Pediatric Weight Management

PWM: Adjunct Therapies (2006)

Citation:

Godoy-Matos A, Carraro L, Vieira A, Oliveira J, Guedes EP, Mattos L, Rangel C, Moreira RO, Coutinho W, Appolinario JC. Treatment of obese adolescents with sibutramine: a randomized, double-blind, controlled study. J Clin Endocrinol Metab. 2005;90:1460-1465.

PubMed ID: 15613431
 
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:
To determine whether sibutramine plus diet and exercise is safe, tolerable and efficacious in a regular clinical setting.
Inclusion Criteria:
  • Boys and girls
  • Aged 14-17 years
  • BMI of 30-45
  • Adult bone age as determined by left hand radiography
Exclusion Criteria:
  • Diabetes mellitus
  • Endocrine diseases predisposing to obesity (e.g. Cushing syndrome)
  • Severe hyperlipidemia (total cholesterol >300 mg/dl or triglycerides >500 mg/dl
  • Systemic or major psychiatric disorders
  • History of bulimia or anorexia
  • Uncontrolled hypertension (diastolic blood pressure >110 mm Hg) or other     cardiovascular diseases
  • Weight loss of 3 kg or more within 2 months or use of weight loss or weight gain drugs within 3 months before recruitment
  • Drug or alcohol abuse
  • Recent tobacco cessation or intention to quit during study period
  • Pregnancy or lactation
Description of Study Protocol:

Recruitment

No recruitment strategy described.

Design

Single blind, 4 week, placebo run-in period followed by a 6 month, randomized, double-blind, placebo-controlled phase.

Blinding used (if applicable)

  • Subjects blinded in the run-in period
  • Subjects and investigators blinded in the 6 month medication protocol
  • Examiner reading the echocardiogram was blinded to group assignment.

Intervention

  • Run in period
    • At initial visit, a complete clinical exam was performed.
    • All subjects received dietary counseling to achieve an energy deficit of 500 kcal/day at the start of the phase. No additional visits to the dietitian were allowed.  The recommended diet composition was approximately 30% from fat, 20% from protein and 50% from CHO.
    • Structured behavioral counseling was not used in order to reproduce a regular clinical setting practice.
    • Physical activity instructions were given by the attendant doctor in a brief written protocol aimed to obtain mainly aerobic moderate exercise for at least 30 min/day
  • Six month medication protocol
    • Participants who completed the run-in period and returned less than 25% of the prescribed placebo capsules were eligible to be randomized to receive sibutramine (10 mg/day) or matching placebo capsules without regard to weight loss during the run-in phase.
    • Subjects were instructed to take their capsule in the morning.
    • Visits were scheduled for every 4 weeks, and subjects were attended by the same doctor throughout the study whenever possible.

Statistical Analysis

  • Baseline characteristics between groups were compared using a two-tailed, unpaired t test.
  • Primary efficacy measures were the change in weight and BMI. Secondary efficacy measures were the change in waist, hip, and waist to hip ratio.
  • Mean absolute change in weight, BMI, waist, hip, and waist to hip ratio from baseline (wk 0) to wk 4, 8, 12, 16, 20 and 24 using repeated measures ANOVA.
  • Linear mixed model analysis was performed for weight and BMI using SAS PROC MIXED (considered an intent to treat analysis).
  • Categorical analysis was performed to determine the proportion of subjects who lost 5% or more, 10% or more, or 15% or more of initial weight (wk 0) to wk 24 using Fischer's exact test.
  • Laboratory variables were analyzed in those with complete data at baseline (visit 2, wk 0) and at wk 12 and 24 using ANOVA for comparison between sibutramine and placebo, and analysis of covariance for comparison between baseline and wk 24.
  • Echocardiography data were analyzed using SIAC software produced by Locus Medical Software.
  • Adverse events and secondary parameters were compared by X2 or Fisher's test.
  • All statistical tests assumed a two-tail analysis with a significance level of 0.05.
Data Collection Summary:

Timing of Measurements

  wk -4 (initial)
wk 0 (baseline)
wk 12 wk 24
clinical exam (ht, wt, waist and hip circumferences, blood pressure, heart rate) x     x
blood tests (lipids, glucose, insulin) x x x x
serum human chorionic gonadotropin-B (females only)   x   x
electrocardiogram x      
echocardiogram   x   x

At each visit (every 4 wk), the following were measured:

  • urinary human chorionic gonadotropin-B (pregnancy test, females)
  • adverse events
  • treatment compliance 

