RISE Pediatric Medication Study
Condition: Prediabetes; Type 2 Diabetes
MeSH terms: Prediabetic State
Intervention: Metformin; Glargine
Intervention MeSH terms: Metformin; Insulin Glargine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 91.0
Sex: All
Minimum age: 10 Years
Maximum age: 19 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Children; Pediatric

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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.

          2. Age 10-19 years

          3. Pubertal development Tanner stage >1 as defined by breast stage >1 in girls, and
             testes >3 cc's in boys.

          4. Body mass index (BMI) ≥85th percentile but ≤50 kg/m2

          5. Self-reported diabetes <6 months in duration

          6. Treatment with metformin for <6 months preceding screening

        Exclusion Criteria:

          1. 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

          2. An underlying disease that affects glucose metabolism other than type 2 diabetes
             mellitus

          3. Taking medications that affect glucose metabolism, or has an underlying condition that
             is likely to require such medications

          4. Treatment with insulin for >1 week preceding screening

          5. Active infections

          6. Renal disease (serum creatinine >1.2 mg/dl) or serum potassium abnormality (<3.4 or
             >5.5 mmol/l)

          7. Anemia (hemoglobin <11 g/dl in girls, <12 g/dl in boys) or known coagulopathy

          8. 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.

          9. History of conditions that may be precipitated or exacerbated by a study drug:

               1. Serum alanine transaminase (ALT) more than 3 times the upper limit of normal

               2. Excessive alcohol intake

               3. Sub-optimally treated thyroid disease

         10. Conditions or behaviors likely to affect the conduct of the RISE Study

               1. Participant and/or parents unable or unwilling to give informed consent

               2. Participant and/or parents unable to adequately communicate with clinic staff

               3. Another household member is a participant or staff member in RISE

               4. Current, recent or anticipated participation in another intervention research
                  project that would interfere with any of the interventions/outcomes in RISE

               5. 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.

               6. Likely to move away from participating clinics in next 2 years

               7. Current (or anticipated) pregnancy and lactation.

               8. A pregnancy that was completed less than 6 months prior to screening.

               9. Breast feeding within 6 months prior to screening.

              10. Women of childbearing potential who are unwilling to use adequate contraception

              11. Major psychiatric disorder that, in the opinion of clinic staff, would impede the
                  conduct of RISE

         11. Additional conditions may serve as criteria for exclusion at the discretion of the
             local site.