A Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes (GRADE)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
ClinicalTrials.gov Identifier: NCT01794143 |
Recruitment Status
:
Active, not recruiting
First Posted
: February 18, 2013
Last Update Posted
: March 30, 2018
|
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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 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 |

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
|
- 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.
- 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.
- 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.

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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01794143

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 |
Study Chair: | David M Nathan, MD | Massachusetts General Hospital |
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 Key Record Dates |
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 |