Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY)

• Glycemic control [ Time Frame: entire study ] [ Designated as safety issue: No ]
• Safety [ Time Frame: entire study ] [ Designated as safety issue: Yes ]
• Insulin sensitivity and secretion [ Time Frame: entire study ] [ Designated as safety issue: No ]
• Body composition [ Time Frame: entire study ] [ Designated as safety issue: No ]
• Nutrition/dietary intake [ Time Frame: entire study ] [ Designated as safety issue: No ]
• Physical activity [ Time Frame: entire study ] [ Designated as safety issue: No ]
• Physical fitness [ Time Frame: entire study ] [ Designated as safety issue: No ]
• Cardiovascular risk factors [ Time Frame: entire study ] [ Designated as safety issue: No ]
• Microvascular complications [ Time Frame: entire study ] [ Designated as safety issue: No ]
• Quality of life and psychological measures [ Time Frame: entire study ] [ Designated as safety issue: No ]
• Resource utilization and cost [ Time Frame: entire study ] [ Designated as safety issue: No ]
• Gene expression [ Time Frame: one time collection of genetic material ] [ Designated as safety issue: No ]

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) has sponsored a consortium of investigators to conduct a clinical treatment trial, Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY).

The primary objective of the TODAY trial is to compare the efficacy of three treatment arms on time to treatment failure based on glycemic control. The secondary aims are to:

• compare and evaluate the safety of the three treatment arms;
• compare the effects of the three treatments on the pathophysiology of type 2 diabetes (T2D) with regards to beta cell function and insulin resistance, body composition, nutrition, physical activity and aerobic fitness, cardiovascular risk factors, microvascular complications, quality of life, and psychological outcomes;
• evaluate the influence of individual and family behaviors on treatment response; and
• compare the relative cost effectiveness of the three treatment arms.

The three treatment regimens are: (1) metformin alone, (2) metformin plus rosiglitazone, and (3) metformin plus an intensive lifestyle intervention called the TODAY Lifestyle Program (TLP). The study recruits patients over a three-year period and follows patients for a minimum of two years. Patients are randomized within two years of the diagnosis of T2D.

• Drug: Metformin
  capsule, 1000 mg bid
• Drug: Rosiglitazone
  capsule, 4 mg bid
• Behavioral: TODAY Lifestyle Program
  a lifestyle change (LC) phase of weekly sessions for months 1-6, followed by a bi-weekly lifestyle maintenance (LM) phase through months 7-12, and a continued contact (CC) phase from months 13 through the end of the study. The CC phase sessions are scheduled monthly for the initial 12 months (study months 13-24) and then quarterly or 4 times a year to the end of the study

• Experimental: 1
  Metformin alone
  Intervention: Drug: Metformin
• Experimental: 2
  Metformin + Rosiglitazone
  Interventions:

  • Drug: Metformin
  • Drug: Rosiglitazone
• Experimental: 3
  Metformin + TODAY Lifestyle Program
  Interventions:

  • Drug: Metformin
  • Behavioral: TODAY Lifestyle Program

• Klingensmith GJ, Pyle L, Arslanian S, Copeland KC, Cuttler L, Kaufman F, Laffel L, Marcovina S, Tollefsen SE, Weinstock RS, Linder B; TODAY Study Group. The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: results from the TODAY study. Diabetes Care. 2010 Sep;33(9):1970-5. Epub 2010 Jun 2.
• Copeland KC, Zeitler P, Geffner M, Guandalini C, Higgins J, Hirst K, Kaufman FR, Linder B, Marcovina S, McGuigan P, Pyle L, Tamborlane W, Willi S; TODAY Study Group. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab. 2011 Jan;96(1):159-67. Epub 2010 Oct 20.
• The TODAY Study Group; Zeitler P, Epstein L, Grey M, Hirst K, Kaufman F, Tamborlane W, Wilfley D. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes. 2007 Apr;8(2):74-87.
• Songer T, Glazner J, Coombs L, Cuttler L, Daniel M, Estrada S, Klingensmith G, Kriska A, Laffel L, Zhang P, for the TODAY Study Group. Examining the economic costs related to lifestyle and pharmacological inerventions in youth with type 2 diabetes. Expert Rev Pharmacoeconomics Outcomes Res, 6(3):315-324, 2006.
• Grey M, Schreiner B, Pyle L. Development of a diabetes education program for youth with type 2 diabetes. Diabetes Educ. 2009 Jan-Feb;35(1):108-16.
• TODAY Study Group. Design of a family-based lifestyle intervention for youth with type 2 diabetes: the TODAY study. Int J Obes (Lond). 2010 Feb;34(2):217-26. Epub 2009 Oct 13. Review.
• TODAY Study Group, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, Arslanian S, Cuttler L, Nathan DM, Tollefsen S, Wilfley D, Kaufman F. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012 Jun 14;366(24):2247-56. Epub 2012 Apr 29.
• Anderson BJ, Edelstein S, Abramson NW, Katz LE, Yasuda PM, Lavietes SJ, Trief PM, Tollefsen SE, McKay SV, Kringas P, Casey TL, Marcus MD. Depressive symptoms and quality of life in adolescents with type 2 diabetes: baseline data from the TODAY study. Diabetes Care. 2011 Oct;34(10):2205-7. Epub 2011 Aug 11.

