RISE Adult Medication Study
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Metformin alone 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
Titrated to 1000 mg BID
Other Names:
|
| Active Comparator: Glargine followed by Metformin 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
Titrated to 1000 mg BID
Other Names:
Drug: Glargine
Titrated to target fasting glucose <90 mg/dl
Other Names:
|
| Placebo Comparator: Placebo Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin. |
Drug: Placebo
Matching to metformin 1000 mg BI
|
| Active Comparator: Liraglutide + Metformin 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
Titrated to 1000 mg BID
Other Names:
Drug: Liraglutide
Titrated to 1.8 mg/day
Other Names:
|
Outcome Measures
Primary Outcome Measures
- ß-cell function measured by hyperglycemic clamp techniques [3-months after a medication washout]
Participants will have 12-months of active therapy and 3-months of washout after which the primary outcome will be assessed.
Secondary Outcome Measures
- Hyperglycemic clamp and oral glucose tolerance test (OGTT) measures of ß-cell function and glucose tolerance [3-months after a medication washout]
Measures derived from the hyperglycemic clamp that are not specified as primary outcomes and measures derived from the OGTT.
Other Outcome Measures
- Hyperglycemic clamp and OGTT measures of ß-cell Function and Glucose Tolerance [After 12 months of active treatment]
Measures derived from the hyperglycemic clamp and the OGTT related to treatment effect at the end of the 12 month active intervention period compared to pre-treatment baseline.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
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)
Exclusion Criteria:
-
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
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Taking medications that affect glucose metabolism, or has an underlying condition that is likely to require such medications
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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)
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Anemia (hemoglobin <11 g/dl in women, <12 g/dl in men) or known coagulopathy
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Cardiovascular disease, including uncontrolled hypertension. Participants must be able to safely tolerate administration of intravenous fluids required during clamp studies.
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History of conditions that may be precipitated or exacerbated by a study drug:
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Pancreatitis
-
Serum alanine transaminase (ALT) more than 3 times the upper limit of normal
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Excessive alcohol intake
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Suboptimally treated thyroid disease
-
Medullary carcinoma of the thyroid or MEN-2 (in participant or a family history)
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Hypertriglyceridemia (>400 mg/dl despite treatment)
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Conditions or behaviors likely to affect the conduct of the RISE Study
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Unable or unwilling to give informed consent
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Unable to adequately communicate with clinic staff
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Another household member is a participant or staff member in RISE
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Current, recent or anticipated participation in another intervention research project that would interfere with any of the interventions/outcomes in RISE
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Weight loss of >5% in past three 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.
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Likely to move away from participating clinics in next two years
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Women of childbearing potential who are unwilling to use adequate contraception
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Current (or anticipated) pregnancy and lactation.
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Major psychiatric disorder that, in the opinion of clinic staff, would impede the conduct of RISE
-
Additional conditions may serve as criteria for exclusion at the discretion of the local site.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Jesse Brown VA Medical Center | Chicago | Illinois | United States | 60612 |
| 2 | University of Chicago | Chicago | Illinois | United States | 60637 |
| 3 | Indiana University | Indianapolis | Indiana | United States | 46202 |
| 4 | VA Puget Sound Health Care System | Seattle | Washington | United States | 98108 |
Sponsors and Collaborators
- RISE Study Group
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
- 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 β-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. Review.
- RISE Consortium. Restoring Insulin Secretion (RISE): design of studies of β-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.
- RISE Adult
- 5U01DK094406-02