RISE Adult Medication Study

NCT01779362 | Completed Phase 3 Results DMC

• 2 other identifiers: RISE Adult5U01DK094406-02
• Study Type: interventional
• Target: 267
• Locations: 1 country
• Sites: 4

Brief Summary

The RISE Adult Medication Study is a 4-arm, 3-center, clinical trial of adults 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. Adult participants (ages 20-65) will be randomized to one of the following treatment regimens: (1) blinded placebo, (2) blinded metformin alone, (3) early intensive insulin treatment with basal insulin glargine followed by open-label metformin, (4) the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide plus open-label 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

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)

• Insulin Sensitivity, M/I

  Clamp measure of insulin sensitivity

  3-months after a medication washout

Secondary Outcomes (2)

• ACPRg

  3-months after a medication washout

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

  Secondary analysis was on all participants with a Month 12 visit.

Study Arms (4)

Metformin alone

ACTIVE COMPARATOR

Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment.

Drug: Metformin

Glargine followed by Metformin

ACTIVE COMPARATOR

Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months.

Drug: Metformin; Drug: Glargine

Placebo

PLACEBO COMPARATOR

Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin.

Drug: Placebo

Liraglutide + Metformin

ACTIVE COMPARATOR

Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).

Drug: Metformin; Drug: Liraglutide

Interventions

Metformin DRUG

Titrated to 1000 mg BID

Also known as: Glucophage

Glargine followed by Metformin; Liraglutide + Metformin; Metformin alone

Liraglutide DRUG

Titrated to 1.8 mg/day

Also known as: Victoza

Liraglutide + Metformin

Glargine DRUG

Titrated to target fasting glucose \<90 mg/dl

Also known as: Insulin glargine, Lantus

Glargine followed by Metformin

Placebo DRUG

Matching to metformin 1000 mg BI

Placebo

Eligibility Criteria

• Age: 20 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Fasting plasma glucose 95-125 mg/dl plus 2-hour glucose ≥140 mg/dl on 75 gm OGTT plus HbA1c ≤7.0%. There is no upper limit for the 2-hour glucose on OGTT.
• Age 20-65 years
• Body mass index (BMI) ≥25 kg/m2 but ≤50 kg/m2
• Self-reported diabetes \<1 year in duration
• Drug naïve (no prior to oral glucose lowering agent(s), insulin or other injectable glucose lowering agents)

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
• Taking medications that affect glucose metabolism, or has an underlying condition that is likely to require such medications
• Active infections
• Renal disease (serum creatinine \>1.4 mg/dl for men; \>1.3 mg/dl for women) or serum potassium abnormality (\<3.4 or \>5.5 mmol/l)
• Anemia (hemoglobin \<11 g/dl in women, \<12 g/dl in men) or known coagulopathy
• Cardiovascular disease, including uncontrolled hypertension. 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:
• Pancreatitis
• Serum alanine transaminase (ALT) more than 3 times the upper limit of normal
• Excessive alcohol intake
• Suboptimally treated thyroid disease
• Medullary carcinoma of the thyroid or MEN-2 (in participant or a family history)
• Hypertriglyceridemia (\>400 mg/dl despite treatment)
• Conditions or behaviors likely to affect the conduct of the RISE Study

Sponsors & Collaborators

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

Study Sites (4)

Jesse Brown VA Medical Center

Chicago, Illinois, 60612, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

VA Puget Sound Health Care System

Seattle, Washington, 98108, United States

Location

Related Publications (15)

• 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

• 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

• 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, Ehrmann DA, Arslanian SA, Barengolts E, Buchanan TA, Caprio S, Edelstein SL, Hannon TS, Kahn SE, Kozedub A, Mather KJ, Nadeau KJ, Sam S, Tripputi M, Xiang AH, El Ghormli L; RISE Consortium. Weight loss and beta-cell responses following gastric banding or pharmacotherapy in adults with impaired glucose tolerance or type 2 diabetes: a randomized trial. Obesity (Silver Spring). 2022 Aug;30(8):1579-1588. doi: 10.1002/oby.23475.

  PMID: 35894078 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

• Gnesin F, Thuesen ACB, Kahler LKA, Madsbad S, Hemmingsen B. Metformin monotherapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Jun 5;6(6):CD012906. doi: 10.1002/14651858.CD012906.pub2.

  PMID: 32501595 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. Lack of Durable Improvements in beta-Cell Function Following Withdrawal of Pharmacological Interventions in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes. Diabetes Care. 2019 Sep;42(9):1742-1751. doi: 10.2337/dc19-0556. Epub 2019 Jun 9.

  PMID: 31178434 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

• 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 DERIVED

• 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 DERIVED

MeSH Terms

Conditions

Prediabetic State; Diabetes Mellitus, Type 2

Interventions

Metformin; Liraglutide; 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; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Insulin, Long-Acting; Insulins; Pancreatic Hormones; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Sharon Edelstein, Lead Research Scientist
• Organization: George Washington University Biostatistics Center

sharone@bsc.gwu.edu

301-881-9260

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• 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: April 1, 2013
• Primary Completion: February 1, 2019
• Study Completion: August 1, 2019
• Last Updated: May 11, 2023
• Results First Posted: May 11, 2023

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will share

Locations

US (4)