Obesity
Conditions
Brief summary
In Protocol #2, we will select 30 obese pubertal and 30 obese prepubertal subjects with an abnormal cytokine profile (i.e. fibrinogen and/or hsCRP concentration greater than or equal to 2 Standard Deviations (SD) above the mean established in our lab for lean controls in Protocol #1). They will be randomly assigned to either lifestyle intervention (diet/exercise) or diet/exercise plus metformin for 6 months. After the 6 month evaluation the subjects will cross over the treatment arms, i.e., those that were doing diet/exercise intervention only will add metformin, those that were doing the diet/exercise plus metformin will discontinue the metformin and continue with diet/exercise changes only. Intrahepatic fat contents will be measured as well. The investigators hypothesize that obese children in these age groups will have increased cardiovascular risk related to their obese state before reaching the currently defined criteria of metabolic syndrome. The investigators hypothesize that these cardiovascular risks can be reduced with lifestyle and drug interventions.
Interventions
DRUGMetformin
Metformin, 250mg by mouth twice a day with meals will be started and if tolerated increased to 500mg twice a day in 3 days in those less than 12 years old and titrated further to 1000mg twice a day if tolerated.
BEHAVIORALDietary modification with caloric restriction
The life style intervention changes will include a hypocaloric diet representing at least a 500 kcal/day reduction based on their dietary histories and Resting Energy Expenditure (REE) determined by the initial calorimetry.
BEHAVIORALEstablishment of exercise protocol
Participants will attend the Fitness Center 3 times per week and supervised by an exercise technician or exercise specialist. Exercise will be individually prescribed for each participant based on their functional abilities. Exercise will consist of 5-10 minutes for warm up and stretching, followed by 15-30 minutes of cardiovascular exercise (i.e. treadmill, bicycle ergometer, rower, nustep, etc), 10-20 minutes of strength training (supervised using weight stack equipment), and 5-10 minutes of cool down and stretching. As children typically do not need an exercise prescription based on heart rate, we will familiarize them with perceived exertion scales and monitor that they are exercising in the moderate to hard range of perception of effort. Participants will be started at 15 minutes of cardiovascular exercise and 10 minutes of strength training exercise, progressing by 2-3 minutes every week until 30 and 20 minutes is achieved for each respectively.
Sponsors
Thrasher Research Fund
Nemours Children's Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
7 Years to 18 Years
Healthy volunteers
Yes
Inclusion criteria
* Ages 7-18 years. * Greater than the 95th percentile body mass index for their age and gender. * Children are in Tanner Stage I or IV or V. * Normal Blood Pressure. * Normal fasting glucose. * Normal lipids. * Menstruating girls must have completed their most recent period at least 2 weeks prior to blood draw. * No recent illness, no chronic illnesses, no routine medications, no smoking or alcohol intake. * Must pass the screening test done in Protocol #1. * Must have higher values than normal for certain blood tests related to heart disease that were measured in Protocol #1.
Exclusion criteria
* Chronic active illnesses. * Recent illnesses. * Use of routine medications, vitamins, herbal remedies, oral contraceptive pills, or other over the counter medications within 4 weeks of blood draw. * History of recent or chronic smoking. * Currently pregnant. * Impaired fasting glucose. * Dyslipidemia. * Actively in puberty. * Weight greater than 300 pounds. * Metal in the abdomen. * History of being overweight greater than 5 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at 6 Months | Baseline and 6 months | Value at 6 months minus value at baseline. HsCRP is an acute phase protein which is a sensitive marker for systemic inflammation. HsCRP concentrations were measured in our laboratory by immuno-nephelometry (Siemens Healthcare Diagnostics, Deerfield IL, USA), with an hsCRP lower sensitivity of 0.156 mg/L. |
| Change From Baseline in Fibrinogen at 6 Months | Baseline and 6 months | Value at 6 months minus value at baseline. Fibrinogen is a hepatic-derived factor directly involved in clotting and in the viscosity characteristics of blood flow. It binds to platelets and contributes to their aggregation, promotes fibrin formation and is also an acute phase reactant that is increased in inflammatory states. Fibrinogen concentrations were measured in our laboratory by immuno-nephelometry (Siemens Healthcare Diagnostics, Deerfield IL, USA). |
| Change From Baseline in Interleukin 6 (IL-6) at 6 Months | Baseline and 6 months | Value at 6 months minus value at baseline. IL-6 is a pro-inflammatory cytokine thought to produce a state of low-grade inflammation in obese individuals. IL-6 stimulates hepatic production of C-reactive protein (CRP), an acute phase protein which is a sensitive marker for systemic inflammation. IL-6 was measured by enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, MN, USA). |
| Change From Baseline in Plasminogen Activator Inhibitor-1 (PAI-1) at 6 Months | Baseline and 6 months | Value at 6 months minus value at baseline. PAI-1 is the primary physiological inhibitor of fibrinolysis and proteolysis. High PAI-1 levels have been linked to thrombosis and fibrosis, insulin resistance and obesity. PAI-1 was measured by ELISA (American Diagnostica, Stamford, CT, USA). |
Countries
United States
Participant flow
Recruitment details
Participants recruited from pediatric endocrinology clinics, in Jacksonville, USA between November 2003 and April 2008.
