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

Diabetes Mellitus, Type II Clinical Trial

— TODAY  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00081328
• Other study ID #: IND - DK61230-TODAY
• Secondary ID: U01DK061230
• Status: Completed
• Phase: Phase 3
• Start date: May 2004
• Est. completion date: February 2014

Study information

• Verified date: July 2021
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 699
• Est. completion date: February 2014
• Est. primary completion date: February 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years to 17 Years

Eligibility

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).

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Diabetes Mellitus, Type II

Intervention

Drug:
• Metformin
capsule, 1000 mg bid
• Rosiglitazone
capsule, 4 mg bid

Behavioral:
• Lifestyle Program
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

Locations

Country	Name	City	State
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	Massachusetts General Hospital Diabetes Center	Boston	Massachusetts
United States	Case Western Reserve	Cleveland	Ohio
United States	University of Colorado Health Sciences Center, The Children's Hospital	Denver	Colorado
United States	Baylor College of Medicine	Houston	Texas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Yale University	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
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	George Washington University Biostatistics Center	Rockville	Maryland
United States	Saint Louis University Health Sciences Center	Saint Louis	Missouri
United States	Washington University Department of Pediatrics	Saint Louis	Missouri
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	State University of New York Upstate Medical University	Syracuse	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (66)

Anderson BJ, Edelstein S, Abramson NW, Katz LE, Yasuda PM, Lavietes SJ, Trief PM, Tollefsen SE, McKay SV, Kringas P, Casey TL, Marcus MD. Depressive symptoms and quality of life in adolescents with type 2 diabetes: baseline data from the TODAY study. Diab — View Citation

Arslanian S, El Ghormli L, Bacha F, Caprio S, Goland R, Haymond MW, Levitsky L, Nadeau KJ, White NH, Willi SM; TODAY Study Group. Adiponectin, Insulin Sensitivity, ß-Cell Function, and Racial/Ethnic Disparity in Treatment Failure Rates in TODAY. Diabetes — View Citation

Arslanian S, El Ghormli L, Haymond MH, Chan CL, Chernausek SD, Gandica RG, Gubitosi-Klug R, Levitsky LL, Siska M, Willi SM; TODAY Study Group. Beta cell function and insulin sensitivity in obese youth with maturity onset diabetes of youth mutations vs typ — View Citation

Arslanian S, El Ghormli L, Young Kim J, Bacha F, Chan C, Ismail HM, Levitt Katz LE, Levitsky L, Tryggestad JB, White NH; TODAY Study Group. The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test: Forerunner of Heightened Glycemic Fa — View Citation

Bacha F, El Ghormli L, Arslanian S, Zeitler P, Laffel LM, Levitt Katz LE, Gandica R, Chang NT, Sprague JE, Macleish SA; TODAY Study Group. Predictors of response to insulin therapy in youth with poorly-controlled type 2 diabetes in the TODAY trial. Pediat — View Citation

Bacha F, Gidding SS, Pyle L, Levitt Katz L, Kriska A, Nadeau KJ, Lima JAC; Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group. Relationship of Cardiac Structure and Function to Cardiorespiratory Fitness and Lean Body Mass i — View Citation

Bacha F, Pyle L, Nadeau K, Cuttler L, Goland R, Haymond M, Levitsky L, Lynch J, Weinstock RS, White NH, Caprio S, Arslanian S; TODAY Study Group. Determinants of glycemic control in youth with type 2 diabetes at randomization in the TODAY study. Pediatr D — View Citation

Baldi JC, Manning PJ, Hofman PL, Walker RJ. Comment on: TODAY Study Group. Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and ß-cell function in TODAY. Diabetes Care 2013;36:1749-1757. Diabetes Care — View Citation

Berkowitz RI, Marcus MD, Anderson BJ, Delahanty L, Grover N, Kriska A, Laffel L, Syme A, Venditti E, Van Buren DJ, Wilfley DE, Yasuda P, Hirst K; TODAY Study Group. Adherence to a lifestyle program for youth with type 2 diabetes and its association with t — View Citation

Bjornstad P, Hughan K, Kelsey MM, Shah AS, Lynch J, Nehus E, Mitsnefes M, Jenkins T, Xu P, Xie C, Inge T, Nadeau K. Effect of Surgical Versus Medical Therapy on Diabetic Kidney Disease Over 5 Years in Severely Obese Adolescents With Type 2 Diabetes. Diabe — View Citation

