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

April 13, 2022 updated by: GRADE Study Group

Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

5047

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

28 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Quarterly for 4 to 7 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Quarterly for 4 to 7 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Quarterly for 4 to 7 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

GRADE Study Group

Collaborators

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

Investigators

  • Study Chair: David M Nathan, MD, Massachusetts General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2013

Primary Completion (Actual)

April 30, 2021

Study Registration Dates

First Submitted

February 13, 2013

First Submitted That Met QC Criteria

February 14, 2013

First Posted (Estimate)

February 18, 2013

Study Record Updates

Last Update Posted (Actual)

April 14, 2022

Last Update Submitted That Met QC Criteria

April 13, 2022

Last Verified

April 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GRADE
  • 1U01DK098246-01 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Type 2 Diabetes

Clinical Trials on Sulfonylurea (glimepiride)

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Turkmenistan

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe