Clinical trial NCT01779375: RISE Pediatric Medication Study
Official title: Restoring Insulin Secretion Pediatric Medication Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Prediabetes
Type 2 Diabetes
Keywords: Children
Pediatric
Lead sponsor: RISE Study Group
Sponsor class: NETWORK
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2013-01-30
Enrollment: 91
Sex: ALL
Minimum age (years): 10
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: ß-cell Response Measured by Hyperglycemic Clamp
timeFrame: 3-months after medication washout (Month 15)
measure: M/I
timeFrame: 3-months after a medication washout
Secondary outcomes:
measure: ACPRg
timeFrame: 3-months after a medication washout
measure: ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12
timeFrame: End of active intervention (Month 12).
measure: Clamp Measure of Insulin Sensitivity
timeFrame: End of active intervention (Month 12)
Other outcomes:
measure: OGTT Measures of ß-cell Function and Glucose Tolerance
timeFrame: After 12 months of active treatment, and 3 and 9 months of washout
Locations:
city: Denver
country: United States
facility: Childrens Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine Pediatric Obesity and Type 2 Diabetes Clinic
state: Connecticut
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
Study officials:
References:
citation: RISE Consortium. Metabolic Contrasts Between Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: II. Observations Using the Oral Glucose Tolerance Test. Diabetes Care. 2018 Aug;41(8):1707-1716. doi: 10.2337/dc18-0243. Epub 2018 Jun 25.
citation: RISE Consortium. Metabolic Contrasts Between Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: I. Observations Using the Hyperglycemic Clamp. Diabetes Care. 2018 Aug;41(8):1696-1706. doi: 10.2337/dc18-0244. Epub 2018 Jun 25.
citation: Hannon TS, Kahn SE, Utzschneider KM, Buchanan TA, Nadeau KJ, Zeitler PS, Ehrmann DA, Arslanian SA, Caprio S, Edelstein SL, Savage PJ, Mather KJ; RISE Consortium. Review of methods for measuring beta-cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium. Diabetes Obes Metab. 2018 Jan;20(1):14-24. doi: 10.1111/dom.13005. Epub 2017 Jun 22.
citation: RISE Consortium. Restoring Insulin Secretion (RISE): design of studies of beta-cell preservation in prediabetes and early type 2 diabetes across the life span. Diabetes Care. 2014;37(3):780-8. doi: 10.2337/dc13-1879. Epub 2013 Nov 5.
citation: RISE Consortium. Impact of Insulin and Metformin Versus Metformin Alone on beta-Cell Function in Youth With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes. Diabetes Care. 2018 Aug;41(8):1717-1725. doi: 10.2337/dc18-0787. Epub 2018 Jun 25.
citation: Utzschneider KM, Tripputi MT, Kozedub A, Barengolts E, Caprio S, Cree-Green M, Edelstein SL, El Ghormli L, Hannon TS, Mather KJ, Palmer J, Nadeau KJ; RISE Consortium. Differential loss of beta-cell function in youth vs. adults following treatment withdrawal in the Restoring Insulin Secretion (RISE) study. Diabetes Res Clin Pract. 2021 Aug;178:108948. doi: 10.1016/j.diabres.2021.108948. Epub 2021 Jul 15.
citation: Kahn SE, Edelstein SL, Arslanian SA, Barengolts E, Caprio S, Ehrmann DA, Hannon TS, Marcovina S, Mather KJ, Nadeau KJ, Utzschneider KM, Xiang AH, Buchanan TA; RISE Consortium; Rise Consortium Investigators:. Effect of Medical and Surgical Interventions on alpha-Cell Function in Dysglycemic Youth and Adults in the RISE Study. Diabetes Care. 2021 Sep;44(9):1948-1960. doi: 10.2337/dc21-0461. Epub 2021 Jun 16.
citation: Sam S, Edelstein SL, Arslanian SA, Barengolts E, Buchanan TA, Caprio S, Ehrmann DA, Hannon TS, Tjaden AH, Kahn SE, Mather KJ, Tripputi M, Utzschneider KM, Xiang AH, Nadeau KJ; RISE Consortium; RISE Consortium Investigators. Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study. Diabetes Care. 2021 Sep;44(9):1938-1947. doi: 10.2337/dc21-0027. Epub 2021 Jun 15.
citation: Kahn SE, Mather KJ, Arslanian SA, Barengolts E, Buchanan TA, Caprio S, Ehrmann DA, Hannon TS, Marcovina S, Nadeau KJ, Utzschneider KM, Xiang AH, Edelstein SL; RISE Consortium; Rise Consortium Investigators:. Hyperglucagonemia Does Not Explain the beta-Cell Hyperresponsiveness and Insulin Resistance in Dysglycemic Youth Compared With Adults: Lessons From the RISE Study. Diabetes Care. 2021 Sep;44(9):1961-1969. doi: 10.2337/dc21-0460. Epub 2021 Jun 15.
citation: Arslanian SA, El Ghormli L, Kim JY, Tjaden AH, Barengolts E, Caprio S, Hannon TS, Mather KJ, Nadeau KJ, Utzschneider KM, Kahn SE; RISE Consortium. OGTT Glucose Response Curves, Insulin Sensitivity, and beta-Cell Function in RISE: Comparison Between Youth and Adults at Randomization and in Response to Interventions to Preserve beta-Cell Function. Diabetes Care. 2021 Mar;44(3):817-825. doi: 10.2337/dc20-2134. Epub 2021 Jan 12.
citation: Hannon TS, Edelstein SL, Arslanian SA, Caprio S, Zeitler PS, Buchanan TA, Ehrmann DA, Mather KJ, Tripputi M, Kahn SE, Nadeau KJ; RISE Consortium. Withdrawal of medications leads to worsening of OGTT parameters in youth with impaired glucose tolerance or recently-diagnosed type 2 diabetes. Pediatr Diabetes. 2020 Dec;21(8):1437-1446. doi: 10.1111/pedi.13129. Epub 2020 Oct 13.
citation: RISE Consortium. Obesity and insulin sensitivity effects on cardiovascular risk factors: Comparisons of obese dysglycemic youth and adults. Pediatr Diabetes. 2019 Nov;20(7):849-860. doi: 10.1111/pedi.12883. Epub 2019 Jul 29.
citation: RISE Consortium; RISE Consortium Investigators. Effects of Treatment of Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes With Metformin Alone or in Combination With Insulin Glargine on beta-Cell Function: Comparison of Responses In Youth And Adults. Diabetes. 2019 Aug;68(8):1670-1680. doi: 10.2337/db19-0299. Epub 2019 Jun 9.