Pediatric Weight Management

PWM: Adjunct Therapies (2006)

Citation:

Chanoine J-P, Hampl S, Jansen C, Boldrin M, Hauptman J. Effect of orlistat on weight and body composition in obese adolescents. A randomized controlled trial. JAMA 2005;293:2873-2883.

PubMed ID: 15956632
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

Orlistat is a gastrointestinal tract lipase inhibitor which decreases intestinal fat absorption by up to 30%. It has been studied in adults, it has a good safety record, is generally well tolerated, and produces clinically meaningful and sustained decreases in weight and BMI when combined with a hypocaloric diet and exercise. Pharmacological treatments have not been extensively studied in children and adolescents. Based on clinical studies in adult populations, it is believed that orlistat may be a useful adjunct to diet, exercise, and behavioral therapy in the treatment of obese adolescents.

Primary objective: To determine the efficacy and safety of orlistat in conjunction with diet, exercise, and behavioral therapy in treating obese adolescents.

Secondary objective: To assess the impact of orlistat treatment on obesity-related risk factors, including waist circumference, lipid levels, and glucose and insulin responses to oral glucose challenge.

Inclusion Criteria:

Screening for participants included a physical examination consisting of Tanner stage assessment, vital signs and physical measurements (weight, height, and waist circumference), and clinical laboratory tests (blood chemistry, glucose and insulin responses to a 2-hour oral glucose tolerance challenge)

Following screening, inclusion criteria included:

  1. adolescents aged 12-16 years
  2. had a BMI 2 units or higher than the US weighted mean for the 95th percentile based on age and sex (using these criteria, minimum BMI for inclusion ranged from 28.5 in boys and 29.5 in girls at 12 years to 31.8 and 31.9, respectively, at 16 years)
  3. had a parent or grardian prepared to attend study visits with them
  4. were willing to be actively involved in behavioral modifications
Exclusion Criteria:

Exclusion criteria included:

  1. BMI of 44 or higher
  2. body weight of 130 kg or higher or less than 55 kg
  3. weight loss of 3 kg or higher within 3 months prior to screening
  4. diabetes requiring antidiabetic medication
  5. obesity associated with genetic disorders
  6. history or presence of psychiatric disease
  7. use of dexamphetamine or methylphenidate
  8. active gastrointestinal tract disorders
  9. ongoing bulimia or laxative use
  10. use of anorexiants or weight-reduction treatments during the 3 months before randomization
Description of Study Protocol:

Recruitment -- Participants were recruited at institutions with established pediatric obesity treatment programs and clinical research expertise. Participants were recruited through advertisements posted in newspapers and in clinics and through direct referrals from family physicians.

Design -- 1 year, multi-center, placebo-controlled study

Following a 2 week, single-blind, placebo lead-in period:

Participants were randomized at a 2 to 1 ratio to receive 120 mg orlistat or placebo 3 times daily in addition to diet, exercise, and behavioral modification therapy. Placebo and orlistat capsules appeared identical.

Blinding used (if applicable)--double-blind during 1 year study

Intervention (if applicable)

A 120 mg dose of orlistat or placebo 3 times daily for 1 year in conjuction with a mildly hypocaloric diet (designed to produce weight loss of 0.5 to 1.0 kg/week; 50% carbohydrate, 20% protein and 30% fat calories), exercise, and behavioral modification therapy (both groups received diet, exercise, and behavioral modification therapy).

General guidelines for diet, exercise, and behavioral modification therapy were supplied to all centers included in the study and each center was allowed to use its own strategy. However, there was no overall study-specific evaluation to measure compliance with these guidelines.

Diet

Caloric requirements were determined by sex and age and baseline body weight, using estimates of total energy requirements based on the World Health Organization equations for basal metabolic rate and corrected for physical activity. Caloric intakes ranged from 1400 kcal/d (body weight <70 kg) to 1800 kcal/d (body weight >100 kg) in boys and from 1200 to 1600 kcal/d for girls. Calories were adjusted if participant reached a BMI of 22 or too rapid weight loss (>1 kg/week). Participants received a daily multivitamin supplement. A dietitian spoke with participants at study visits about compliance with diet.

