 30 days prior to screening or currently planned major surgery

9. 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.

10. Plans for pregnancy during the course of the study for women of child-bearing potential

11. 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)

12. History of congestive heart failure (NYHA 3 or greater)

13. History of pancreatitis

14. History of cancer, other than non-melanoma skin cancer, that required therapy in the 5 years prior to randomization

15. Personal or family history of MEN-2 or family history of medullary thyroid cancer

16. Estimated GFR (eGFR) <30 ml/min/1.73 m2 or end stage renal disease requiring renal replacement therapy

17. History of severe liver disease or acute hepatitis or ALT > 3 times upper limit of normal

18. Current alcoholism or excessive alcohol intake

19. Previous organ transplant

20. 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)

21. Treatment with atypical antipsychotics

22. 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

23. Clinically or medically unstable with expected survival <1 year

24. Unwillingness to permit sites to contact the PCP to communicate information about the study and the participant's data

25. No non-study PCP or inability to identify such a PCP (who will provide non-study care) by the time of final run-in

26. Participation in another interventional clinical trial

27. Previous randomization in the GRADE study

28. In the opinion of the principal investigator (PI), any other factor, including language barrier, likely to limit compliance with the protocol

Related Conditions & MeSH terms

• Comparative Effectiveness of Glycemia-lowering Medications
• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes

Intervention

Drug:
• Sulfonylurea (glimepiride)
Used in accordance with labeling and/or usual practice.
• DPP-4 inhibitor (sitagliptin)
Used in accordance with labeling and/or usual practice
• GLP-1 receptor agonist (liraglutide)
Used in accordance with labeling and/or usual practice.
• Insulin (glargine)
Used in accordance with labeling and/or usual practice.

Locations

Country	Name	City	State
United States	University of New Mexico School of Medicine	Albuquerque	New Mexico
United States	University of Michigan	Ann Arbor	Michigan
United States	Pennington Biomedical Research Center	Baton Rouge	Louisiana
United States	University of Alabama-Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Albert Einstein College of Medicine	Bronx	New York
United States	State University of New York (SUNY)-Downstate Medical Center	Brooklyn	New York
United States	University of Cincinnati	Cincinnati	Ohio
United States	Case Western Reserve University School of Medicine	Cleveland	Ohio
United States	Baylor Endocrine Center	Dallas	Texas
United States	University of Texas-Southwestern Medical Center	Dallas	Texas
United States	Atlanta VA Medical Center	Decatur	Georgia
United States	University of Colorado	Denver	Colorado
United States	Kaiser Permanente of Georgia	Duluth	Georgia
United States	Duke University Medical Center	Durham	North Carolina
United States	University of North Carolina Diabetes Care Center	Durham	North Carolina
United States	Pacific Health Research and Education Institute (VA Pacific Islands)	Honolulu	Hawaii
United States	Baylor College of Medicine	Houston	Texas
United States	MedStar Health Research Institute	Hyattsville	Maryland
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	South Florida VA Foundation (Miami VA)	Miami	Florida
United States	International Diabetes Center	Minneapolis	Minnesota
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Columbia University Naomi Berrie Diabetes Center	New York	New York
United States	Mount Sinai St. Luke's Hospital	New York	New York
United States	University of Nebraska	Omaha	Nebraska
United States	Southwestern American Indian Center	Phoenix	Arizona
United States	Kaiser Permanente Northwest	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Texas Health Science Center	San Antonio	Texas
United States	Veterans Medical Research Foundation, San Diego (San Diego VA)	San Diego	California
United States	Seattle Institute for Biomedical and Clinical Research	Seattle	Washington

Sponsors (10)

Lead Sponsor	Collaborator
GRADE Study Group	Becton, Dickinson and Company, Bristol-Myers Squibb, Centers for Disease Control and Prevention, Merck Sharp & Dohme Corp., National Heart, Lung, and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Novo Nordisk A/S, Roche Diagnostics, Sanofi

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Time to HbA1c>7.5%, while receiving study medications and basal insulin	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.	Quarterly for 4 to 7 years
Primary	Time to HbA1c>=7%, while receiving metformin and the randomly assigned study medication	The primary metabolic outcome is the time to primary failure defined as an HbA1c>=7% (53mmol/mol), subsequently confirmed.	Quarterly for 4 to 7 years
Secondary	Time to HbA1c>7.5%, while receiving metformin and the randomly assigned study medication.	The secondary metabolic outcome is time to HbA1c>7.5% (58 mmol/mol), confirmed.	Quarterly for 4 to 7 years