Prediabetes, Type 2 Diabetes
Conditions
Keywords
Children, Pediatric
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.
Interventions
DRUGMetformin
DRUGGlargine
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
RISE Study Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 19 Years
Healthy volunteers
Yes
Inclusion criteria
1. 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. 2. Age 10-19 years 3. Pubertal development Tanner stage \>1 as defined by breast stage \>1 in girls, and testes \>3 cc's in boys. 4. Body mass index (BMI) ≥85th percentile but ≤50 kg/m2 5. Self-reported diabetes \<6 months in duration 6. Treatment with metformin for \<6 months preceding screening
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 mellitus 3. Taking medications that affect glucose metabolism, or has an underlying condition that is likely to require such medications 4. Treatment with insulin for \>1 week preceding screening 5. Active infections 6. Renal disease (serum creatinine \>1.2 mg/dl) or serum potassium abnormality (\<3.4 or \>5.5 mmol/l) 7. Anemia (hemoglobin \<11 g/dl in girls, \<12 g/dl in boys) or known coagulopathy 8. 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. 9. History of conditions that may be precipitated or exacerbated by a study drug: 1. Serum alanine transaminase (ALT) more than 3 times the upper limit of normal 2. Excessive alcohol intake 3. Sub-optimally treated thyroid disease 10. Conditions or behaviors likely to affect the conduct of the RISE Study 1. Participant and/or parents unable or unwilling to give informed consent 2. Participant and/or parents 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% of body weight in the past 3 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 2 years 7. Current (or anticipated) pregnancy and lactation. 8. A pregnancy that was completed less than 6 months prior to screening. 9. Breast feeding within 6 months prior to screening. 10. Women of childbearing potential who are unwilling to use adequate contraception 11. Major psychiatric disorder that, in the opinion of clinic staff, would impede the conduct of RISE 11. Additional conditions may serve as criteria for exclusion at the discretion of the local site.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ß-cell Response Measured by Hyperglycemic Clamp | 3-months after medication washout (Month 15) | Clamp measures of ß-cell response, co-primary outcomes |
| M/I | 3-months after a medication washout | Clamp measure of insulin sensitivity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ACPRg | 3-months after a medication washout | First phase response |
| ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | End of active intervention (Month 12). | Participants had 12-months of active therapy. Secondary results at the end of active intervention. |
| Clamp Measure of Insulin Sensitivity | End of active intervention (Month 12) | Participants had 12-months of active therapy. Secondary results at the end of active intervention. |
Other
| Measure | Time frame | Description |
|---|---|---|
| OGTT Measures of ß-cell Function and Glucose Tolerance | After 12 months of active treatment, and 3 and 9 months of washout | Measures derived the OGTT at the end of the 12 month active intervention period, and following a 3-month and 9-month washout. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin Alone Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day). | 47 |
| Glargine Followed by Metformin Basal insulin glargine was titrated to achieve a morning fasting blood glucose of 85-95 mg/dl and continued through 3 months after which metformin was titrated as in the Metformin alone arm and continued for 9 months. | 44 |
| Total | 91 |
Baseline characteristics
| Characteristic | Metformin Alone | Glargine Followed by Metformin | Total |
|---|---|---|---|
| 2-hour OGTT glucose | 184.2 mg/dl STANDARD_DEVIATION 50.2 | 183.5 mg/dl STANDARD_DEVIATION 44.5 | 183.9 mg/dl STANDARD_DEVIATION 47.3 |
| Age, Categorical <=18 years | 47 Participants | 42 Participants | 89 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Continuous | 13.9 Years STANDARD_DEVIATION 2.1 | 14.9 Years STANDARD_DEVIATION 2 | 14.4 Years STANDARD_DEVIATION 2.1 |
| BMI | 36.9 kg/m^2 STANDARD_DEVIATION 6.4 | 36.5 kg/m^2 STANDARD_DEVIATION 6.4 | 36.7 kg/m^2 STANDARD_DEVIATION 6.4 |
| Fasting glucose | 109.2 mg/dl STANDARD_DEVIATION 19.7 | 107.5 mg/dl STANDARD_DEVIATION 14.1 | 108.3 mg/dl STANDARD_DEVIATION 17.1 |
| HbA1c | 5.7 % of glycosylated hemoglobin STANDARD_DEVIATION 0.6 | 5.7 % of glycosylated hemoglobin STANDARD_DEVIATION 0.6 | 5.7 % of glycosylated hemoglobin STANDARD_DEVIATION 0.6 |
