Diabetes Mellitus, Hypertension, Metabolic Disease, Obesity, Sleep Apnea Syndrome
Conditions
Keywords
Dyslipidemia, Race, Body Fat, Visceral Fat, Sleep Apnea, Fat-Soluble Vitamins, Type 2 Diabetes, Obesity, Childhood Obesity
Brief summary
Obesity is a condition affecting one-third off the U.S. population and is a major risk actor for the development of Type 2 diabetes, hyperlipidemia (increased levels of fat in the blood), hypertension (high blood pressure), and other disorders of the heart and lungs. Individuals with the onset of obesity during childhood or adolescence are at an increased risk of obesity-related, diseases, both during adolescence and later in adult life. African American girls and women are at an increased risk for obesity, and have substantial rates of obesity-related diseases and causes of death. Further, many African American adult women fail to respond to many of the therapeutic approaches used to treat obesity. At present there are no medical therapies proven effective for the correction of severe obesity in children or adolescents. One medication that may have a favorable risk-benefit ratio in pediatric populations is Orlistat (Xenical, Hoffmann LaRoche). Orlistat works by preventing the action of enzymes in the digestive process, interfering with the absorption of approximately 1/3 of the fat eaten in the diet. Xenical appears to be effective for reducing weight and obesity-associated diseases in obese adults. Researchers propose to determine the safety, tolerability, and efficacy of Xenical in 12-17 year old severely obese African American and Caucasian children and adolescents who have one or more obesity-related disease (hypertension, hyperlipidemia, sleep apnea, hepatic steatosis, insulin resistance, impaired glucose tolerance, or Type 2 diabetes).
Detailed description
Obesity is a condition affecting one-third of the adult U.S. population and is a major risk factor for the development of Type 2 diabetes, hyperlipidemia, hypertension, and other cardiovascular and respiratory disorders. Individuals with the onset of obesity during childhood or adolescence are at increased risk for obesity-related, comorbid conditions, both during adolescence and later in life. African American girls and women are at particular risk for obesity, and have substantial rates of obesity-related morbidity and mortality. Further, African American adult women have a less satisfactory response to many therapeutic approaches used to treat obesity. At present, there are no medical therapies proven effective for the amelioration of severe obesity in children or adolescents. One medication that may have a favorable risk-benefit ratio in pediatric populations is orlistat (Xenical(Trademark), Hoffmann LaRoche). Orlistat acts by inhibiting gastrointestinal lipases, interfering with the absorption of approximately 1/3 of ingested dietary fat. Orlistat appears to be effective for reducing weight and obesity-associated comorbidities in obese adults. We propose to determine the safety, tolerability, and efficacy of orlistat in 12-17 year-old severely obese African American and Caucasian children and adolescents who have one or more obesity-related comorbidity (hypertension, hyperlipidemia, sleep apnea, hepatic steatosis, insulin-resistance, impaired glucose tolerance, or Type 2 diabetes). Under this protocol, we have conducted an open-label pilot study of orlistat in twenty subjects, suggesting orlistat has a similar side effect profile in adolescents as in adults. We wish to determine the safety and efficacy of orlistat in reducing obesity-related comorbidities using a randomized, double-blind, placebo-controlled clinical trial. All study participants will be enrolled in a psycho-educational weight loss program that includes nutrition education, cognitive-behavioral self-monitoring strategies, and promotion of physical activity. We will also study the effects of orlistat on fat preferences, and study the influence of genetic variables on energy expenditure and weight loss during treatment. A group of healthy, non-overweight children and adolescents will complete questionnaires and exercise studies as a control group for interpretation of results in overweight children and adolescents, but will not undergo phlebotomy or receive any medication.
Interventions
DRUGOrlistat
Subjects receive drug for 6 months plus a 12 week intensive behavioral weight los program. Subjects return for monthly visits for 3 more months.
DRUGPlacebo
Subjects receive drug for 6 months plus a 12 week intensive behavioral weight los program. Subjects return for monthly visits for 3 more months.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Roche Pharma AG
Jack Yanovski
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Good general health. Individuals taking medications for obesity-related comorbid conditions will not be excluded. Obesity: body mass index for age and triceps skinfold above the 95th percentile (determined by NHANES I age-, sex-, and race- specific data). All subjects will be required to be over 60 kg in body weight. Evidence for a quantifiable obesity-related comorbidity. Examples include: systolic or diastolic hypertension (determined by age-specific charts); frank Type 2 diabetes, impaired glucose tolerance assessed by oral glucose tolerance testing; hyperinsulinemia (defined as a fasting insulin greater than 15 mIU/mL); significant hyperlipidemia (total cholesterol greater than 200 mg/dL, LDL cholesterol greater than 129 mg/dL or fasting triglycerides greater than 200 mg/dL); hepatic steatosis (SGPT or SGOT above normal range with negative hepatitis studies) or sleep apnea documented by a sleep study. Age 12 to 17 years at the start of the study. For girls with childbearing potential, a negative pregnancy test before taking and while taking study medication. Sexually active females must be using an effective form of birth control. These methods include total abstinence (no sex), oral contraceptives (the pill), an intrauterine device (IUD), levonogestrol implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). If one of these cannot be used, contraceptive foam with a condom is recommended. Race of all four grandparents self-identified as either all Caucasian or all African American.
Exclusion criteria
Volunteers will be excluded (and referred to non-experimental treatment programs) for the following reasons: Presence of renal, hepatic (other than obesity-related steatosis), gastrointestinal, most endocrinologic (e.g., Cushing syndrome), or pulmonary disorders (other than either asthma not requiring continuous medication or sleep apnea-related disorders); Adolescent girls who are pregnant, who are currently nursing an infant, or who are having unprotected intercourse; Individuals who have, or whose parent or guardians have, current substance abuse or a psychiatric disorder or other condition which, in the opinion of the investigators, would impede competence or compliance or possibly hinder completion of the study; Subjects who regularly use prescription medications unrelated to the complications of obesity. Oral contraceptive use will be permitted, provided the contraceptive has been used for at least two months before starting study medication. The use of over-the-counter and prescription medications will be reviewed on a case-by-case basis; depending on the medication, subjects who have continued to take prescription medication for at least 3 months prior to study entry may be eligible; Recent use (within six months) of anorexiant medications for the purpose of weight reduction; Inability to undergo MRI (e.g., volunteers with metal within their bodies including cardiac pacemakers, neural pacemakers, aneurysmal clips, shrapnel, ocular foreign bodies, cochlear implants, non-detachable electronic or electromechanical devices such as infusion pumps, nerve stimulators, bone growth stimulators, etc. that are contraindications). For pilot study participants, hypersensitivity or allergy to methylene blue. Individuals with documented G6PD deficiency will be excluded. INCLUSION CRITERIA: HEALTHY CONTROL CHILDREN AND ADOLESCENTS: Volunteers will qualify for inclusion if they meet the following criteria: 1. Good general health. 2. Age 12-17 years at study entry. 3. Body mass index (BMI) for age above the 5th percentile and below 85th percentile, which is considered normal weight by CDC growth chart standards. 4. For females with childbearing potential, a negative pregnancy test at initial evaluation. 5. Race of all four grandparents self-identified as either all Caucasian or all African American.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in BMI Standard Deviation Score | baseline to 6 months | Body Mass index standard deviation score calculated for age and sex according to Centers for Disease Control standards. See: Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11 2002; (246): 1-190. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight | baseline to 6 months | Weight in kg |
| Change in Body Mass Index | baseline to 6 months | BMI is calculated in kg/m2. Change from baseline to 6 months of treatment |
| Change in Body Fat (kg) | baseline to 6 months | body fat distribution measures obtained from Dual-energy X-ray Absorptiometry (DEXA) |
| Effect of Race on Change in Weight (kg) | baseline to 6 months | Difference in change of weight in kg according to race (Non-Hispanic White versus Non-Hispanic Black) |
Countries
United States
Participant flow
Recruitment details
Accrual for RCT began in 1999 and ended in 2008. All subjects were screened at the NIH Clinical Center.
