Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY)
Condition: Diabetes Mellitus, Type II
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

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.
    

Detailed description: 
      T2DM has dramatically increased throughout the world in many ethnic groups and among people
      with diverse social and economic backgrounds. Over the last decade, the increase in the
      number of children and youth with T2DM has been labeled an "epidemic". Before the 1990s, it
      was rare for most pediatric centers to have patients with T2DM. By 1994, T2DM patients
      represented up to 16% of new cases of diabetes in children in urban areas, and by 1999,
      depending on geographic location, the range of percent of new cases due to T2DM was between
      8-45% and disproportionately represented in minority populations.

      T2DM in children and youth, as in adults, is due to the combination of insulin resistance and
      relative β-cell failure. It appears that there are a host of genetic and environmental risk
      factors for insulin resistance and limited β-cell reserve. The epidemic of pediatric T2DM is
      coincident with the rise in the number of children who are overweight or at risk for
      overweight and with a decrease in the physical activity pattern of youth. There has been a
      strong association between T2DM and the onset of puberty, a positive family history of T2DM,
      and elements of the metabolic syndrome such as acanthosis nigricans and polycystic ovarian
      syndrome (PCOS).

      Preceding the development of frank diabetes, children and youth experience a period of
      prediabetes. Prediabetes is defined as either elevated fasting glucose or impaired glucose
      tolerance. Despite the dramatic increase in the number of cases of prediabetes and T2DM in
      pediatric populations, there have been no published large-scale studies investigating the
      pathophysiology, treatment, and complications of these disorders in children and youth. The
      long-term complications and costs associated with T2DM make such studies imperative. Between
      1997 and 2002, the estimated cost of diabetes with regard to direct medical cost increased
      from $44 billion to $92 billion, and the total cost increased from $98 billion to $132
      billion. The vast majority of monies are spent on the long-term complications of this
      disorder. Since the long-term microvascular and cardiovascular complications relate to
      duration of diabetes and to control of glycemia, it could be hypothesized that the increasing
      number of children and youth diagnosed with T2DM, if not effectively treated, could
      dramatically add to the economic burden of this disease over the ensuing decades.

      Except in American Indian youth, there are no population-based data available with regard to
      prevalence of T2DM. Instead, only clinic-based reports indicate that there has been a
      tremendous increase in the number of children and adolescents with T2DM. T2DM occurs almost
      exclusively in children and youth who are overweight or at risk for overweight (BMI > 85th
      percentile for age). At the time of diagnosis, most pediatric patients are in the midst of
      Tanner Stage 2-4 puberty. Puberty contributes to insulin resistance due to augmentation of
      growth hormone secretion, and if these normal pubertal physiologic changes are not
      compensated for by increased insulin secretion, frank diabetes will develop. Half to
      three-quarters of patients have a parent and close to ninety percent have at least one first
      or second degree relative with T2DM. The clinical presentation of T2DM in youth ranges from
      mild asymptomatic hyperglycemia to severe ketoacidosis. In those who present with clinical
      symptoms due to hyperglycemia, glycosuria and weight loss are present in 20-40%, ketonuria is
      present in 33% and ketoacidosis is found in 5-10%. Patients without clinical symptoms are
      diagnosed as the result of routine blood or urine testing during a health care visit or by
      investigating a variety of complaints such as chronic infection, sleep apnea, hyperlipidemia,
      hypertension, and hirsutism or irregular periods associated with PCOS. It may be difficult to
      distinguish T1DM from T2DM at presentation. The absence of autoantibodies is a prerequisite
      for the diagnosis of T2DM. In addition, evidence of residual insulin secretion is suggestive
      of T2DM rather than T1DM.

      Patients with T2DM have dual abnormalities of insulin resistance and insulin deficiency. It
      is hypothesized that to achieve the level of glycemic control required to optimize long-term
      outcome and decrease or prevent microvascular complications, treatment regimens should
      theoretically be designed to improve insulin resistance and preserve residual β-cell
      function. The available anti-diabetic agents have not been adequately evaluated in pediatric
      patients. This is particularly relevant with regard to using combination therapy to improve
      glycemic control or lifestyle interventions aimed at obesity and sedentary behavior.
    

Intervention name(s): Metformin; Rosiglitazone; Lifestyle Program
Intervention type(s): Drug; Drug; Behavioral
Intervention description(s): 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
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment