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

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 : Completed
First Posted : February 18, 2013
Last Update Posted : April 14, 2022
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 LLC
Novo Nordisk A/S
Roche Diagnostics
Sanofi
Centers for Disease Control and Prevention
Information provided by (Responsible Party):
GRADE Study Group

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)
Actual Enrollment : 5047 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
Actual Primary Completion Date : April 30, 2021

Resource links provided by the National Library of Medicine


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, Older Adult)
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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Information from the National Library of Medicine

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


Locations
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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 LLC
Novo Nordisk A/S
Roche Diagnostics
Sanofi
Centers for Disease Control and Prevention
Investigators
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Study Chair: David M Nathan, MD Massachusetts General Hospital
  Study Documents (Full-Text)

Documents provided by GRADE Study Group:
Study Protocol  [PDF] March 17, 2017
Statistical Analysis Plan: GRADE Study  [PDF] October 5, 2017
Statistical Analysis Plan: Manuscript - Long Term Differences in Metabolic Status (OP1)  [PDF] March 22, 2022
Statistical Analysis Plan: Manuscript - Microvascular and Cardiovascular Outcomes (OP2)  [PDF] April 8, 2022
Informed Consent Form  [PDF] October 5, 2017

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: GRADE Study Group
ClinicalTrials.gov Identifier: NCT01794143    
Other Study ID Numbers: GRADE
1U01DK098246-01 ( U.S. NIH Grant/Contract )
First Posted: February 18, 2013    Key Record Dates
Last Update Posted: April 14, 2022
Last Verified: April 2022
Keywords provided by GRADE Study Group:
Treatment of Type 2 diabetes
Comparative effectiveness research
Clinical trial
Patient-centered outcomes
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Sitagliptin Phosphate
Liraglutide
Glimepiride
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