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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 : Active, not recruiting
First Posted : February 18, 2013
Last Update Posted : August 12, 2019
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

Tracking Information
First Submitted Date  ICMJE February 13, 2013
First Posted Date  ICMJE February 18, 2013
Last Update Posted Date August 12, 2019
Study Start Date  ICMJE May 2013
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 14, 2013)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01794143 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2013)
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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 14, 2013)
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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes
Official Title  ICMJE Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Type 2 Diabetes
  • Comparative Effectiveness of Glycemia-lowering Medications
Intervention  ICMJE
  • Drug: Sulfonylurea (glimepiride)
    Used in accordance with labeling and/or usual practice.
    Other Name: Glimepiride
  • Drug: DPP-4 inhibitor (sitagliptin)
    Used in accordance with labeling and/or usual practice
    Other Name: Sitagliptin
  • Drug: GLP-1 receptor agonist (liraglutide)
    Used in accordance with labeling and/or usual practice.
    Other Name: Liraglutide
  • Drug: Insulin (glargine)
    Used in accordance with labeling and/or usual practice.
    Other Name: Lantus
Study Arms  ICMJE
  • Active Comparator: Sulfonylurea (glimepiride)
    Sulfonylurea
    Intervention: Drug: Sulfonylurea (glimepiride)
  • Active Comparator: DPP-4 inhibitor
    DPP-4 inhibitor (sitagliptin)
    Intervention: Drug: DPP-4 inhibitor (sitagliptin)
  • Active Comparator: GLP-1 receptor agonist
    GLP-1 receptor agonist (liraglutide)
    Intervention: Drug: GLP-1 receptor agonist (liraglutide)
  • Active Comparator: Insulin (glargine)
    Insulin (glargine), Lantus
    Intervention: Drug: Insulin (glargine)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 29, 2019)
5047
Original Estimated Enrollment  ICMJE
 (submitted: February 14, 2013)
5000
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01794143
Other Study ID Numbers  ICMJE GRADE
1U01DK098246-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GRADE Study Group
Study Sponsor  ICMJE GRADE Study Group
Collaborators  ICMJE
  • 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  ICMJE
Study Chair: David M Nathan, MD Massachusetts General Hospital
PRS Account GRADE Study Group
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP