Clinical Trial Result Information

Protocol number
M37017

Title of Study
Effect of orlistat in the prevention of weight regain and in long-term weight maintenance in abdominally obese patients after a very low calorie diet (VLCD).

Sponsor
F. Hoffmann-La Roche Ltd

Company division
Pharmaceutical

Product name
Xenical

Generic name
orlistat

Therapeutic area
Obesity

Clinical study summary
This was a 36-month, randomized, multi-center, double-blind placebo-controlled, parallel group study of Xenical (orlistat) to prevent weight regain in patients with abdominal obesity. Prior to randomization to either Xenical or placebo, patients were placed on a VLCD (600–800 Kcal/day) for 8 weeks. A district dietician provided dietary counseling at every visit. Food records were dispensed 4 times during the study. Body weight, blood pressure, heart rate, waist and hip circumferences and waist/hip ratios, laboratory values, eating behavior, quality of life, adverse events and intercurrent medications were monitored at intervals throughout the study.

Study center(s)
8 clinics: 1 in Sweden, 1 in Norway, 3 in Denmark, 3 in Finland.

Phase of development
IV

Objectives
Primary: To demonstrate the effect of Xenical on the prevention of weight regain compared with a placebo-controlled group over 36 months of treatment after 8 weeks of weight loss with a VLCD.

Secondary: (1) To evaluate the effect of Xenical on metabolic parameters (HbA1c, fasting plasma glucose (FPG), fasting insulin, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and blood pressure; (2) To evaluate the effect of Xenical on atherosclerosis; (3) To evaluate the effect of Xenical on eating behavior; (4) To evaluate the functional capacity and quality of life in patients treated with Xenical in comparison with patients given placebo.

Safety: To evaluate the safety profile of Xenical in this population of patients.

Methodology
Prior to randomization patients were placed on a VLCD (600–800 Kcal/day for 8 weeks). Patients were randomized to receive either Xenical 120mg tid or placebo tid. Dietary counseling took place at every visit by a district nurse or a dietician. Food records were dispensed to the patient at screening, Weeks 32 and 72, and Month 33. Body weight was recorded at every visit. Blood pressure and heart rate were measured at screening and each visit up to Week 24 then at Weeks 36, 52, 64, and 76, and Months 21, 24, 27, 30, 33, and 36. The waist and hip circumferences and waist/hip ratio were measured at screening, baseline, Weeks 12, 24, 36, 52, and 76, and Months 24, 30, and 36. Laboratory parameters (FPG, insulin, HbA1c, c-peptide, fibrinogen, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides) were measured at screening, Week –8, baseline, Weeks 12, 24, 36, 52, and 76, and Months 24 and 36. Laboratory tests were performed at screening, baseline, Weeks 24, 52, and 76, and Months 24 and 36. Eating behavior was recorded at screening, Weeks 4, 32, and 72, and Months 21 and 33. Quality of life was recorded at Week –8, baseline, Weeks 24, 52, and 76, and Months 24, 30, and 36. AEs and intercurrent medication were recorded at every visit.

Number of patients (planned/analyzed)
309 randomized.

Diagnosis and main criteria for inclusion
Adult patients 18–65 years of age; body mass index (BMI) ≥30-≤45kg/m2; waist≥102 cm males,≥92 cm females; ≥1 of the following risk factors: early non-insulin dependent diabetes mellitus/impaired fasting glucose or dyslipidemia. Patients should have completed an 8-week VLCD period and had a weight reduction of ≥5% during the VLCD period.

Test product, dose and mode of administration or test procedure
Xenical 120 mg/po/3 times daily.

Duration of treatment
36 months.

Reference therapy, dose and mode of administration or reference procedure
Placebo.

Criteria for evaluation (efficacy, safety)
Primary: prevention of weight-gain over 36 months. Secondary: effect on HbA1c, fasting plasma glucose, fasting insulin, total cholesterol, HDL- and LDL-cholesterol,triglycerides, blood pressure, atherosclerosis, eating behaviour, quality of life.

Statistical methods
Patients were randomly assigned in equal numbers to each group using a minimization algorithm. Central randomization was used.

