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 mellitus (T2DM) 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 T2DM.

Condition	Treatment or Intervention	Phase
Diabetes Mellitus, Type II	Drug: Metformin  Drug: Metformin plus Rosiglitazone  Behavior: Metformin plus Lifestyle Intervention	Phase III

Ages Eligible for Study:  10 Years   -   17 Years,  Genders Eligible for Study:  Both

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.

Kathryn    

California
      Children's Hospital Los Angeles, Los Angeles,  California,  90027,  United States; Recruiting
Colorado
      University of Colorado Health Sciences Center, The Children's Hospital, Denver,  Colorado,  80262,  United States; Recruiting
Connecticut
      Yale University, New Haven,  Connecticut,  06520,  United States; Recruiting
Massachusetts
      Massachusetts General Hospital Diabetes Center, Boston,  Massachusetts,  02114,  United States; Recruiting
Missouri
      Washington University Department of Pediatrics, St. Louis,  Missouri,  63110,  United States; Recruiting
New York
      State University of New York Upstate Medical University, Syracuse,  New York,  13210,  United States; Recruiting
Ohio
      Case Western Reserve, Cleveland,  Ohio,  44106,  United States; Recruiting
Oklahoma
      University of Oklahoma, Oklahoma City,  Oklahoma,  93104,  United States; Recruiting
Pennsylvania
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States; Recruiting
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States; Recruiting
Texas
      University of Texas Health Science Center at San Antonio, San Antonio,  Texas,  78229,  United States; Recruiting
      Baylor College of Medicine, Houston,  Texas,  77030,  United States; Recruiting

Study chairs or principal investigators

Francine Kaufman, MD,  Study Chair,  Children's Hospital Los Angeles   

Study ID Numbers:  DK61230
Record last reviewed:  May 2004
Record first received:  April 8, 2004
ClinicalTrials.gov Identifier:  NCT00081328
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2004-10-27