Pre-assignment details
375 participants recruited; 177 obese participants screened, 111 excluded (62 did not meet inclusion criteria and 4 refused participation).
Participants by arm
| Arm | Count |
|---|---|
| Diet/Exercise Only, Then Diet/Exercise Plus Metformin Diet/Exercise only in first intervention period and Diet/Exercise plus Metformin in second intervention period (no washout period). | 31 |
| Diet/Exercise Plus Metformin, Then Diet/Exercise Only Diet/Exercise plus Metformin in first intervention period and Diet/Exercise only in second intervention period (no washout period). | 35 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention -Baseline to 6Months | Impaired Glucose Tolerance at Screening | 2 | 0 |
| First Intervention -Baseline to 6Months | Lost to Follow-up | 3 | 3 |
| First Intervention -Baseline to 6Months | No Longer Interested | 6 | 7 |
| First Intervention -Baseline to 6Months | Relocation | 1 | 2 |
| Second Intervention -6Months to 12Months | Lost to Follow-up | 4 | 3 |
| Second Intervention -6Months to 12Months | No Longer Interested | 0 | 2 |
| Second Intervention -6Months to 12Months | Relocation | 1 | 0 |
Baseline characteristics
| Characteristic | Diet/Exercise Plus Metformin, Then Diet/Exercise Only | Diet/Exercise Only, Then Diet/Exercise Plus Metformin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 35 Participants | 31 Participants | 66 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 12.3 years STANDARD_DEVIATION 0.5 | 12 years STANDARD_DEVIATION 0.4 | 12.2 years STANDARD_DEVIATION 2.7 |
| Region of Enrollment United States | 35 participants | 31 participants | 66 participants |
| Sex: Female, Male Female | 20 Participants | 16 Participants | 36 Participants |
| Sex: Female, Male Male | 15 Participants | 15 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 31 | 0 / 35 |
| serious Total, serious adverse events | 0 / 31 | 0 / 35 |
Outcome results
Primary
Change From Baseline in Fibrinogen at 6 Months
Value at 6 months minus value at baseline. Fibrinogen is a hepatic-derived factor directly involved in clotting and in the viscosity characteristics of blood flow. It binds to platelets and contributes to their aggregation, promotes fibrin formation and is also an acute phase reactant that is increased in inflammatory states. Fibrinogen concentrations were measured in our laboratory by immuno-nephelometry (Siemens Healthcare Diagnostics, Deerfield IL, USA).
