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

Study Description

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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

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	5000 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 2013
Estimated Primary Completion Date :	July 2021

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Sulfonylurea (glimepiride); Sulfonylurea	Drug: Sulfonylurea (glimepiride); Used in accordance with labeling and/or usual practice.; Other Name: 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 Name: 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 Name: Liraglutide
Active Comparator: Insulin (glargine); Insulin (glargine), Lantus	Drug: Insulin (glargine); Used in accordance with labeling and/or usual practice.; Other Name: Lantus

Outcome Measures

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Primary Outcome Measures :

1. Time to HbA1c>=7%, while receiving metformin and the randomly assigned study medication [ Time Frame: 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 :

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

Other Outcome Measures:

1. Time to HbA1c>7.5%, while receiving study medications and basal insulin [ Time Frame: 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

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Ages Eligible for Study:	30 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

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

Sponsors and Collaborators

GRADE Study Group

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

National Heart, Lung, and Blood Institute (NHLBI)

Becton, Dickinson and Company

Bristol-Myers Squibb

Merck Sharp & Dohme Corp.

Novo Nordisk A/S

Roche Diagnostics

Sanofi

Investigators

Study Chair:	David M Nathan, MD	Massachusetts General Hospital

  Study Documents (Full-Text)

Documents provided by GRADE Study Group:

Statistical Analysis Plan  [PDF] October 5, 2017

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	GRADE Study Group
ClinicalTrials.gov Identifier:	NCT01794143 History of Changes
Other Study ID Numbers:	GRADE; 1U01DK098246-01 ( U.S. NIH Grant/Contract )
First Posted:	February 18, 2013
Last Update Posted:	March 30, 2018
Last Verified:	March 2018

Keywords provided by GRADE Study Group:

Treatment of Type 2 diabetes; Comparative effectiveness research; Clinical trial; Patient-centered outcomes

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Insulin, Globin Zinc; Glimepiride; Insulin; Sitagliptin Phosphate; Insulin Glargine; Liraglutide; Dipeptidyl-Peptidase IV Inhibitors	Hypoglycemic Agents; Physiological Effects of Drugs; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Immunosuppressive Agents; Immunologic Factors