Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY)
- Conditions
- Diabetes Mellitus, Type II
- Interventions
- Registration Number
- NCT00081328
- Lead Sponsor
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 699
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 2 Metformin Metformin + Rosiglitazone 3 Lifestyle Program Metformin + Lifestyle Program 2 Rosiglitazone Metformin + Rosiglitazone 3 Metformin Metformin + Lifestyle Program 1 Metformin Metformin alone
- Primary Outcome Measures
Name Time Method Treatment Failure (Loss of Glycemic Control) Study duration - 2 years to 6.5 years of follow up from randomization Defined as A1c persistently \>=8% over a 6-month period or persistent metabolic decompensation (inability to wean insulin within 3 months of initiation or the occurrence of a second episode within three months of discontinuing insulin)
- Secondary Outcome Measures
Name Time Method Comorbidity -- Triglycerides Dyslipidemia Data collected at baseline and during follow-up - 2 years to 6.5 years from randomization. A diagnosis was made by an out-of-range value \>=150 mg/dL sustained over 6 months or on appropriate lipid lowering medication.
Body Composition -- Waist Circumference 24 months Waist circumference (cm) measured at the iliac crest at its outermost point with the measuring tape placed around the participant in a horizontal plane parallel to the floor at the mark and the measurement teken at the end of normal expiration without the tape compressing the skin. The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time.
Body Composition -- BMI 24 months Body mass index (BMI) measured in kg per meters squared. The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time.
Body Composition -- Fat Mass 24 months Determined by DXA whole body scan. The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time. In addition, in about 1/3 of participants DXA scans could not be obtained on participants weighing more than 300 pounds (136 kg), the upper limit in size set by the machine manufacturers. Scans were considered invalid if a body part (e.g., arm, leg) was completely off or partially off the scanner, there was hand-hip overlap, or there was motion or movement during the scan.
Comorbidity -- Hypertension Data collected at baseline and during follow-up - 2 years to 6.5 years from randomization. A diagnosis was made by an out-of-range value \>=95th percentile or systolic \>=130 or diastolic \>=80 sustained over 6 months or on an anti-hypertensive medication.
Comorbidity -- LDL Dyslipidemia Data collected at baseline and during follow-up - 2 years to 6.5 years from randomization. A diagnosis was made from out-of-range value \>= 130 mg/dL sustained over 6 months or put on lipid lowering medication.
Number of Serious Adverse Events Reported as occurred during study follow-up - 2 years to 6.5 years from randomization. Number of serious adverse events reported during the trial. Participant could have multiple episodes reported.
Insulin Secretion 24 months Insulinogenic index determined from OGTT as difference in insulin at 30 minutes minus 0 minutes divided by difference in glucose at 30 minutes minus 0 minutes. The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time.
Body Composition -- Bone Density 24 months Measured by DXA, both whole body scan and AP-spine scan. The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time. In addition, in about 1/3 of participants DXA scans could not be obtained on participants weighing more than 300 pounds (136 kg), the upper limit in size set by the machine manufacturers. Scans were considered invalid if a body part (e.g., arm, leg) was completely off or partially off the scanner, there was hand-hip overlap, or there was motion or movement during the scan.
Insulin Sensitivity 24 months All participants were followed to 24 months. Insulin sensitivity is measured from OGTT as inverse of fasting insulin (mL/uU). The analysis sample includes only participants with 24 month data who had not experienced the primary outcome by that time.
Trial Locations
- Locations (16)
Yale University
🇺🇸New Haven, Connecticut, United States
George Washington University Biostatistics Center
🇺🇸Rockville, Maryland, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Washington University Department of Pediatrics
🇺🇸Saint Louis, Missouri, United States
Massachusetts General Hospital Diabetes Center
🇺🇸Boston, Massachusetts, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
University of Colorado Health Sciences Center, The Children's Hospital
🇺🇸Denver, Colorado, United States
Joslin Diabetes Center
🇺🇸Boston, Massachusetts, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
Case Western Reserve
🇺🇸Cleveland, Ohio, United States
University of Oklahoma
🇺🇸Oklahoma City, Oklahoma, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Baylor College of Medicine
🇺🇸Houston, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Saint Louis University Health Sciences Center
🇺🇸Saint Louis, Missouri, United States