RISE Adult Medication Study

Study Overview
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Brief Summary
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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.

Official Title
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Restoring Insulin Secretion Adult Medication Study

Conditions
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Prediabetes, Type 2 Diabetes

Intervention / Treatment
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* Drug: Metformin
* Drug: Liraglutide
* Drug: Glargine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 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 Unable or unwilling to give informed consent Unable to adequately communicate with clinic staff Another household member is a participant or staff member in RISE Current, recent or anticipated participation in another intervention research project that would interfere with any of the interventions/outcomes in RISE 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. Likely to move away from participating clinics in next two years Women of childbearing potential who are unwilling to use adequate contraception Current (or anticipated) pregnancy and lactation. 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.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin alone<br>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<br>* Titrated to 1000 mg BID<br>* Other names: Glucophage;|
| Active Comparator: Glargine followed by Metformin<br>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<br>* Titrated to 1000 mg BID<br>* Other names: Glucophage;Drug: Glargine<br>* Titrated to target fasting glucose <90 mg/dl<br>* Other names: Insulin glargine, Lantus;|
| Placebo Comparator: Placebo<br>Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin. | Drug: Placebo<br>* Matching to metformin 1000 mg BI<br>|
| Active Comparator: Liraglutide + Metformin<br>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<br>* Titrated to 1000 mg BID<br>* Other names: Glucophage;Drug: Liraglutide<br>* Titrated to 1.8 mg/day<br>* Other names: Victoza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACPRg | First phase response from the hyperglycemic clamp | 3-months after a medication washout | 
| ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | Participants had 12-months of active therapy. Secondary results at the end of active intervention. | Secondary analysis was on all participants with a Month 12 visit. |