Time frame: Baseline and 6 months
Population: 1 Subject in the Diet/Exercise plus Metformin, then Diet/Exercise (Pubertal) Group did not have a Fibrinogen level available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diet/Exercise, Then Diet/Exercise Plus Metformin (Prepubertal) | Change From Baseline in Fibrinogen at 6 Months | 58.5 mg/dL |
| Diet/Exercise, Then Diet/Exercise Plus Metformin (Pubertal) | Change From Baseline in Fibrinogen at 6 Months | -105 mg/dL |
| Diet/Exercise Plus Metformin, Then Diet/Exercise (Prepubertal) | Change From Baseline in Fibrinogen at 6 Months | 0.00 mg/dL |
| Diet/Exercise Plus Metformin, Then Diet/Exercise (Pubertal) | Change From Baseline in Fibrinogen at 6 Months | -33 mg/dL |
Primary
Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at 6 Months
Value at 6 months minus value at baseline. HsCRP is an acute phase protein which is a sensitive marker for systemic inflammation. HsCRP concentrations were measured in our laboratory by immuno-nephelometry (Siemens Healthcare Diagnostics, Deerfield IL, USA), with an hsCRP lower sensitivity of 0.156 mg/L.
Time frame: Baseline and 6 months
Population: 1 Subject in the Diet/Exercise plus Metformin, then Diet/Exercise (Pubertal) Group did not have an hsCRP level available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diet/Exercise, Then Diet/Exercise Plus Metformin (Prepubertal) | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at 6 Months | -0.37 mg/dL |
| Diet/Exercise, Then Diet/Exercise Plus Metformin (Pubertal) | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at 6 Months | -1.78 mg/dL |
| Diet/Exercise Plus Metformin, Then Diet/Exercise (Prepubertal) | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at 6 Months | -0.29 mg/dL |
| Diet/Exercise Plus Metformin, Then Diet/Exercise (Pubertal) | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) at 6 Months | 0.00 mg/dL |
Primary
Change From Baseline in Interleukin 6 (IL-6) at 6 Months
Value at 6 months minus value at baseline. IL-6 is a pro-inflammatory cytokine thought to produce a state of low-grade inflammation in obese individuals. IL-6 stimulates hepatic production of C-reactive protein (CRP), an acute phase protein which is a sensitive marker for systemic inflammation. IL-6 was measured by enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, MN, USA).
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diet/Exercise, Then Diet/Exercise Plus Metformin (Prepubertal) | Change From Baseline in Interleukin 6 (IL-6) at 6 Months | -0.66 pg/mL |
| Diet/Exercise, Then Diet/Exercise Plus Metformin (Pubertal) | Change From Baseline in Interleukin 6 (IL-6) at 6 Months | -0.99 pg/mL |
| Diet/Exercise Plus Metformin, Then Diet/Exercise (Prepubertal) | Change From Baseline in Interleukin 6 (IL-6) at 6 Months | 0.2 pg/mL |
| Diet/Exercise Plus Metformin, Then Diet/Exercise (Pubertal) | Change From Baseline in Interleukin 6 (IL-6) at 6 Months | -0.35 pg/mL |
Primary
Change From Baseline in Plasminogen Activator Inhibitor-1 (PAI-1) at 6 Months
Value at 6 months minus value at baseline. PAI-1 is the primary physiological inhibitor of fibrinolysis and proteolysis. High PAI-1 levels have been linked to thrombosis and fibrosis, insulin resistance and obesity. PAI-1 was measured by ELISA (American Diagnostica, Stamford, CT, USA).
Time frame: Baseline and 6 months
Population: 1 Subject in the Diet/Exercise plus Metformin, then Diet/Exercise (Pubertal) Group and 1 Subject in the Diet/Exercise, then Diet/Exercise plus Metformin (Pubertal) Group did not have a PAI-1 level available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Diet/Exercise, Then Diet/Exercise Plus Metformin (Prepubertal) | Change From Baseline in Plasminogen Activator Inhibitor-1 (PAI-1) at 6 Months | 6.98 ng/ML |
| Diet/Exercise, Then Diet/Exercise Plus Metformin (Pubertal) | Change From Baseline in Plasminogen Activator Inhibitor-1 (PAI-1) at 6 Months | -46.84 ng/ML |
| Diet/Exercise Plus Metformin, Then Diet/Exercise (Prepubertal) | Change From Baseline in Plasminogen Activator Inhibitor-1 (PAI-1) at 6 Months | 0.55 ng/ML |
| Diet/Exercise Plus Metformin, Then Diet/Exercise (Pubertal) | Change From Baseline in Plasminogen Activator Inhibitor-1 (PAI-1) at 6 Months | -34.42 ng/ML |