Roche trials database

Protocol number:

ML16868

Title of Study:

Multi-factorial approach associated with orlistat (Xenical) for 4 years' weight loss maintenance in obese patients

Sponsor:

Roche Pharma (Schweiz) AG

Company division:

Pharmaceutical

Product name:

Xenical

Generic name:

orlistat [Xenical]

Therapeutic area:

• Obesity

Clinical study summary:

Prospective, open-label, one-arm, one-centre national phase IV study in Switzerland.

Study center(s):

Single centre in Switzerland

Phase of development:

IV

Objectives:

The primary objective was to determine the efficacy of a multifactorial approach associated with Orlistat in the weight loss (≥10%) maintenance during 4 years.

The secondary objectives were as follows:

• To determine if the eating behavior changes during the weight management phase
• To determine if the physical activity changes during the weight management phase
• To determine if the psychological factors (anxiety and depression) change during the weight management phase
• To determine if the body composition (bioimpedence, skinfold thickness and waist to hip ratio) and resting energy expenditure (calorimetry) change during the weight management phase
• To determine if the metabolic parameters (glucose, insulin, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, leptin and arterial blood pressure) change during the weight management phase
• To determine if the insulin resistance measured by clamp changes during the weight management phase
• To determine the cardiovascular risks factors (atherosclerosis measured by carotid thickness) related to insulin resistance (euglycaemic clamp) and to neurovegetative balance (24h holter)

Methodology:

Patients satisfying the entry criteria for the study at screening phase (≤ 21 days prior to baseline) were enrolled. Different weight management approach was applied according to the fact that the patients presented a weight gain of ≥ 2.5% or not.

During year 1, every 2 month a visit with the following examinations/measures was done: weight, vital signs, concomitant illness and medication, adverse events, diet and physical activity counselling. Eating behaviour (binge eating, EDI2), physical activity evaluation (PAFQ) and psychological evaluation (HAD) were done every 6 months. Physical examination, metabolism (body composition, calorimetry) and lab exam (haematology and chemistry) were performed after one year (visit 12).

During years 2-4, patients were followed every 3 months and different weight management approach was applied according to the fact that the patient presents a weight gain of ≥2.5% or not. Weight, vital signs, concomitant illness and medication, adverse events, diet and physical activity counselling were documented every 3 months. Eating behaviour (binge eating), PAFQ and HAD were done every 6 months, eating disorder inventory (EDI2) was done once a year. Physical examination, body composition, calorimetry) and lab exam (haematology and chemistry) were performed every year. IMT sonography, 24 h holter, insulin resistance and calorimetry were assessed at the end of the study (visit 20). Orlistat intake, if any, was recorded at each visit.

Safety was assessed by recording adverse events, concomitant medications documented and clinical laboratory test performed at screening and during the whole study period. ECG measurements were done at screening and final visit.

Number of patients (planned/analyzed):

50 patients planned; 45 patients analyzed for efficacy, 38 patients analyzed for safety

Diagnosis and main criteria for inclusion:

Adult patients (18-65 years old) with a body mass index (BMI) = 30 or  = 28 with risk factors (diabetes, hypertension, hyperlipemia) before weight loss and documented weight loss of  = 10% before baseline.

Test product, dose and mode of administration or test procedure:

Orlistat 120 mg capsules taken orally; dosage: 120 mg Orlistat TID for 2 months if weight ≥2.5% from baseline weight; 120 mg Orlistat TID for 3 days (max) on special occasions (invitation, feast, birthdays, anniversary)

Duration of treatment:

4 years

Reference therapy, dose and mode of administration or reference procedure:

N/A

Criteria for evaluation (efficacy, safety):

Efficacy:

Primary: Stable body weight with weight gain <2.5%

Secondary: Binge eating disorder; physical activity evaluation scale; eating disorder inventory; hospital anxiety and depression scale; diagnosis of anxiety and depression; Xenical special occasions intake; psychological and other counselling

Safety: Safety profile was assessed on the basis of adverse events (AEs), laboratory values and electrocardiogram (ECG) results.

Statistical methods:

Descriptive statistics were used for summarizing and analysis of primary and secondary efficacy parameters.

Summary (efficacy, safety, other results):

Efficacy:  Primary efficacy results: 50 obese patients were recruited and 34 patients completed the prescribed course of the study while 16 patients withdrew from the study before the study end at 4 years. Considering the efficacy population without imputation of missing data, the summary statistics of change in body weight from baseline to 2 years is a negative value of -1.71% which fulfils the primary efficacy study objective.

At 4 years, the change from baseline to 4 years of follow up shows a median of 2.0 kg weight gain (2.5%) which does not completely fulfil the primary efficacy endpoint: the weight gain from baseline is less than 2.5% after 2 and 4 years of follow up.

Secondary efficacy results: No changes were observed for binge eating disorder, for psychological factors (anxiety and depression), for body composition (bioimpedence, skinfold thickness and waist to hip ratio) and resting energy expenditure (calorimetry), for the metabolic parameters (glucose, insulin, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, leptin and arterial blood pressure), or for insulin resistance measured by clamp during the 4 years weight management phase. 22% of the patients had no Orlistat intake, 19% only occasional Orlistat intake and 16% occasional and short term continuous intake. 56% of the patients had no psychological support, 20% had behavioural therapy, 18% cognitive therapy and 24% educational workshops.

Safety: Overall, 65.8% of the patients reported adverse events during the study. The most frequently recorded adverse event was back pain (10.5%), followed by irritable bowel syndrome, sinusitis and respiratory tract infection, arthralgia, headache, depression, anxiety and gastric bypass (each 7.9% of patients). No serious adverse events and no deaths occurred in this study.

Conclusions:

This first study with Orlistat associated to a multifactorial approach for a 4 years weight loss maintenance is extremely positive in weight loss maintenance after 2 years, but a trend to weight regain is observed from year 3 to year 4 with a weight gain of 2.5%, which is at the limit of the primary efficacy endpoint of less than 2.5% of weight gain. Perhaps this can be explained by the important mean weight loss of 16% before study entry which is high compared to the study criteria of at least 10% weight loss.

The study shows that no other parameters considered appear to be predictive of weight loss maintenance at 4 years except for weight loss before baseline: patients with a weight gain of more than 2.5% have significantly lost more weight before the study entry compared to the no weight gain patients. The second parameter which appears to be predictive is the body image in satisfaction factor of the EDI scale: a higher body image in satisfaction is predictive of positive weight maintenance of body weight. In fact, not only body weight loss per se is important but also psychological factors such as body image.

Date of report:

06.10.2009

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