Clinical trial NCT01794143: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes
Comparative Effectiveness of Glycemia-lowering Medications
Keywords: Treatment of Type 2 diabetes
Comparative effectiveness research
Clinical trial
Patient-centered outcomes
Lead sponsor: GRADE Study Group
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: National Heart, Lung, and Blood Institute (NHLBI)
name: Becton, Dickinson and Company
name: Bristol-Myers Squibb
name: Merck Sharp & Dohme LLC
name: Novo Nordisk A/S
name: Roche Diagnostics GmbH
name: Sanofi
name: Centers for Disease Control and Prevention
First posted: 2013-02-18
Enrollment: 5047
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Time to HbA1c>=7%, while receiving metformin and the randomly assigned study medication
timeFrame: Quarterly for 4 to 7 years
Secondary outcomes:
measure: Time to HbA1c>7.5%, while receiving metformin and the randomly assigned study medication.
timeFrame: Quarterly for 4 to 7 years
Other outcomes:
measure: Time to HbA1c>7.5%, while receiving study medications and basal insulin
timeFrame: Quarterly for 4 to 7 years
Locations:
city: Birmingham
country: United States
facility: University of Alabama-Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Southwestern American Indian Center
state: Arizona
city: San Diego
country: United States
facility: Veterans Medical Research Foundation, San Diego (San Diego VA)
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Miami
country: United States
facility: South Florida VA Foundation (Miami VA)
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical Center
state: Georgia
city: Duluth
country: United States
facility: Kaiser Permanente of Georgia
state: Georgia
city: Honolulu
country: United States
facility: Pacific Health Research and Education Institute (VA Pacific Islands)
state: Hawaii
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baton Rouge
country: United States
facility: Pennington Biomedical Research Center
state: Louisiana
city: Hyattsville
country: United States
facility: MedStar Health Research Institute
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: International Diabetes Center
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska
state: Nebraska
city: Albuquerque
country: United States
facility: University of New Mexico School of Medicine
state: New Mexico
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: Brooklyn
country: United States
facility: State University of New York (SUNY)-Downstate Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Naomi Berrie Diabetes Center
state: New York
city: New York
country: United States
facility: Mount Sinai St. Luke's Hospital
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Durham
country: United States
facility: University of North Carolina Diabetes Care Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University School of Medicine
state: Ohio
city: Portland
country: United States
facility: Kaiser Permanente Northwest
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Endocrine Center
state: Texas
city: Dallas
country: United States
facility: University of Texas-Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Seattle
country: United States
facility: Seattle Institute for Biomedical and Clinical Research
state: Washington
Study officials:
affiliation: Massachusetts General Hospital
name: David M Nathan, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.