Dependent Variables

  • Weight
  • BMI
  • Waist circumference: measured at the minimal circumference between iliac crest and last rib edge
  • Hip circumference: measured at the greatest circumfrence through the major trochanters
  • Blood pressure: measured with the subject seated after 5 min of rest
  • Heart rate: measured with the subject seated after 5 min of rest
  • Echocardiography: performed using a phased array, commercially available, ultrasound system. Procedure described in detail.
  • Biochemical: measured after a 12 hr fast with a venous blood sample
    • Glucose: measured using glucose oxidase method
    • Total cholesterol: standard enzymatic spectrophotometric techniques
    • Triglycerides: standard enzymatic spectrophotometric techniques
    • HDL cholesterol: standard enzymatic spectrophotometric techniques
    • LDL cholesterol: calculated with the equation of Friedewald
    • VLDL cholesterol
    • Total cholesterol/HDL cholesterol: calculated
    • Insulin: determined by RIA
  • Adverse events
  • Compliance: assessed by counting prescribed vs returned capsules

Independent Variables

  • sibutramine (10 mg daily)
  • placebo
Description of Actual Data Sample:

Initial N:

68 subjects were included in the run-in period. Eight subjects were not randomized at the baseline visit. Five were lost during the run-in phase. One had a concomitant medical condition (i.e. repeated episodes of hyposglycemia) and was discontinued. Two patients returned for the baseline visit but refused to continue in the study. Therefore, no subject was withdrawn due to nonadherence to placebo in the run in phase.

Sixty subjects were randomized to either sibutramine or placebo.

Baseline Characteristics of study participants (mean + SD)

  Female     Male
   
  Sibutramine Placebo P Sibutramine Placebo P
Characteristic (n=25) (n=24)   (n=5) (n=6)  
Wk -4 (Run in)            
Age (yr) 115.9+1.1 16.3 +1.16 0.177 16.7+0.6 16.7+0.6 0.932
Wt (kg) 100.5+14.2 94+13.6 0.107 117.1+11.7 113.4+10.0 0.583
Ht (m) 1.64+0.06 1.62+0.08 0.435 1.77+0.08 1.74+0.05 0.516
BMI (kg/m2) 37.5+3.8 35.8+4.2 0.135 37.6+4.3 37.4+1.9 0.907
Waist (cm) 99.6+8.1 96.9+7.0 0.228 106.8+8.7 106.3+4.4 0.910
Hip (cm)  123.0+8.2 120.0+7.9
0.199
119.5+5.6
121.5+5.3
0.577
Wk 0 (Baseline)            
Wt (kg)  97.7+14.9 91.9+13.1
0.154
115.2+14.7
110.2+8.8
0.495
Wt loss (kg)  -2.85+2.15 -2.15+3.20
0.369
-1.92+4.4
-3.27+2.74
0.546
(range)  -6.1 to -0.5
-7.8 to -0.9
0.369
-9.3 to -1.7
-5.8 to - 0.9
 

Attrition (final N):

Of the 60 subjects randomized at the baseline visit, 10 subjects withdrew during the study - eight in the placebo group and 2 in the sibutramine group. None withdrew because of an adverse event.

Reasons for withdrawal in the placebo group:
  • nonadherence to the protocol or loss of follow up (6 subjects)
  • consent withdrawal (1 subject)
  • pregnancy (1 subject)
Reasons for withdrawal in the sibutramine group:
  • new job (1 subject)
  • BMI of <25 was attained (1 subject)

Age: Adolescent, aged 14-17 yr

Ethnicity: Not described

Other relevant demographics: Not described

Anthropometrics (e.g., were groups same or different on important measures)

Location: Department of Nutrology and Metabolism, Rio de Janeiro, Brazil

Summary of Results:

Weight/BMI

Sibutramine group (from week 0) lost significantly more weight and experienced significantly greater reduction in BMI, waist and hip circumferences.

Weight and BMI Change (mean + SD)

Parameters Sibutramine Placebo
  (n=30) (n=30)
Weight (kg) -10.3+6.6a -2.4+2.5
BMI (kg/m2) -3.6+2.5a -0.9+0.9
Waist (cm) -7.2+5.5a -1.8+2.6
Hip (cm) -7.0+5.5a -1.1+2.1
Waist/hip ratio -0.01+0.03 -0.01+0.02
a P < 0.001 (by ANOVA)

Mean difference in the percent change in BMI and weight from baseline to end point was statistically significant starting at wk 4 and remained so throughout the rest of the  study. (P<0.05 in all weeks).

An analysis was performed using a linear mixed model for weight and BMI:

  • After wk 24 the sibutramine group lost 10.39 kg (SE=0.75) and the placebo group lost 2.78 kg (SE=.82); P < 0.001.
  • Examining the change through time, the overall estimated mean difference between the two slopes was 7.60 kg (SE=1.11); P < 0.001.
  • At wk 24, mean BMI reduction was 3.67 kg/m2 (SE=0.35) for the sibutramine group and 1.10 kg/mfor the placebo group (SE=0.38); P < 0.001.
  • Over time the sibutramine group reduced 2.58 kg/m2 (SE=0.52; P < 0.001) more than the placebo group

Number of patients achieving weight loss of 5%, 10%, and 15% according to group assignment at wk 24.

