Official Title: “Safety and Efficacy of Orlistat (Xenical, Hoffmann LaRoche) in African American and Caucasian Children and Adolescents With Obesity-Related Comorbid Conditions”

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).

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study

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.

Intervention(s) in this Clinical Trial

• Drug: Orlistat
  • Subjects receive drug plus a weight loss program.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Lipase Inhibitor medication studied for ability to alter body weight and body composition.
• Placebo Comparator: 2
  • Control capsules for metformin

Primary Measures

• Changes in body weight and adipose tissue as determined by FMI-standard deviation score (BMI-SDS), air displacement plethysmography, and DXA scan.
  • Time Frame: 6 months
    Safety Issue?: No

Secondary Measures

• Changes in skinfold thickness, body circumferences, BIA, and MRI, the insulin and glucose values from the clamp study, changes in blood pressure, total cholesteraol, triglycerides, HDL cholesteraol, LDL, small dense LDL, leptin, and IGFBP1.
  • Time Frame: 6 months
    Safety Issue?: Yes

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.

EXCLUSION CRITERIA: HEALTHY CONTROL CHILDREN AND ADOLESCENTS:

Volunteers will be excluded for the following reasons:

• 1. Presence of past or present medical problems which would impair performance during the exercise tests;
• 2. Females who are pregnant, or who are currently nursing an infant;
• 3. Individuals who have, or whose parent or guardian has, current substance abuse or a psychiatric disorder or other condition that in the opinion of the investigators would impede competence or possibly hinder completion of the study;
• 4. Recent weight change of more than 3% of body weight in the past two months;
• 5. Recent use (within six months) of anorexiant medications for the purpose of weight reduction;
• 6. Physical impairments that would prevent completion of either the walk/run test or the cycle test.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 12 Years

Maximum Age for this Clinical Trial: 17 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00001723

Study ID Number: 980111

ClinicalTrials.gov Identifier: NCT00001723

Health Authority: United States: Federal Government

NIH Clinical Center Detailed Web Page