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

• ClinicalTrials.gov Identifier: NCT01794143
• Recruitment Status: Completed
• First Posted: February 18, 2013
• Last Update Posted: April 14, 2022
• Sponsor: GRADE Study Group
• 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

Tracking Information

• First Submitted Date: February 13, 2013
• First Posted Date: February 18, 2013
• Last Update Posted Date: April 14, 2022
• Study Start Date: May 2013
• Actual Primary Completion Date: April 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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: 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: A Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes
• Official Title: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Type 2 Diabetes
• Comparative Effectiveness of Glycemia-lowering Medications

Intervention

• 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

• 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 *

• GRADE Study Research Group; Nathan DM, Lachin JM, Bebu I, Burch HB, Buse JB, Cherrington AL, Fortmann SP, Green JB, Kahn SE, Kirkman MS, Krause-Steinrauf H, Larkin ME, Phillips LS, Pop-Busui R, Steffes M, Tiktin M, Tripputi M, Wexler DJ, Younes N. Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes. N Engl J Med. 2022 Sep 22;387(12):1075-1088. doi: 10.1056/NEJMoa2200436.
• GRADE Study Research Group; Nathan DM, Lachin JM, Balasubramanyam A, Burch HB, Buse JB, Butera NM, Cohen RM, Crandall JP, Kahn SE, Krause-Steinrauf H, Larkin ME, Rasouli N, Tiktin M, Wexler DJ, Younes N. Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes. N Engl J Med. 2022 Sep 22;387(12):1063-1074. doi: 10.1056/NEJMoa2200433.
• Barzilay JI, Ghosh A, Busui RP, Ahmann A, Balasubramanyam A, Banerji MA, Cohen RM, Green J, Ismail-Beigi F, Martin CL, Seaquist E, Luchsinger JA; GRADE Research Group. The cross-sectional association of cognition with diabetic peripheral and autonomic neuropathy-The GRADE study. J Diabetes Complications. 2021 Dec;35(12):108047. doi: 10.1016/j.jdiacomp.2021.108047. Epub 2021 Sep 15.
• Utzschneider KM, Younes N, Rasouli N, Barzilay JI, Banerji MA, Cohen RM, Gonzalez EV, Ismail-Beigi F, Mather KJ, Raskin P, Wexler DJ, Lachin JM, Kahn SE; GRADE Research Group. Shape of the OGTT glucose response curve: relationship with beta-cell function and differences by sex, race, and BMI in adults with early type 2 diabetes treated with metformin. BMJ Open Diabetes Res Care. 2021 Sep;9(1):e002264. doi: 10.1136/bmjdrc-2021-002264.
• Luchsinger JA, Younes N, Manly JJ, Barzilay J, Valencia W, Larkin ME, Falck-Ytter C, Krause-Steinrauf H, Pop-Busui R, Florez H, Seaquist E; GRADE Research Group; GRADE Research Group Investigators:. Association of Glycemia, Lipids, and Blood Pressure With Cognitive Performance in People With Type 2 Diabetes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2021 Oct;44(10):2286-2292. doi: 10.2337/dc20-2858. Epub 2021 Jul 20.
• Cherrington AL, Krause-Steinrauf H, Bebu I, Naik AD, Walker E, Golden SH, Gonzalez JS; GRADE Research Group. Study of emotional distress in a comparative effectiveness trial of diabetes treatments: Rationale and design. Contemp Clin Trials. 2021 Aug;107:106366. doi: 10.1016/j.cct.2021.106366. Epub 2021 Mar 22.
• Utzschneider KM, Younes N, Rasouli N, Barzilay J, Banerji MA, Cohen RM, Gonzalez EV, Mather KJ, Ismail-Beigi F, Raskin P, Wexler DJ, Lachin JM, Kahn SE; GRADE Research Group. Association of glycemia with insulin sensitivity and beta-cell function in adults with early type 2 diabetes on metformin alone. J Diabetes Complications. 2021 May;35(5):107912. doi: 10.1016/j.jdiacomp.2021.107912. Epub 2021 Mar 17.
• Rasouli N, Younes N, Utzschneider KM, Inzucchi SE, Balasubramanyam A, Cherrington AL, Ismail-Beigi F, Cohen RM, Olson DE, DeFronzo RA, Herman WH, Lachin JM, Kahn SE; GRADE Research Group. Association of Baseline Characteristics With Insulin Sensitivity and beta-Cell Function in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study Cohort. Diabetes Care. 2021 Feb;44(2):340-349. doi: 10.2337/dc20-1787. Epub 2020 Dec 17.
• Sivitz WI, Phillips LS, Wexler DJ, Fortmann SP, Camp AW, Tiktin M, Perez M, Craig J, Hollander PA, Cherrington A, Aroda VR, Tan MH, Krakoff J, Rasouli N, Butera NM, Younes N; GRADE Research Group. Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight. Diabetes Care. 2020 May;43(5):940-947. doi: 10.2337/dc19-1769. Epub 2020 Mar 5.
• Wexler DJ, Krause-Steinrauf H, Crandall JP, Florez HJ, Hox SH, Kuhn A, Sood A, Underkofler C, Aroda VR; GRADE Research Group. Baseline Characteristics of Randomized Participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care. 2019 Nov;42(11):2098-2107. doi: 10.2337/dc19-0901. Epub 2019 Aug 7.
• Behringer-Massera S, Browne T, George G, Duran S, Cherrington A, McKee MD; GRADE Research Group. Facilitators and barriers to successful recruitment into a large comparative effectiveness trial: a qualitative study. J Comp Eff Res. 2019 Jul;8(10):815-826. doi: 10.2217/cer-2019-0010. Epub 2019 Aug 1.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 29, 2019): 5047
• Original Estimated Enrollment (submitted: February 14, 2013): 5000
• Study Completion Date: Not Provided
• Actual Primary Completion Date: April 30, 2021 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 30 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01794143
• Other Study ID Numbers: GRADE; 1U01DK098246-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: GRADE Study Group
• Original Responsible Party: Same as current
• Current Study Sponsor: GRADE Study Group
• Original Study Sponsor: Same as current

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

Investigators

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

• PRS Account: GRADE Study Group
• Verification Date: April 2022