Behavioral Modification

Staff at study centers were to support behavioral modification techniques which generally included:

  • recording food intake and physical activity
  • limiting high-calorie and high-fat foods in the home
  • restricting food intake to dining areas at meal times
  • eating slowly
  • avoiding snacking
  • encouraging participants to understand their cues for overeating and substituting new behaviors for overeating

Exercise Counseling

Strength, flexibility, and aerobic exercises were included in the exercise plan and participants were encouraged by a behavioral psycholgist at study visits to reduce sedentary behaviors.

Monitoring of Adverse Events

In addition to the above, participants were questioned about adverse events, with particular attention directed toward gastrointestinal tract adverse events (possible effects of orlistat).

Statistical Analysis -- Analyses were performed using mixed-model ANOVA

Change from baseline was analyzed using center, treatment, and treatment by center as covariates

Body weight and BMI were corected for age and sex by z-scores based on Centers for Disease Control and Prevention charts

Between-group treatment differences with 95% confidence intervals and P-values were calculated based on least-squares means (LSM)

P<0.05 was considered statistically significant.

Data Collection Summary:

Anthropometrics:

Weight and height were measured every 2 weeks for the first 4 months and then every 2 months until end of study. Waist circumference was measured every month for the first 4 months and then every 2 months until end of study. Methodology not described.

A subset of participants--215 in orlistat group and 107 in the placebo group--underwent dual-energy x-ray absorptiometry to measure fat-free mass at baseline and at end of study.

Clinical Laboratory:

Blood samples (lipids, glucose and insulin responses to oral glucose challenge) were taken on Day 1 and after 3, 6, 9, and 12 months. Blood samples were taken in the morning following an overnight fast.

In addition, at each visit, participants were questioned on the presence of gastrointestinal tract adverse effects.

Dependent Variables (from baseline to end of study)

  • changes in BMI
  • change in body weight 
  • changes in waist circumference
  • changes in laboratory tests: lipids and glucose levels
  • changes in body composition
  • adverse events (ex., gastrointestinal tract adverse events)

Independent Variables

  •  treatment group (orlistat or placebo)
  • diet, exercise and behavioral modification

Control Variables (covariates)

  • center
  • treatment
  • treatment by center
Description of Actual Data Sample:

 Initial N: 533 participants randomly assigned and received either placebo or orlistat: 181 to placebo group and 352 to orlistat group 

 

Placebo (n =181)   Orlistat (n = 352)  
Female (n, %) Male (n, %) Female (n, %) Male (n, %)
 129 (71%)  52 (29%)  228 (65%)  124 (35%)

Attrition (final N):  117 completed placebo (64%); 232 completed orlistat (65%)

Placebo (n = 117)   Orlistat (n = 232)  
Female (n, %) Male (n, %) Female (n, %) Male (n, %)
86 (74%) 31 (26%) 161 (69%) 71 (31%)

Age: 12-16 y

Placebo-- Mean + SD: 13.5 + 1.2 y

Orlistat--Mean + SD: 13.7 + 1.4 y

Ethnicity: at baseline:

Ethnicity Placebo (%) Orlistat (%)
White 78% 75%
Black 14% 19%
Other  8%  6%

Anthropometrics  (at baseline): not statistically different at baseline

Measurement (+ SD) Placebo Orlistat
Weight, kg  95.1 + 14.2  97.7 + 15.0
Ht, cm  163.7 + 7.7  165.2 + 8.4
BMI  35.4 + 4.1  35.7 + 4.2
Weight circumference, cm  104.5 + 10.6  106.4 + 10.9

Location: location--clinic; geographic region--US and Canada

Summary of Results:

Antropometrics:

During the first 12 weeks after randomization, both groups experienced a mean decrease in BMI.  After week 12 until the end of the study, BMI stabilized with orlistat but increased beyond baseline with placebo.

In regard to body weight, both groups lost week during the first 4 weeks of the study. From week 4 to week 12, participants treated with orlistat continued to lose weight. In contrast, placebo-treated participants stabilized between weeks 4 through 12. After week 12, both groups gained weight until end of study, but weight gain was significantly greater with placebo.

Changes from baseline to end of study (Confidence Levels not presented; only P values)

 

Variables

Orlistat (n = 352)

(LSM)

Placebo (n = 181)

(LSM)

Statistical Significance of Group Difference (P values)

BMI

-0.55

+0.31

.001

Body weight, kg

 +0.53

 +3.14

 <.001

Waist circumference, cm

 -1.33

 +0.12

 <.05

Compared with 15.7% of the placebo group, 26.5% of participants taking orlistat had a 5% or higher decrease in BMI (P = 0.005).