| Race/Ethnicity, Customized All othe | 6 Participants | 3 Participants | 9 Participants |
| Race/Ethnicity, Customized Black | 9 Participants | 14 Participants | 23 Participants |
| Race/Ethnicity, Customized Hispanic | 20 Participants | 14 Participants | 34 Participants |
| Race/Ethnicity, Customized Non-hispanic white | 12 Participants | 13 Participants | 25 Participants |
| Sex: Female, Male Female | 38 Participants | 27 Participants | 65 Participants |
| Sex: Female, Male Male | 9 Participants | 17 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 44 |
| other Total, other adverse events | 30 / 47 | 30 / 44 |
| serious Total, serious adverse events | 5 / 47 | 2 / 44 |
Outcome results
Primary
M/I
Clamp measure of insulin sensitivity
Time frame: 3-months after a medication washout
Population: All participants with a Month 15 visit
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin Alone | M/I | 1.48 x 10-5 mmol/kg/min per pmol/L |
| Glargine Followed by Metformin | M/I | 1.70 x 10-5 mmol/kg/min per pmol/L |
Comparison: Analyses were completed on a log scale and re-exponentiated for presentation.p-value: >0.05Regression, Linear
Primary
ß-cell Response Measured by Hyperglycemic Clamp
Clamp measures of ß-cell response, co-primary outcomes
Time frame: 3-months after medication washout (Month 15)
Population: Primary analysis was on all participants able to have a M15 visit. 2 participants in the metformin alone arm decompensated at M12 and were unable to remain off treatment until M15. A sensitivity analysis including these 2 participants using 1/2 of the worst value among all other participants did not alter the results.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Metformin Alone | ß-cell Response Measured by Hyperglycemic Clamp | Steady State C-peptide | 4.82 nmol/L |
| Metformin Alone | ß-cell Response Measured by Hyperglycemic Clamp | ACPRmax | 6.92 nmol/L |
| Glargine Followed by Metformin | ß-cell Response Measured by Hyperglycemic Clamp | Steady State C-peptide | 4.18 nmol/L |
| Glargine Followed by Metformin | ß-cell Response Measured by Hyperglycemic Clamp | ACPRmax | 5.95 nmol/L |
Comparison: Seemingly unrelated regression was used to compare treatment arms on the combination of insulin sensitivity (M/I as calculated from the hyperglycemic clamp) and insulin secretion (steady-state C-peptide and ACPRmax as co-primary; ACPRg as major secondary,). See statistical analysis plan for further details and R code.p-value: >0.05Regression, Linear
Secondary
ACPRg
First phase response
Time frame: 3-months after a medication washout
Population: Primary analysis was on all participants able to have a M15 visit.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin Alone | ACPRg | 1.11 nmol/L |
| Glargine Followed by Metformin | ACPRg | 1.12 nmol/L |
Secondary
Clamp Measure of Insulin Sensitivity
Participants had 12-months of active therapy. Secondary results at the end of active intervention.
Time frame: End of active intervention (Month 12)
Population: Secondary analysis was on all participants with a Month 12 visit.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin Alone | Clamp Measure of Insulin Sensitivity | 1.52 x 10-5 mmol/kg/min per pmol/L |
| Glargine Followed by Metformin | Clamp Measure of Insulin Sensitivity | 1.93 x 10-5 mmol/kg/min per pmol/L |
Secondary
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.
Time frame: End of active intervention (Month 12).
Population: Secondary analysis was on all participants with a Month 12 visit.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Metformin Alone | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | Steady State C-peptide | 4.78 nmol/L |
| Metformin Alone | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACPRmax | 6.95 nmol/L |
| Metformin Alone | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACPRg | 1.06 nmol/L |
| Glargine Followed by Metformin | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | Steady State C-peptide | 4.37 nmol/L |
| Glargine Followed by Metformin | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACPRmax | 5.79 nmol/L |
| Glargine Followed by Metformin | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACPRg | 1.03 nmol/L |
Comparison: Analyses were completed on a log scale and re-exponentiated for display.p-value: >0.05Regression, Linear
Other Pre-specified
OGTT Measures of ß-cell Function and Glucose Tolerance
Measures derived the OGTT at the end of the 12 month active intervention period, and following a 3-month and 9-month washout.
Time frame: After 12 months of active treatment, and 3 and 9 months of washout