RISE Adult Medication Study

RISE Study Group

Status and phase: Completed; Phase 3

Conditions: Prediabetes; Type 2 Diabetes

Treatments: Drug: Placebo; Drug: Liraglutide; Drug: Glargine; Drug: Metformin

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT01779362

RISE Adult

5U01DK094406-02 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Enrollment: 267 patients

Sex: All

Ages: 20 to 65 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

1. 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.
2. Age 20-65 years
3. Body mass index (BMI) ≥25 kg/m2 but ≤50 kg/m2
4. Self-reported diabetes <1 year in duration
5. Drug naïve (no prior to oral glucose lowering agent(s), insulin or other injectable glucose lowering agents)

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

3. Taking medications that affect glucose metabolism, or has an underlying condition that is likely to require such medications

4. Active infections

5. 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)

6. Anemia (hemoglobin <11 g/dl in women, <12 g/dl in men) or known coagulopathy

7. Cardiovascular disease, including uncontrolled hypertension. Participants must be able to safely tolerate administration of intravenous fluids required during clamp studies.

8. History of conditions that may be precipitated or exacerbated by a study drug:

   1. Pancreatitis
   2. Serum alanine transaminase (ALT) more than 3 times the upper limit of normal
   3. Excessive alcohol intake
   4. Suboptimally treated thyroid disease
   5. Medullary carcinoma of the thyroid or MEN-2 (in participant or a family history)
   6. Hypertriglyceridemia (>400 mg/dl despite treatment)

9. Conditions or behaviors likely to affect the conduct of the RISE Study

   1. Unable or unwilling to give informed consent
   2. 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% 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.
   6. Likely to move away from participating clinics in next two years
   7. Women of childbearing potential who are unwilling to use adequate contraception
   8. Current (or anticipated) pregnancy and lactation.
   9. Major psychiatric disorder that, in the opinion of clinic staff, would impede the conduct of RISE

10. Additional conditions may serve as criteria for exclusion at the discretion of the local site.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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267 participants in 4 patient groups, including a placebo group

Metformin alone

Active Comparator group

Description:

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.

Treatment:

Drug: Metformin

Glargine followed by Metformin

Active Comparator group

Description:

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.

Treatment:

Drug: Metformin

Drug: Glargine

Placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo

Liraglutide + Metformin

Active Comparator group

Description:

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).

Treatment:

Drug: Metformin

Drug: Liraglutide