4.5% of the placebo group and 13.3% of the orlistat group had a 10% or greater decrease in BMI (P = 0.002).

In the subset with dual-energy x-ray absorptiometry measurements (no Confidence levels or P values presented):

Measurement Placebo (n = 107) Orlistat (n = 215)
Body weight, kg +1.68 -0.35
Fat mass, kg -0.6 -2.53

Participants in the orlistat group lost more fat mass than those in the placebo group (~2401 g vs. ~380 g; P = 0.03)

Thus, the difference in absolute weight experienced by participants receiving orlistat was mostly due to a loss in fat mass, suggesting a favorable change in body composition.

There was no significant center by treatment interaction (P = 0.81), indicating that the treatment effect across centers was similar

Laboratory:

No significant differences were found between the 2 treatment groups with respect to changes in any of the laboratory tests--lipid or glucose levels.

Other Findings:

In general, levels of fat-soluble vitamins A, D, E, and beta-carotene increased in both groups during the study; as expected with daily multivitamin supplementation.

Adverse events--Mild to moderate gastrointestinal tract adverse events occurred in 9% to 50% of the orlistat group and 1% to 13% of the placebo group. This led to 2% of participants in orlistat group discontinuing treatment as opposed to only 3 participants in placebo group (<1%).

Author Conclusion:

Authors' Comments:

This is the first long-term study investigating the efficacy and safety of orlistat in adolescents.

Treatment with 120 mg of orlistat 3 times daily in combination with a reduced-calorie diet, exercise, and behavioral modification over the course of one year statistically significantly decreased BMI, waist circumference, and body fat compared with placebo. The results must be interpreted considering the characteristics of an adolescent population. Because adolescents' bodies are growing and acquiring muscle, bone, and skin, quantifying the effects of weight management therapy in adolescents require the use of age- and sex-corrected growth curves and BMI values.

BMI decreased with orlistat but increased with placebo. The relationship between the changes in BMI and body composition is explained through the dual-energy x-raay absorptiometry results obtained from a subset of study population. The increase in fat-free mass and bone mineral content was similar in both groups, reflecting normal growth. In contrast, change in fat mass was markedly different between groups. The placebo group experienced an increase in body weight (+1.68 kg) with a decrease of 0.6 kg in fat mass while the orlistat group experienced a decrease in body weight (-0.35 kg) and a decrease of 2.53 kg in fat mass. Thus, the weight difference between the placebo and orlistat groups was mostly due to a difference in fat mass suggesting a favorable change in body composition.

The adverse event profiles revealed that gastrointestinal tract adverse events were more common in the orlistat group; these adverse events were generally mild to moderate in intensity and may relate to the mechanism of action of orlistat.

Comparison with placebo-controlled studies in obese adults treated with orlistat: 

Compared with 15.7% of the placebo group, 26.5% of the orlistat group had a 5% or higher decrease in BMI; and 4.5% and 13.3%, respectively had a 10% or higher decrease in BMI. These values are similar to those reported in studies of obese adults in which orlistat-treated participants were up to 2.0 times more likely to experience a 5% or higher decrease in weight than placebo recipients and up to 2.5 times more likely to experience a 10% or higher decrease than placebo recipients.

Funding Source:
Reviewer Comments:

Limitations of study included:

  • Diet, exercise, and behavioral modification components were not standardized between centers. However, the absence of a significant center by treatment interaction suggest that the treatment effect across centers was similar.
  • The study was performed in a predominantly white population (77% orlistat and 80% placebo); generalizability to other ethnic groups may be limited
  • Most participants were female (69% orlistat and 74% placebo) 
  • Average participant was at ~98th percentile for obesity, so not known if less obese adolescents would acheive similar results
  • Number of participants and length of study do not allow for assessment of safety beyond one year
  • Attrition rates were high for both treatment groups (35%-36%) 
  • Although inclusion criteria included that participants' parent(s) were to attend study visits with them, parents roles were not discussed
  • Funding support from Hoffmann-LaRoche Ltd; possible bias
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? No
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? ???
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? ???
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? ???