RISE Pediatric Medication Study

NCT01779375 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: RISE Pediatric5U01DK094406-02
• Study Type: interventional
• Target: 91
• Locations: 1 country
• Sites: 4

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

Keywords

Children; Pediatric

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• ACPRg

  3-months after a medication washout

• ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12

  End of active intervention (Month 12).

• Clamp Measure of Insulin Sensitivity

  End of active intervention (Month 12)

Other Outcomes (1)

• OGTT Measures of ß-cell Function and Glucose Tolerance

  After 12 months of active treatment, and 3 and 9 months of washout

Study Arms (2)

Metformin alone

ACTIVE COMPARATOR

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

Drug: Metformin

Glargine followed by Metformin

ACTIVE COMPARATOR

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; Drug: Glargine

Interventions

Metformin DRUG

Also known as: Glucophage

Glargine followed by Metformin; Metformin alone

Glargine DRUG

Also known as: Insulin glargine, Lantus

Glargine followed by Metformin

Eligibility Criteria

• Age: 10 Years - 19 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• RISE Study Group: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (4)

Childrens Hospital Colorado

Denver, Colorado, 80045, United States

Location

Yale School of Medicine Pediatric Obesity and Type 2 Diabetes Clinic

New Haven, Connecticut, 06511, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Related Publications (14)

• 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.

  PMID: 29941498 BACKGROUND

• 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.

  PMID: 29941497 BACKGROUND

• 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.

  PMID: 28493515 BACKGROUND

• 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.

  PMID: 24194506 BACKGROUND

• 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.

  PMID: 29941500 RESULT

• 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.

  PMID: 36938582 DERIVED

• 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.

  PMID: 34274407 DERIVED

• 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.

  PMID: 34135015 DERIVED

• 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.

  PMID: 34131048 DERIVED

• 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.

  PMID: 34131047 DERIVED

• 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.

  PMID: 33436401 DERIVED

• 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.

  PMID: 32985775 DERIVED

• 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.

  PMID: 31301210 DERIVED

• 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.

  PMID: 31178433 DERIVED

MeSH Terms

Conditions

Prediabetic State; Diabetes Mellitus, Type 2

Interventions

Metformin; Insulin Glargine

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Insulin, Long-Acting; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Sharon Edelstein
• Organization: George Washington University Biostatistics Center

sharone@bsc.gwu.edu

3018819260

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 28, 2013
• First Posted: January 30, 2013
• Study Start: June 16, 2013
• Primary Completion: July 12, 2017
• Study Completion: April 1, 2018
• Last Updated: April 14, 2023
• Results First Posted: October 9, 2018

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Through the NIDDK repository in 2020, indefinitely.
• Access Criteria: Following NIDDK repository instructions.

Locations

US (4)