Bjornstad P, Laffel L, Lynch J, El Ghormli L, Weinstock RS, Tollefsen SE, Nadeau KJ; TODAY Study Group. Elevated Serum Uric Acid Is Associated With Greater Risk for Hypertension and Diabetic Kidney Diseases in Obese Adolescents With Type 2 Diabetes: An Ob — View Citation

Bjornstad P, Nehus E, El Ghormli L, Bacha F, Libman IM, McKay S, Willi SM, Laffel L, Arslanian S, Nadeau KJ; TODAY Study Group. Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of — View Citation

Chadwick JQ, Copeland KC, Branam DE, Erb-Alvarez JA, Khan SI, Peercy MT, Rogers ME, Saunkeah BR, Tryggestad JB, Wharton DF. Genomic Research and American Indian Tribal Communities in Oklahoma: Learning From Past Research Misconduct and Building Future Trusting Partnerships. Am J Epidemiol. 2019 Jul 1;188(7):1206-1212. doi: 10.1093/aje/kwz062. — View Citation

Chadwick JQ, Copeland KC, Daniel MR, Erb-Alvarez JA, Felton BA, Khan SI, Saunkeah BR, Wharton DF, Payan ML. Partnering in research: a national research trial exemplifying effective collaboration with American Indian Nations and the Indian Health Service. Am J Epidemiol. 2014 Dec 15;180(12):1202-7. doi: 10.1093/aje/kwu246. Epub 2014 Nov 11. — View Citation

Chadwick JQ, Van Buren DJ, Morales E, Timpson A, Abrams EL, Syme A, Preske J, Mireles G, Anderson B, Grover N, Laffel L. Structure to utilize interventionists' implementation experiences of a family-based behavioral weight management program to enhance the dissemination of the standardized intervention: The TODAY study. Clin Trials. 2017 Aug;14(4):406-412. doi: 10.1177/1740774517707727. Epub 2017 May 9. — View Citation

Chernausek SD, Arslanian S, Caprio S, Copeland KC, El ghormli L, Kelsey MM, Koontz MB, Orsi CM, Wilfley D. Relationship Between Parental Diabetes and Presentation of Metabolic and Glycemic Function in Youth With Type 2 Diabetes: Baseline Findings From the — View Citation

Copeland KC, Zeitler P, Geffner M, Guandalini C, Higgins J, Hirst K, Kaufman FR, Linder B, Marcovina S, McGuigan P, Pyle L, Tamborlane W, Willi S; TODAY Study Group. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY coh — View Citation

Delahanty L, Kriska A, Edelstein S, Amodei N, Chadwick J, Copeland K, Galvin B, El Ghormli L, Haymond M, Kelsey MM, Lassiter C, Milaszewski K, Syme A, Mayer-Davis E. Self-reported dietary intake of youth with recent onset of type 2 diabetes: results from — View Citation

Dhaliwal R, Shepherd JA, El Ghormli L, Copeland KC, Geffner ME, Higgins J, Levitsky LL, Nadeau KJ, Weinstock RS, White NH; TODAY Study Group. Changes in Visceral and Subcutaneous Fat in Youth With Type 2 Diabetes in the TODAY Study. Diabetes Care. 2019 Au — View Citation

Gandica R, Zeitler P. Update on Youth-Onset Type 2 Diabetes: Lessons Learned from the Treatment Options for Type 2 Diabetes in Adolescents and Youth Clinical Trial. Adv Pediatr. 2016 Aug;63(1):195-209. doi: 10.1016/j.yapd.2016.04.013. Epub 2016 Jun 3. Rev — View Citation

Gidding SS, Bacha F, Bjornstad P, Levitt Katz LE, Levitsky LL, Lynch J, Tryggestad JB, Weinstock RS, El Ghormli L, Lima JAC; TODAY Study Group. Cardiac Biomarkers in Youth with Type 2 Diabetes Mellitus: Results from the TODAY Study. J Pediatr. 2018 Jan;19 — View Citation

Grey M, Schreiner B, Pyle L. Development of a diabetes education program for youth with type 2 diabetes. Diabetes Educ. 2009 Jan-Feb;35(1):108-16. doi: 10.1177/0145721708325156. — View Citation

Ievers-Landis CE, Walders-Abramson N, Amodei N, Drews KL, Kaplan J, Levitt Katz LE, Lavietes S, Saletsky R, Seidman D, Yasuda P; Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group. Longitudinal Correlates of Health Risk Beh — View Citation

Inge TH, Laffel LM, Jenkins TM, Marcus MD, Leibel NI, Brandt ML, Haymond M, Urbina EM, Dolan LM, Zeitler PS; Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) Consortia. — View Citation

Kaar JL, Schmiege SJ, Drews K, Higgins J, Walders-Abramson N, Isganaitis E, Willi SM, Marcus MD, Zeitler PS, Kelsey MM. Evaluation of the longitudinal change in health behavior profiles across treatment groups in the TODAY clinical trial. Pediatr Diabetes — View Citation

Katz LL, Anderson BJ, McKay SV, Izquierdo R, Casey TL, Higgins LA, Wauters A, Hirst K, Nadeau KJ; TODAY Study Group. Correlates of Medication Adherence in the TODAY Cohort of Youth With Type 2 Diabetes. Diabetes Care. 2016 Nov;39(11):1956-1962. Epub 2016 — View Citation

Kelsey MM, Braffett BH, Geffner ME, Levitsky LL, Caprio S, McKay SV, Shah R, Sprague JE, Arslanian SA; TODAY Study Group. Menstrual Dysfunction in Girls From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study. J Clin Endocrin — View Citation

Kelsey MM, Geffner ME, Guandalini C, Pyle L, Tamborlane WV, Zeitler PS, White NH; Treatment Options for Type 2 Diabetes in Adolescents and Youth Study Group. Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the T — View Citation

Kleinberger JW, Copeland KC, Gandica RG, Haymond MW, Levitsky LL, Linder B, Shuldiner AR, Tollefsen S, White NH, Pollin TI. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet Med. 2018 Jun;20(6 — View Citation

Klingensmith GJ, Pyle L, Arslanian S, Copeland KC, Cuttler L, Kaufman F, Laffel L, Marcovina S, Tollefsen SE, Weinstock RS, Linder B; TODAY Study Group. The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: results from the TO — View Citation

Klingensmith GJ, Pyle L, Nadeau KJ, Barbour LA, Goland RS, Willi SM, Linder B, White NH; TODAY Study Group. Pregnancy Outcomes in Youth With Type 2 Diabetes: The TODAY Study Experience. Diabetes Care. 2016 Jan;39(1):122-9. doi: 10.2337/dc15-1206. Epub 201 — View Citation

Kriska A, Delahanty L, Edelstein S, Amodei N, Chadwick J, Copeland K, Galvin B, El ghormli L, Haymond M, Kelsey M, Lassiter C, Mayer-Davis E, Milaszewski K, Syme A. Sedentary behavior and physical activity in youth with recent onset of type 2 diabetes. Pe — View Citation

Kriska A, El Ghormli L, Copeland KC, Higgins J, Ievers-Landis CE, Levitt Katz LE, Trief PM, Wauters AD, Yasuda PM, Delahanty LM; TODAY Study Group. Impact of lifestyle behavior change on glycemic control in youth with type 2 diabetes. Pediatr Diabetes. 20 — View Citation

Laffel L, Chang N, Grey M, Hale D, Higgins L, Hirst K, Izquierdo R, Larkin M, Macha C, Pham T, Wauters A, Weinstock RS; TODAY Study Group. Metformin monotherapy in youth with recent onset type 2 diabetes: experience from the prerandomization run-in phase — View Citation

Larkin ME, McGuigan P, Richards D, Blumenthal K, Milaszewski K, Higgins L, Schanuel J, Long C. Collaborative Staffing Model for Multiple Sites: Reducing the challenges of study coordination in complex, multi-site clinical trials. Appl Clin Trials. 2011 Jan 1;20(1):30-35. — View Citation

Larkin ME, Walders-Abramson N, Hirst K, Keady J, Ievers-Landis CE, Venditti EM, Yasuda PM. Effects of comorbid conditions on health-related quality of life in youth with Type 2 diabetes: the TODAY clinical trial. Diabetes Manag (Lond). 2015 Nov;5(6):431-4 — View Citation

Levitt Katz L, Gidding SS, Bacha F, Hirst K, McKay S, Pyle L, Lima JA; TODAY Study Group. Alterations in left ventricular, left atrial, and right ventricular structure and function to cardiovascular risk factors in adolescents with type 2 diabetes partici — View Citation

