Safety and Efficacy of Xenical in Children and Adolescents With Obesity-Related Diseases

• ClinicalTrials.gov Identifier: NCT00001723
• Recruitment Status: Completed
• First Posted: November 4, 1999
• Results First Posted: December 18, 2012
• Last Update Posted: December 18, 2012
• Sponsor: Jack Yanovski
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Roche Pharma AG
• Information provided by (Responsible Party): Jack Yanovski, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Tracking Information

• First Submitted Date: November 3, 1999
• First Posted Date: November 4, 1999
• Results First Submitted Date: October 11, 2012
• Results First Posted Date: December 18, 2012
• Last Update Posted Date: December 18, 2012
• Study Start Date: May 1998
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 15, 2012)

Change in BMI Standard Deviation Score [ Time Frame: 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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: November 15, 2012)

• Change in Body Weight [ Time Frame: baseline to 6 months ]
  Weight in kg
• Change in Body Mass Index [ Time Frame: baseline to 6 months ]
  BMI is calculated in kg/m2. Change from baseline to 6 months of treatment
• Change in Body Fat (kg) [ Time Frame: baseline to 6 months ]
  body fat distribution measures obtained from Dual-energy X-ray Absorptiometry (DEXA)
• Effect of Race on Change in Weight (kg) [ Time Frame: baseline to 6 months ]
  Difference in change of weight in kg according to race (Non-Hispanic White versus Non-Hispanic Black)

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Diabetes Mellitus
• Hypertension
• Metabolic Disease
• Obesity
• Sleep Apnea Syndrome

Intervention

• Drug: 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.
  Other Name: Xenical (orlistat)capsules
• Drug: 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.
  Other Name: Placebo capsule

Study Arms

• Placebo Comparator: Placebo
  Matching placebo 120 mg TID x 6 months plus a behavioral weight loss program
  Intervention: Drug: Placebo
• Experimental: Orlistat
  Orlistat 120 mg TID for 6 months plus a behavioral weight loss program
  Intervention: Drug: Orlistat

Publications *

• Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA. 1994 Jul 20;272(3):205-11. doi: 10.1001/jama.272.3.205.
• Drent ML, Larsson I, William-Olsson T, Quaade F, Czubayko F, von Bergmann K, Strobel W, Sjostrom L, van der Veen EA. Orlistat (Ro 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study. Int J Obes Relat Metab Disord. 1995 Apr;19(4):221-6.
• Must A, Jacques PF, Dallal GE, Bajema CJ, Dietz WH. Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. N Engl J Med. 1992 Nov 5;327(19):1350-5. doi: 10.1056/NEJM199211053271904.
• Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J. Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial. JAMA. 2005 Jun 15;293(23):2873-83. doi: 10.1001/jama.293.23.2873. Erratum In: JAMA. 2005 Sep 28;294(12):1491.
• McDuffie JR, Calis KA, Uwaifo GI, Sebring NG, Fallon EM, Frazer TE, Van Hubbard S, Yanovski JA. Efficacy of orlistat as an adjunct to behavioral treatment in overweight African American and Caucasian adolescents with obesity-related co-morbid conditions. J Pediatr Endocrinol Metab. 2004 Mar;17(3):307-19. doi: 10.1515/jpem.2004.17.3.307.
• McDuffie JR, Calis KA, Booth SL, Uwaifo GI, Yanovski JA. Effects of orlistat on fat-soluble vitamins in obese adolescents. Pharmacotherapy. 2002 Jul;22(7):814-22. doi: 10.1592/phco.22.11.814.33627.
• McDuffie JR, Calis KA, Uwaifo GI, Sebring NG, Fallon EM, Hubbard VS, Yanovski JA. Three-month tolerability of orlistat in adolescents with obesity-related comorbid conditions. Obes Res. 2002 Jul;10(7):642-50. doi: 10.1038/oby.2002.87.
• Schvey NA, Shank LM, Tanofsky-Kraff M, Ramirez S, Altman DR, Swanson T, Rubin AG, Kelly NR, LeMay-Russell S, Byrne ME, Parker MN, Broadney MM, Brady SM, Yanovski SZ, Yanovski JA. Weight-based teasing in youth: Associations with metabolic and inflammatory markers. Pediatr Obes. 2021 Mar;16(3):e12729. doi: 10.1111/ijpo.12729. Epub 2020 Oct 15.
• Han JC, Reyes-Capo DP, Liu CY, Reynolds JC, Turkbey E, Turkbey IB, Bryant J, Marshall JD, Naggert JK, Gahl WA, Yanovski JA, Gunay-Aygun M. Comprehensive Endocrine-Metabolic Evaluation of Patients With Alstrom Syndrome Compared With BMI-Matched Controls. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2707-2719. doi: 10.1210/jc.2018-00496.
• Radin RM, Tanofsky-Kraff M, Shomaker LB, Kelly NR, Pickworth CK, Shank LM, Altschul AM, Brady SM, Demidowich AP, Yanovski SZ, Hubbard VS, Yanovski JA. Metabolic characteristics of youth with loss of control eating. Eat Behav. 2015 Dec;19:86-9. doi: 10.1016/j.eatbeh.2015.07.002. Epub 2015 Jul 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 15, 2012): 200
• Original Enrollment (submitted: June 23, 2005): 425
• Actual Study Completion Date: October 2011
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Eligibility 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.

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00001723
• Other Study ID Numbers: 980111; 98-CH-0111 ( Other Identifier: NICHD IRB )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Jack Yanovski, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Original Responsible Party: Not Provided
• Current Study Sponsor: Jack Yanovski
• Original Study Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Roche Pharma AG

Investigators

• Principal Investigator: Jack A Yanovski, M.D.; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: November 2012