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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Studies to Treat Or Prevent Pediatric Type 2 Diabetes (STOPP-T2D) Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Clinical Trial

Conditions
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Diabetes Mellitus, Type II

Intervention / Treatment
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* Drug: Metformin
* Drug: Rosiglitazone
* Behavioral: Lifestyle Program


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Metformin alone | Drug: Metformin<br>* capsule, 1000 mg bid<br>|
| Experimental: 2<br>Metformin + Rosiglitazone | Drug: Metformin<br>* capsule, 1000 mg bid<br>Drug: Rosiglitazone<br>* capsule, 4 mg bid<br>|
| Experimental: 3<br>Metformin + Lifestyle Program | Drug: Metformin<br>* capsule, 1000 mg bid<br>Behavioral: Lifestyle Program<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Failure (Loss of Glycemic Control) | 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) | Study duration - 2 years to 6.5 years of follow up from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | 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. | 24 months | 
| Number of Serious Adverse Events | Number of serious adverse events reported during the trial. Participant could have multiple episodes reported. | Reported as occurred during study follow-up - 2 years to 6.5 years from randomization. | 
| Insulin Secretion | 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. | 24 months | 
| Body Composition -- BMI | 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. | 24 months | 
| Body Composition -- Waist Circumference | 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. | 24 months | 
| Body Composition -- Bone Density | 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. | 24 months | 
| Body Composition -- Fat Mass | 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. | 24 months | 
| Comorbidity -- Hypertension | 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. | Data collected at baseline and during follow-up - 2 years to 6.5 years from randomization. | 
| Comorbidity -- LDL Dyslipidemia | A diagnosis was made from out-of-range value >= 130 mg/dL sustained over 6 months or put on lipid lowering medication. | Data collected at baseline and during follow-up - 2 years to 6.5 years from randomization. | 
| Comorbidity -- Triglycerides Dyslipidemia | A diagnosis was made by an out-of-range value >=150 mg/dL sustained over 6 months or on appropriate lipid lowering medication. | Data collected at baseline and during follow-up - 2 years to 6.5 years from randomization. |