Summary (efficacy, safety, other results)
A total of 309 patients were randomized: 153 to Xenical and 156 to placebo. One hundred and nine (109) patients (35.3%), 51 in the Xenical group and 58 in the placebo group, discontinued the study prematurely, 8 in each group due to AEs.

The success rate after 3 years, when calculated from the start of VLCD treatment at Week –8, was 67% in the Xenical group and 56% in the placebo group (P=0.0370).

Weight loss during VLCD was 14 kg (12%) in the Xenical group and 14 kg (13%) in the placebo group. After VLCD, the increase in weight was +4.6 kg in the Xenical group and +7.6 kg in the placebo group. For the whole study period, ie, screening to Month 36, the relative mean weight loss was 8.3% (9.3 kg) in the Xenical group and 6.4% (7.3 kg) in the placebo group (P=0.028; P=0.032).

The absolute mean reduction in BMI from screening to Month 36 was –3.0 in the Xenical group and –2.1 in the placebo group. The absolute mean reduction in waist circumference was 7.7 cm in the Xenical group and 5.4 cm in the placebo group.

The absolute mean reductions from screening to Month 36 in HbA1c, glucose, insulin, c-peptide, and fibrinogen were –0.69%, –0.49 mmol/L, –26 pmol/L,+ 0.05 nmol/L and –2.1 μmol/L in the Xenical group and –0.51%, –0.32 mmol/L, –12 pmol/L, +0.16 nmol/L and –2.3 μmol/L in the placebo group.

The absolute mean reductions from screening to Month 36 in total cholesterol, serum HDL cholesterol, serum LDL cholesterol, triglycerides, and lipoprotein A were – 0.46 mmol/L, + 0.04 mmol/L, –0.34 mmol/L, –0.38 mmol/L, and + 6.0 mg/L in the Xenical group and –0.46 mmol/L, +0.06 mmol/L, –0.38 mmol/L, –0.43 mmol/L, and –0.08 mg/L in the placebo group.

The absolute mean reduction from screening to Month 36 in systolic blood pressure was –7.8 mmHg in the Xenical group and –8.2 mmHg in the placebo group. The absolute mean reduction in diastolic blood pressure was –3.7 mmHg in the Xenical group and –4.7 mmHg in the placebo group. The absolute mean reduction in heart rate from screening to Month 36 was –2.3 seconds in the Xenical group and – 1.2 seconds in the placebo group.

The most commonly reported AEs (incidence ≥10%) in the Xenical group were fatty/oily stool (22.9%), flatulence (11.8%), increased defecation (13.7%), liquid stools (14.4%), loose stools (20.3%), oily spotting (20.3%), abdominal pain (21.6%), enteritis (11.1%), back pain (16.3%), headache (16.3%), upper respiratory tract infection (20.3%), and influenza syndrome (39.8%); in the placebo group, most commonly reported AEs in the placebo group were flatulence (10.3%), decreased defecation (10.3%), increased defecation (12.2%), liquid stools (12.2%), abdominal pain (19.2%), headache (16.7%), hypertension (11.5%), back pain (14.7%), coughing (12.8%), pharyngitis (14.1%), upper respiratory tract infection (17.3%), and influenza syndrome (38.5%). Eighteen patients in the Xenical group and 28 patients in the placebo group experienced serious adverse events. The causality for all the serious adverse events was assessed as unrelated, or remotely related.

A slight improvement in quality of life during treatment was observed in both groups. Eating disorder measurements showed improvement in both groups.

Conclusions
This study shows that treatment with Xenical in conjunction with a diet and weight-management program after VLCD produce significantly better weight maintenance than dietary intervention alone in patients with metabolic syndrome. Moreover, Xenical treatment was associated with a greater improvement in metabolic profile. These observations suggest that treatment with Xenical may be beneficial for patients with obesity and metabolic syndrome after an initial weight reduction period with VLCD.

Publications (references, if available)
Sjostrom L, Rissanen A, Boldrin M et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 1998; 352:160-161.

Date of report
6/13/2003