Inclusion Criteria (during Screening and Run-in period):

• Diabetes by ADA criteria (laboratory determinations of fasting glucose ≥ 126 mg/dL, random glucose ≥ 200 mg/dL, or two-hour OGTT glucose ≥ 200 mg/dL) documented and confirmed in medical record. For patients diagnosed with diabetes during screening who have a normal fasting glucose but an elevated two-hour glucose during an OGTT, the HbA1c must be ≥ 6%.
• Duration since diagnosis less than two years by date of randomization.
• BMI ≥ 85th percentile documented at time of diagnosis or at screening.
• Fasting C-peptide at screening (drawn at least one week after treatment for ketosis or acidosis, if applicable) > 0.6 ng/mL.
• Absence of pancreatic autoimmunity (both GAD and ICA512 negative).
• Age 10-17, with randomization prior to 18th birthday.
• Signed informed consent/assent forms for the pre-randomization period.
• A family member or adult closely involved in the daily activities of the child agrees to participate in the child's treatment.
• Fluency in English or Spanish for both child and family member.
• Patient and family able to fully participate in trial protocol in the opinion of the investigator.

Exclusion Criteria (during Screening and Run-in period):

• Participating in another interventional research study protocol in the past 30 days.
• Genetic syndrome or disorder known to affect glucose tolerance other than diabetes.
• Patient on inhaled steroids at dose above 1000 mcg daily Flovent equivalent.
• Patient on a course of oral steroids within the last 60 days or on oral steroids more than 20 days during the past year.
• Patient on medication(s) that are known to affect insulin sensitivity or secretion within the last 30 days.
• Patient on medication(s) that are known to cause weight gain within the last 30 days.
• Patient on any weight-loss medication(s) within the last 30 days.
• Patient on medication(s) known to affect the metabolism of study drug.
• Inability to comprehend the lowest grade level at which lifestyle intervention materials are prepared, for both child and participating family member.
• Females who are pregnant, planning to become pregnant within two years of enrollment, or who admit sexual activity without appropriate contraception.
• Calculated creatinine clearance < 70 mL/min.
• Any transaminase > 2.5 ULN. If any transaminase 1.5-2.5 times ULN, then patient must be appropriately evaluated by PCP (minimum evaluation includes ceruloplasmin level, alpha-1 antitrypsin phenotype, ANA, anti-smooth muscle antibody, anti-LKM antibody, anti-HCV, and anti-HBc total antibody not IgM, iron, and TIBC) and is eligible if all other causes for elevation are ruled out and it is presumed due only to non-alcoholic fatty liver disease (NAFLD).
• Diabetic ketoacidosis (DKA) at any time after diagnosis unless only a single episode of DKA related to a significant medical illness.
• Physical limitations preventing patient from being randomized to the lifestyle intervention.
• Patient plans to leave the geographic area within one calendar year.
• Abnormal reticulocyte count or HbA1c chromatogram at time of screening.
• Admitted use of anabolic steroids within the past 60 days.
• Other significant organ system illness or condition (including psychiatric or developmental disorder) that would prevent participation in the opinion of the investigator.
• Patient participates in a formal weight-loss program.

Inclusion Criteria (post Run-in and Randomization):

• Duration since diagnosis less than 2 years at randomization.
• HbA1c < 8% on metformin alone.
• Age 10-17, with randomization before patient is 18 years old.
• Signed consent/assent forms for randomization and the post-randomization phase.
• A family member or adult closely involved in the daily activities of the child agrees to participate in the child's treatment.
• Fluency in English or Spanish for both child and family member.
• Patient and family able to fully participate in trial protocol in the opinion of the investigator.

Exclusion Criteria (post Run-in and Randomization):

• Refractory hypertension: average systolic blood pressure ≥ 150 mmHg or average diastolic blood pressure ≥ 95 mmHg despite appropriate medical therapy.
• Refractory hyperlipidemia: total cholesterol > 300 mg/dL or LDL > 190 mg/dL or triglycerides > 800 mg/dL, despite appropriate medical therapy.
• Refractory anemia: hematocrit < 30% or hemoglobin < 10 gm/dL despite appropriate medical therapy.
• Patient on a thiazolidinedione (TZD) within the last 12 weeks.
• Patient on non-study diabetes medications within the past 6 weeks.
• Patient on inhaled steroids at dose above 1000 mcg daily Flovent equivalent.
• Patient on a course of oral steroids within the last 60 days or on oral steroids more than 20 days during the past year.
• Patient on medication(s) that are known to affect insulin sensitivity or secretion within the last 30 days.
• Patient on medication(s) that are known to cause weight gain within the last 30 days.
• Patient on any weight-loss medication(s) within the last 30 days.
• Patient on medication(s) known to affect the metabolism of study drug.
• Inability to comprehend the lowest grade level at which lifestyle intervention materials are prepared, for both child and participating family member, assessed by mastery of standard diabetes education program administered during run-in.
• Inability to comply with requirements of study during run-in period.
• Females who are pregnant, planning to become pregnant within two years of enrollment, or who admit sexual activity without appropriate contraception.
• Calculated creatinine clearance < 70 mL/min.
• Physical limitations preventing patient from being randomized to the lifestyle intervention.
• Patient plans to leave the geographic area within one calendar year.
• Admitted use of anabolic steroids within 60 days.
• Other significant organ system illness or condition (including psychiatric or developmental disorder) that would prevent participation in the opinion of the investigator.
• Patient participates in a formal weight loss program.
• Episode of DKA during the run-in.30.
• Edema at the time of randomization (a participant who experiences edema during run-in must have recovered within 2 weeks and be edema free for 1 week prior to randomization).