Pre-assignment details
Most subjects screened but not enrolled (101) did not have an obesity-related comorbid condition (i.e., hypertension or dyslipidemia). 16 met a medical exclusion, and 13 declined participation after undergoing initial evaluation.
Participants by arm
| Arm | Count |
|---|---|
| Orlistat Orlistat 120 mg TID for 6 months plus a behavioral weight loss program
Orlistat : Subjects receive drug for 6 months plus a 12 week intensive behavioral weight los program. Subjects return for monthly visits for 3 more months. | 100 |
| Placebo Matching placebo 120 mg TID x 6 months plus a behavioral weight loss program
Placebo : Subjects receive drug for 6 months plus a 12 week intensive behavioral weight los program. Subjects return for monthly visits for 3 more months. | 100 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 6 | 7 |
| Overall Study | Lack of family interest | 4 | 5 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | medication intolerance | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Orlistat | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 100 Participants | 100 Participants | 200 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 | 14.52 years STANDARD_DEVIATION 1.46 | 14.65 years STANDARD_DEVIATION 1.38 | 14.59 years STANDARD_DEVIATION 1.41 |
| Region of Enrollment United States | 100 participants | 100 participants | 200 participants |
| Sex: Female, Male Female | 66 Participants | 65 Participants | 131 Participants |
| Sex: Female, Male Male | 34 Participants | 35 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 95 / 100 | 94 / 100 |
| serious Total, serious adverse events | 0 / 100 | 2 / 100 |
Outcome results
Primary
Change in BMI Standard Deviation Score
Body Mass index standard deviation score calculated for age and sex according to Centers for Disease Control standards. See: Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11 2002; (246): 1-190.
Time frame: baseline to 6 months
Population: Multiple imputation analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Orlistat | Change in BMI Standard Deviation Score | -0.12 Standard Deviation Score | Standard Error 0.02 |
| Placebo | Change in BMI Standard Deviation Score | -0.06 Standard Deviation Score | Standard Error 0.02 |
p-value: 0.007ANCOVA
Secondary
Change in Body Fat (kg)
body fat distribution measures obtained from Dual-energy X-ray Absorptiometry (DEXA)
Time frame: baseline to 6 months
Population: Multiple Imputation analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Orlistat | Change in Body Fat (kg) | -3.2 kg | Standard Error 0.55 |
| Placebo | Change in Body Fat (kg) | -1.7 kg | Standard Error 0.53 |
Secondary
Change in Body Mass Index
BMI is calculated in kg/m2. Change from baseline to 6 months of treatment
Time frame: baseline to 6 months
Population: Muliple imputation analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Orlistat | Change in Body Mass Index | -1.44 kg per square meter | Standard Error 0.26 |
| Placebo | Change in Body Mass Index | -0.50 kg per square meter | Standard Error 0.2 |
Secondary
Change in Body Weight
Weight in kg
Time frame: baseline to 6 months
Population: Multiple imputation analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Orlistat | Change in Body Weight | -2.9 kg | Standard Error 0.7 |
| Placebo | Change in Body Weight | -0.6 kg | Standard Error 0.7 |
Secondary
Effect of Race on Change in Weight (kg)
Difference in change of weight in kg according to race (Non-Hispanic White versus Non-Hispanic Black)
Time frame: baseline to 6 months
Population: Multiple imputation analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Orlistat | Effect of Race on Change in Weight (kg) | -2.126 kg | Standard Error 0.812 |
| Placebo | Effect of Race on Change in Weight (kg) | -3.742 kg | Standard Error 1.046 |
| Placebo - Non-Hispanic Blacks | Effect of Race on Change in Weight (kg) | 0.415 kg | Standard Error 0.835 |
| Placebo - Non-Hispanic Whites | Effect of Race on Change in Weight (kg) | -1.580 kg | Standard Error 1.013 |