Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY)
Condition: Diabetes Mellitus, Type II
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Metformin; Rosiglitazone; Lifestyle Program
Intervention description: capsule, 1000 mg bid; capsule, 4 mg bid; 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
Intervention MeSH terms: Metformin; Rosiglitazone
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 699.0
Sex: All
Minimum age: 10 Years
Maximum age: 17 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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).