Reduction in initial wt (%) Sibutramine
[no, (%)]
Placebo
[no, (%)]
>5 22 (73.3)a 3 (10.0)
>10 14 (46.6)a 0 (0.0)
>15 7 (23.3)a 0 (0.0)
a P < 0.001 (by Fisher's exact test)

Blood Pressure, Heart Rate and Echocardiography

  1. No statistical difference was observed between groups in cardiovascular parameters
  2. Systolic and diastolic pressures as well as heart rated tended to decrease more in the placebo than in the sibutramine group.
  3. Baseline echocardiogram did not show any morphological valvular abnormalities or any diastolic dysfunction. At wk 24 no valvular morphological abnormalities, diastolic dysfunction or increased degree of valvular regurgitation were noted (24 subjects in sibutramine group, 15 subjects in placebo group had both baseline and 24 wk echo data). No changes in left atrium diameter, left ventricular ejection fraction or left ventricular mass in sibutramine group compared with baseline echocardiogram.
Biochemical Parameters
  1. No differences were found when the groups were compared at the different time points (baseline, wk 12, and wk 24).
  2. There was a significant decrease in triglycerides and VLDL cholesterol levels at wk 24 in the sibutramine group compared with the baseline values.
  3. There was a trend toward significance (P=0.07) in the calculated total cholesterol/HDL cholesterol ratio in the sibutramine group between wk 24 and baseline.
  4. There was no difference in any parameter in the placebo group.
  Sibutramine     Placebo    
Parameter Baseline week 12 week 24 Baseline Week 12 Week 24
  (n=27) (n=27) (n=25) (n=21) (n=21) (n=19)
Glucose  87.0+7.6 87.0+9.3
86.4+8.2
84.1+8.2
84.2+6.0
84.3+11.4
Total cholesterol  174.1+40.7 163.8+31.2
160.0+26.5
175.2+34.4
167.1+29.8
172.2+33.9
Triglycerides  112.7+65.8 87.8+37.9
74.7+25.3a
100.1+48.6
87.2+36.6
 83.5+26.6
HDL cholesterol  33.6+8.9 36.5+7.7
39.3+11.1
36.5+5.7
37.6+7.0
36.8+8.2
LDL cholesterol 117.9+36.5 110.5+32.2
102.7+24.2
118.7+31.0
111.6+29.9
117.2+33.9
VLDL cholesterol  22.6+13.2 18.0+7.9
14.5+5.2a
20.0+9.7
17.8+7.3
17.5+5.3
Insulin  15.8+6.5 14.7+6.9
13.2+5.5
14.9+6.0
15.1+5.2
13.7+4.7
total chol to
HDL chol
 5.0+1.1 4.6+1.4
4.2+1.1b
4.7+1.0
4.6+1.2
4.8+1.4

a P < 0.05 vs baseline
b P < 0.07

Adverse Events

  1. At wk 24, the difference between groups was statistically significant only for costipation, which occured in 40% sibutramine treated subjects vs 13% placebo treated subjects (P =0.039 by Fisher's test).
  2. No subject withdrew due to adverse events.
  3. No serious adverse event or rare event was reported during the study.
Author Conclusion:
  1. In a typical clinical setting, the addition of sibutramine to a hypocaloric diet and moderate exercise counseling induced significantly more weight loss in obese adolescents than diet and exercise counseling alone.
  2. Our results demonstrated consistent improvements with sibutramine treatment in mean percentage, absolute weight and BMI reduction using an intention to treat analysis.
  3. The proportion of subjects who lost at least 10% of initial body weight was more than five times greater with sibutramine treatment compared with placebo.
  4. About 25% of subjects in the sibutramine group lost 15% or more of initial body weight.
  5. Analysis of anthropometric measures, including waist and hip circumferences, also indicated favorable results for sibutramine.
  6. Short term treatment with sibutramine does not seem to be associated with morphological valvular abnormalities.
  7. Significant decrease in triglycerides and VLDL levels in the sibutramine treated group.
Funding Source:
Reviewer Comments:

Limitations:

  • Randomization process not described.
  • Diet and physical activity not assessed.
  • No compliance data presented for the sibutramine or placebo groups e.g. capsules consumed vs capsules prescribed.
  • Study supported by a grant from Abbott Laboratories. Knoll Pharmaceutical, subsequently Abbott Laboratories, provided and manufactured both placebo and sibutramine capsules.
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? ???
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) No
  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")? Yes
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? No
  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? No
  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? Yes
  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? Yes
  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)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
  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? No
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? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes