Patients
We sought healthy male and female general practice patients, aged 18 to 65 years, who were mildly to moderately obese (body mass index [BMI] = 27 to 40 kg/m2), who had not lost more than 3 kg of weight during the previous 3 months, whose obesity was not of endocrine origin, and who did not have diabetes mellitus. All patients we enrolled were identified by primary care physicians. They had to have a seated pulse rate of 100 beats per minute or lower and a seated diastolic blood pressure of 100 mm Hg or lower. Hypertensive patients were included only if the condition had been stabilized with medication for 6 months. Patients receiving laxatives, anorectic agents, diuretics (except where stabilized for 6 months or more), bulking agents, antidepressants, or any other medication that in the opinion of the investigator might alter body weight were excluded. The patients completed the self-assessment Clinical Global Impressions questionnaire32,33 and the Beck Depression Inventory. The objective of this was to identify patients who might be likely to have unusual weight changes in the context of the trial because of depression, and was not done for psychiatric evaluation. Those assessed by the investigator to be more than borderline depressed were excluded.
Trial Protocol
Because of the lack of a clear definition of obesity at the time of the initiation of our study and the lack of a clear definition of the patients for whom sibutramine treatment would be appropriate, protocol amendments permitted enrollment of a few patients with BMIs of 25 to 44 kg/m2 (BMI Ž40 kg/m2 is considered extremely obese). Depression and anxiety inventories were completed by a subset of patients at the study outset.34 The investigator carried out a dietary inquiry for each eligible patient, and these patients were given standardized dietary advice and dietary advice sheets to be followed throughout the study. They were told to include certain foods in their diet each day: 12 oz of vegetables and fresh fruit; 6 oz of bread, cereal, potatoes, or rice; and 10 oz of skim milk; and they were told to substitute low-calorie foods such as fresh fruits and baked potatoes for sugary and fried foods such as chocolate and biscuits. The patients’ overall success in complying with dietary advice was assessed by the investigator using a 10-cm visual analog question scale labeled with opposite and extreme answers at either end (“easy to follow dietary advice” to “unable to follow dietary advice”).
Eligible patients then entered a 2-week single-blind placebo run-in period. At the end of the run-in period (month 0), those who still met the entry criteria entered the 12-month double-blind treatment phase of the study. Entry was restricted to those able to follow dietary advice as determined by the investigator. The patients were randomized in a double-blind fashion to once-daily treatment with placebo or sibutramine 10 mg or 15 mg dispensed in identical capsules, which were prepackaged and coded by the sponsor according to a computer-generated randomization list. The patients were assessed at monthly visits (month 0-month 12) during treatment and 1 week and 1 month after the completion of treatment. Patients withdrawing during treatment were assessed at that time and again 1 month after withdrawal. Beck Depression and State Anxiety inventories were performed on a subset of patients at the last treatment visit and at the 1-week follow-up visit to confirm lack of residual psychological changes due to medications.
At each visit, the investigator recorded the patient’s weight in indoor clothing. Waist and hip circumferences were measured at months 0, 6, and 12. Heart rate and blood pressure were recorded at every visit, and details of reported adverse events were recorded. Electrocardiograms and routine laboratory safety tests were performed at screening, 6 months, and 12 months.
Outcome Measures
The primary end point was the study outcome (measured on a categorical scale) on the basis of either the percentage weight loss at the end of the study or the reason for premature withdrawal.35 The outcome measures were weight loss (kg), percentage weight loss, weight loss of at least 5% and at least 10%, change in BMI, and change in waist/hip ratio.
Statistical Analysis
Calculations were performed on the difference between treatment groups in weight change between baseline and month12. Eighty-three patients completing treatment in each study group would be required to detect a difference in weight change of 4.0 kg with 90% power at the 5% significance level, assuming a standard deviation of 7.38 kg. Allowing for a forecast withdrawal rate of 45%, the desired sample size at enrollment was 184 patients per group or 552 for the entire study.