RISE Pediatric Medication Study

NCT ID: NCT01779375

Last Updated: 2023-04-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 91 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-06-16
• Study Completion Date: 2018-04-30

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.

Conditions

Prediabetes; Type 2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Metformin alone

Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).

Group Type: ACTIVE_COMPARATOR

Metformin

Intervention Type: DRUG

Glargine followed by 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.

Group Type: ACTIVE_COMPARATOR

Metformin

Intervention Type: DRUG

Glargine

Intervention Type: DRUG

Interventions

Metformin

Intervention Type: DRUG

Glargine

Intervention Type: DRUG

Other Intervention Names

Glucophage; Insulin glargine, Lantus

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.

• Minimum Eligible Age: 10 Years
• Maximum Eligible Age: 19 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

RISE Study Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Childrens Hospital Colorado

Denver, Colorado, United States

Yale School of Medicine Pediatric Obesity and Type 2 Diabetes Clinic

New Haven, Connecticut, United States

Indiana University

Indianapolis, Indiana, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 29941498 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 29941497 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28493515 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24194506 (View on PubMed)

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.

Reference Type: RESULT

PMID: 29941500 (View on PubMed)

Tjaden AH, Edelstein SL, Arslanian S, Barengolts E, Caprio S, Cree-Green M, Lteif A, Mather KJ, Savoye M, Xiang AH, Kahn SE. Reproducibility of Glycemic Measures Among Dysglycemic Youth and Adults in the RISE Study. J Clin Endocrinol Metab. 2023 Sep 18;108(10):e1125-e1133. doi: 10.1210/clinem/dgad135.

Reference Type: DERIVED

PMID: 36938582 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34274407 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34135015 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34131048 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34131047 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33436401 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32985775 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31301210 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31178433 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

5U01DK094406-02

Identifier Type: NIH

Identifier Source: secondary_id

View Link

RISE Pediatric

Identifier Type: -

Identifier Source: org_study_id