RISE Pediatric Medication Study

Phase 3

Completed

• Conditions: Prediabetes; Type 2 Diabetes
• Interventions: Drug: Metformin; Drug: Glargine

• Registration Number: NCT01779375
• Lead Sponsor: RISE Study Group

Brief 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2013-01-28
• Study First Submitted QC: 2013-01-28
• Study First Posted: 2013-01-30
• Study Start: 2013-06-16
• Primary Completion: 2017-07-12
• Study Completion: 2018-04
• Results First Submitted: 2018-08-30
• Results First Submitted QC: 2018-10-01
• Results First Posted: 2018-10-09
• Status Verified: 2023-04
• Last Update Submitted: 2023-04-12
• Last Update Posted: 2023-04-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 91

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Glargine followed by Metformin	Glargine	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.
Metformin alone	Metformin	Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).
Glargine followed by Metformin	Metformin	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (4)

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

Yale School of Medicine Pediatric Obesity and Type 2 Diabetes Clinic; 🇺🇸 New Haven, Connecticut, United States

Childrens Hospital Colorado; 🇺🇸 Denver, Colorado, United States

Indiana University; 🇺🇸 Indianapolis, Indiana, United States