RISE Pediatric Medication Study

Study Overview
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Brief Summary
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The RISE Pediatric Medication Study is a 2-arm, 4-center, clinical trial of children with prediabetes and early type 2 diabetes to address the hypothesis that aggressive glucose lowering will lead to recovery of beta-cell function that will be sustained after withdrawal of treatment. Pediatric participants (ages 10-19) will be randomized to one of the following treatment regimens: (1) metformin alone or (2) early intensive treatment with basal insulin glargine followed by metformin. The primary clinical question RISE will address is: Are improvements in ß-cell function following 12 months of active treatment maintained for 3 months following the withdrawal of therapy? Secondary outcomes will assess durability of glucose tolerance following withdrawal of therapy, and whether biomarkers obtained in the fasting state predict parameters of ß-cell function, insulin sensitivity and glucose tolerance and the response to an intervention.

Official Title
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Restoring Insulin Secretion Pediatric Medication Study

Conditions
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Prediabetes, Type 2 Diabetes

Intervention / Treatment
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* Drug: Metformin
* Drug: Glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fasting plasma glucose ≥90 mg/dl plus 2-hour glucose ≥140 mg/dl on 75 gm OGTT plus laboratory-based HbA1c ≤8.0% if treatment naïve. There is no upper limit for the 2-hour glucose on OGTT. In those taking metformin laboratory-based HbA1c must be ≤7.5% if on metformin for <3 months and ≤7.0% if on metformin for 3-6 months. Age 10-19 years Pubertal development Tanner stage >1 as defined by breast stage >1 in girls, and testes >3 cc's in boys. Body mass index (BMI) ≥85th percentile but ≤50 kg/m2 Self-reported diabetes <6 months in duration Treatment with metformin for <6 months preceding screening Exclusion Criteria: Underlying disease likely to limit life span and/or increase risk of intervention or an underlying condition that is likely to limit ability to participate in outcomes assessment An underlying disease that affects glucose metabolism other than type 2 diabetes mellitus Taking medications that affect glucose metabolism, or has an underlying condition that is likely to require such medications Treatment with insulin for >1 week preceding screening Active infections Renal disease (serum creatinine >1.2 mg/dl) or serum potassium abnormality (<3.4 or >5.5 mmol/l) Anemia (hemoglobin <11 g/dl in girls, <12 g/dl in boys) or known coagulopathy Cardiovascular disease, including uncontrolled hypertension defined as average systolic or diastolic blood pressure > 99 percentile for age or >135/90, despite adequately prescribed antihypertensive medications. Participants must be able to safely tolerate administration of intravenous fluids required during clamp studies. History of conditions that may be precipitated or exacerbated by a study drug: Serum alanine transaminase (ALT) more than 3 times the upper limit of normal Excessive alcohol intake Sub-optimally treated thyroid disease Conditions or behaviors likely to affect the conduct of the RISE Study Participant and/or parents unable or unwilling to give informed consent Participant and/or parents unable to adequately communicate with clinic staff Another household member is a participant or staff member in RISE Current, recent or anticipated participation in another intervention research project that would interfere with any of the interventions/outcomes in RISE Weight loss of ≥5% of body weight in the past 3 months for any reason other than post-partum weight loss. Participants taking weight loss drugs or using preparations taken for intended weight loss are excluded. Likely to move away from participating clinics in next 2 years Current (or anticipated) pregnancy and lactation. A pregnancy that was completed less than 6 months prior to screening. Breast feeding within 6 months prior to screening. Women of childbearing potential who are unwilling to use adequate contraception Major psychiatric disorder that, in the opinion of clinic staff, would impede the conduct of RISE Additional conditions may serve as criteria for exclusion at the discretion of the local site.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin alone<br>Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). | Drug: Metformin<br> <br> * Other names: Glucophage;|
| Active Comparator: Glargine followed by Metformin<br>Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 85-95 mg/dl, followed by metformin (titrated up to 2000 mg/day) for 9 months. | Drug: Metformin<br> <br> * Other names: Glucophage;Drug: Glargine<br> <br> * Other names: Insulin glargine, Lantus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ß-cell Response Measured by Hyperglycemic Clamp | Clamp measures of ß-cell response, co-primary outcomes | 3-months after medication washout (Month 15) | 
| M/I | Clamp measure of insulin sensitivity | 3-months after a medication washout | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACPRg | First phase response | 3-months after a medication washout | 
| ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | Participants had 12-months of active therapy. Secondary results at the end of active intervention. | End of active intervention (Month 12). | 
| Clamp Measure of Insulin Sensitivity | Participants had 12-months of active therapy. Secondary results at the end of active intervention. | End of active intervention (Month 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Children, Pediatric