Levitt Katz LE, Bacha F, Gidding SS, Weinstock RS, El Ghormli L, Libman I, Nadeau KJ, Porter K, Marcovina S; TODAY Study Group. Lipid Profiles, Inflammatory Markers, and Insulin Therapy in Youth with Type 2 Diabetes. J Pediatr. 2018 May;196:208-216.e2. do — View Citation

Marcus MD, Wilfley DE, El Ghormli L, Zeitler P, Linder B, Hirst K, Ievers-Landis CE, van Buren DJ, Walders-Abramson N; TODAY Study Group. Weight change in the management of youth-onset type 2 diabetes: the TODAY clinical trial experience. Pediatr Obes. 20 — View Citation

Narasimhan S, Weinstock RS. Youth-onset type 2 diabetes mellitus: lessons learned from the TODAY study. Mayo Clin Proc. 2014 Jun;89(6):806-16. doi: 10.1016/j.mayocp.2014.01.009. Epub 2014 Apr 3. — View Citation

Rockette-Wagner B, Storti KL, Edelstein S, Delahanty LM, Galvin B, Jackson A, Kriska AM. Measuring Physical Activity and Sedentary Behavior in Youth with Type 2 Diabetes. Child Obes. 2017 Feb;13(1):72-77. doi: 10.1089/chi.2015.0151. Epub 2016 Feb 9. — View Citation

Ryder JR, Xu P, Nadeau KJ, Kelsey MM, Xie C, Jenkins T, Inge TH, Bjornstad P. Effect of surgical versus medical therapy on estimated cardiovascular event risk among adolescents with type 2 diabetes and severe obesity. Surg Obes Relat Dis. 2021 Jan;17(1):2 — View Citation

Shah AS, El Ghormli L, Gidding SS, Bacha F, Nadeau KJ, Levitt Katz LE, Tryggestad JB, Leibel N, Hale DE, Urbina EM. Prevalence of arterial stiffness in adolescents with type 2 diabetes in the TODAY cohort: Relationships to glycemic control and other risk — View Citation

Shah AS, El Ghormli L, Vajravelu ME, Bacha F, Farrell RM, Gidding SS, Levitt Katz LE, Tryggestad JB, White NH, Urbina EM. Heart Rate Variability and Cardiac Autonomic Dysfunction: Prevalence, Risk Factors, and Relationship to Arterial Stiffness in the Tre — View Citation

Shah R, McKay SV, Levitt Katz LE, El Ghormli L, Anderson BJ, Casey TL, Higgins L, Izquierdo R, Wauters AD, Chang N; TODAY Study Group. Adherence to multiple medications in the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) cohort: — View Citation

Songer T, Glazner J, Coombs LP, Cuttler L, Daniel M, Estrada S, Klingensmith G, Kriska A, Laffel L, Zhang P; the TODAY Study Group. Examining the economic costs related to lifestyle and pharmacological interventions in youth with Type 2 diabetes. Expert Rev Pharmacoecon Outcomes Res. 2006 Jun 1;6(3):315-324. — View Citation

Songer TJ, Haymond MW, Glazner JE, Klingensmith GJ, Laffel LM, Zhang P, Hirst K; TODAY Study Group. Healthcare and associated costs related to type 2 diabetes in youth and adolescence: the TODAY clinical trial experience. Pediatr Diabetes. 2019 Sep;20(6):702-711. doi: 10.1111/pedi.12869. Epub 2019 Jun 6. — View Citation

TODAY Study Group, Wilfley D, Berkowitz R, Goebel-Fabbri A, Hirst K, Ievers-Landis C, Lipman TH, Marcus M, Ng D, Pham T, Saletsky R, Schanuel J, Van Buren D. Binge eating, mood, and quality of life in youth with type 2 diabetes: baseline data from the tod — View Citation

TODAY Study Group, Zeitler P, Epstein L, Grey M, Hirst K, Kaufman F, Tamborlane W, Wilfley D. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes. 2007 Apr;8(2):74-87. — View Citation

TODAY Study Group, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, Arslanian S, Cuttler L, Nathan DM, Tollefsen S, Wilfley D, Kaufman F. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012 Jun 14;366(24):2247- — View Citation

TODAY Study Group. Design of a family-based lifestyle intervention for youth with type 2 diabetes: the TODAY study. Int J Obes (Lond). 2010 Feb;34(2):217-26. doi: 10.1038/ijo.2009.195. Epub 2009 Oct 13. Review. — View Citation

TODAY Study Group. Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: the TODAY clinical trial. Diabetes Care. 2013 Jun;36(6):1758-64. doi: 10.2337/dc12-2388. — View Citation

TODAY Study Group. Rapid rise in hypertension and nephropathy in youth with type 2 diabetes: the TODAY clinical trial. Diabetes Care. 2013 Jun;36(6):1735-41. doi: 10.2337/dc12-2420. Erratum in: Diabetes Care. 2013 Aug;36(8):2448. — View Citation

TODAY Study Group. Retinopathy in youth with type 2 diabetes participating in the TODAY clinical trial. Diabetes Care. 2013 Jun;36(6):1772-4. doi: 10.2337/dc12-2387. — View Citation

TODAY Study Group. Safety and tolerability of the treatment of youth-onset type 2 diabetes: the TODAY experience. Diabetes Care. 2013 Jun;36(6):1765-71. doi: 10.2337/dc12-2390. — View Citation

TODAY Study Group. Treatment effects on measures of body composition in the TODAY clinical trial. Diabetes Care. 2013 Jun;36(6):1742-8. doi: 10.2337/dc12-2534. — View Citation

Tryggestad JB, Shah RD, Braffett BH, Bacha F, Gidding SS, Gubitosi-Klug RA, Shah AS, Urbina EM, Levitt Katz LE; TODAY Study Group. Circulating adhesion molecules and associations with HbA1c, hypertension, nephropathy, and retinopathy in the Treatment Opti — View Citation

Tryggestad JB, Willi SM. Complications and comorbidities of T2DM in adolescents: findings from the TODAY clinical trial. J Diabetes Complications. 2015 Mar;29(2):307-12. doi: 10.1016/j.jdiacomp.2014.10.009. Epub 2014 Oct 29. Review. — View Citation

Van Buren DJ, Wilfley DE, Marcus MD, Anderson B, Abramson NW, Berkowitz R, Ievers-Landis C, Trief P, Yasuda P, Hirst K; TODAY Study Group. Depressive symptoms and glycemic control in youth with type 2 diabetes participating in the TODAY clinical trial. Di — View Citation

Venditti EM, Tan K, Chang N, Laffel L, McGinley G, Miranda N, Tryggestad JB, Walders-Abramson N, Yasuda P, Delahanty L; TODAY Study Group. Barriers and strategies for oral medication adherence among children and adolescents with Type 2 diabetes. Diabetes — View Citation

Walders-Abramson N, Anderson B, Larkin ME, Chang N, Venditti E, Bzdick S, Tryggestad JB, Tan K, Geffner ME, Hirst K. Benefits and barriers to participating in longitudinal research of youth-onset type 2 diabetes: Results from the TODAY retention survey. C — View Citation

Walders-Abramson N, Venditti EM, Ievers-Landis CE, Anderson B, El Ghormli L, Geffner M, Kaplan J, Koontz MB, Saletsky R, Payan M, Yasuda P; Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group. Relationships among stressful l — View Citation

Weinstock RS, Braffett BH, McGuigan P, Larkin ME, Grover NB, Walders-Abramson N, Laffel LM, Chan CL, Chang N, Schwartzman BE, Barajas RA, Celona-Jacobs N, Haymond MW; TODAY Study Group. Self-Monitoring of Blood Glucose in Youth-Onset Type 2 Diabetes: Resu — View Citation

Weinstock RS, Drews KL, Caprio S, Leibel NI, McKay SV, Zeitler PS; TODAY Study Group. Metabolic syndrome is common and persistent in youth-onset type 2 diabetes: Results from the TODAY clinical trial. Obesity (Silver Spring). 2015 Jul;23(7):1357-61. doi: — View Citation

Weinstock RS, Trief PM, El Ghormli L, Goland R, McKay S, Milaszewski K, Preske J, Willi S, Yasuda PM. Parental Characteristics Associated With Outcomes in Youth With Type 2 Diabetes: Results From the TODAY Clinical Trial. Diabetes Care. 2015 May;38(5):784 — View Citation

Zeitler P, Hirst K, Copeland KC, El Ghormli L, Levitt Katz L, Levitsky LL, Linder B, McGuigan P, White NH, Wilfley D; TODAY Study Group. HbA1c After a Short Period of Monotherapy With Metformin Identifies Durable Glycemic Control Among Adolescents With Ty — View Citation

* Note: There are 66 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.

External Links

•   public access to intervention materials used in TODAY