Randomized Placebo-Controlled Trial of Long-Term Treatment with Sibutramine in Mild to Moderate Obesity

Journal of Family Practice, June, 2001 by Ian G. Smith, Michael A. Goulder

METHODS

The Nottinghamshire Independent Ethics Committee (Boots) approved our study, and all patients gave informed consent in writing. Our study was conducted in accordance with the Declaration of Helsinki (1983 revision).

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/[m.sup.2]), 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 questionnaire[32,33] 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/[m.sup.2] (BMI [is greater than or equal to] 40 kg/[m.sup.2] 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.