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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
GRADE Study Group
ClinicalTrials.gov Identifier:
NCT01794143
First received: February 13, 2013
Last updated: July 7, 2017
Last verified: July 2017
  Purpose
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 Intervention 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
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study

Resource links provided by NLM:


Further study details as provided by GRADE Study Group:

Primary Outcome Measures:
  • 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:
  • 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:
  • 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.


Estimated Enrollment: 5000
Study Start Date: May 2013
Estimated Primary Completion Date: August 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01794143

  Hide Study Locations
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
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
Albert Einstein College of Medicine
The Bronx, 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
  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 )
Study First Received: February 13, 2013
Last Updated: July 7, 2017

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

ClinicalTrials.gov processed this record on September 21, 2017