Impact of Roflumilast on Visceral Adiposity and Metabolic Profile in Chronic Obstructive Pulmonary Disease

Phase 2

Terminated

• Conditions: Metabolic Syndrome; Chronic Obstructive Pulmonary Disease
• Interventions: Drug: Placebo; Drug: Roflumilast

• Registration Number: NCT01701934
• Lead Sponsor: Laval University

Brief Summary

The purpose of this study is to determine whether roflumilast can improve metabolic profile and reduce visceral adiposity in patients with chronic obstructive pulmonary disease (COPD).

Detailed Description

Although underweight has been the traditional nutritional concern in patients with COPD, overweight and obesity are becoming important issues in this disease. In a rehabilitation study, investigators found that 66% of patients with moderate to severe COPD were either overweight or obese according to the WHO obesity classification (BMI ≥ 25 kg/m2). Obesity and COPD being two frequent conditions, it is important to understand the nature of their interactions.

Obesity, particularly in its visceral form is associated with a plethora of metabolic consequences that increases the risk of cardiovascular diseases. This would seem relevant to COPD which is in itself an important risk factor for cardiovascular diseases. The presence of obesity, particularly visceral obesity, may thus define in patients with COPD a clinical phenotype at high risk of cardiovascular diseases. In this context, it is relevant to note that the prevalence of metabolic syndrome is increased in COPD. Although fat distribution has not been precisely assessed in COPD studies, increased waist circumference is common in this disease suggesting that visceral obesity is part of the obesity syndrome seen in COPD.

Given the relationship between COPD, obesity and the metabolic syndrome and cardiovascular diseases, it is tempting to suggest that visceral obesity is likely to be frequent in COPD (as in the general population) and that the profound metabolic and inflammatory perturbations associated with this form of overweight/obesity could play a central role in the link between COPD and cardiovascular diseases.

Roflumilast, a Phosphodiesterase-4 inhibitor, has been recently evaluated as an anti-inflammatory medication in patients with COPD. Roflumilast, alone or in combination with long-acting bronchodilators, provide modest but significant improvement in lung function along with reductions in the rate of exacerbation in patients with moderate to severe COPD. A very interesting observation that was made in these 12-month duration studies was that the use of roflumilast was associated with an average reduction in body weight of 2 kg that took place during the first 6 months of the trials and remained relatively stable throughout the rest of the trials. The mechanisms and the precise effects of roflumilast on body composition and adipose tissue distribution have not been studied in great detail. However, available data suggest that roflumilast induces a preferential loss in body fat mass in comparison to fat-free mass. It remains to be seen whether roflumilast specifically affects visceral versus subcutaneous adipose tissue. The improved insulin sensitivity reported in one study in the presence of an apparently trivial weight loss (0.7 kg compared to placebo) may suggest that a selective loss of visceral adipose tissue may have been produced in response to roflumilast therapy.

These observations, although not definitive, suggest that roflumilast could be used not only to treat the respiratory component of COPD but also to modulate the metabolic aspect of this disease including visceral adiposity, features of the metabolic syndrome and significant co-morbidities of COPD.

Study Timeline

• Study First Submitted: 2012-10-03
• Study First Submitted QC: 2012-10-03
• Study First Posted: 2012-10-05
• Study Start: 2013-02
• Primary Completion: 2014-10
• Status Verified: 2014-11
• Last Update Submitted: 2014-11-10
• Last Update Posted: 2014-11-11
• Study Completion: 2014-12

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Male
• Target Recruitment: 14

Inclusion Criteria

• Gave an informed consent
• Forced expiratory volume in 1 second < 80% predicted
• Forced expiratory volume in 1 second / Forced vital capacity < 70%
• No exacerbation in the last 4 weeks
• Current or ex-smoker
• Smoking history of at least 10 pack/year
• Body mass index of at least 25 kg/m2
• Waist circumference of at least 94 cm
• Fasting blood triglycerides of at least 1.7 mmol/L

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Exclusion Criteria

• Any significant pulmonary pathology other than COPD
• Under oxygen therapy more than 12 hours per day
• More than 2 exacerbation episodes in the last 12 months
• The patient is currently participating to the active phase of a rehabilitation program
• Patient has been under roflumilast therapy prior to enrollment
• Unstable hypertriglyceridemia or hypercholesterolemia
• Under diabetes therapy (hypoglycemic agent or insulin)
• Cancer history in the last 5 years (except basal cell carcinoma)
• Moderate or severe hepatic impairment
• Used prednisone or systemic corticosteroids in the last 4 weeks

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo pill	Placebo	Placebo pill, once daily for 6 months
Roflumilast	Roflumilast	Roflumilast 500 mcg, once daily for 6 months

Primary Outcome Measures

Name	Time	Method
Change in intrabdominal adiposity	At baseline and 6 months later	Measured by CT scan.

Secondary Outcome Measures

Name	Time	Method
Change in body mass index	At baseline and 6 months later
Change in waist circumference	At baseline and 6 months later
Change in waist-to-hip circumference ratio	At baseline and 6 months later
Change in blood metabolic profile	At baseline and 6 months later	Blood glucose, insulin, triglycerides, apolipoprotein B, LDL/HDL cholesterol, C-reactive protein will be measured.
Change in body composition	At baseline and 6 months later	As measured by dual-energy X-ray absorptiometry (DEXA).
Change in subcutaneous adiposity	At baseline and 6 months later	As measured by CT scan.
Change in liver fat	At baseline and 6 months later	As measured by CT scan

Trial Locations

Locations (5)

Centre hospitalier de l'Université de Montréal; 🇨🇦 Montréal, Quebec, Canada

Institut universitaire de cardiologie et de pneumologie de Québec; 🇨🇦 Québec, Quebec, Canada

St. Paul's Hospital; 🇨🇦 Vancouver, British Columbia, Canada

Montreal Chest Institute; 🇨🇦 Montréal, Quebec, Canada

Hôpital régional de Saint-Jérôme; 🇨🇦 Saint-Jérôme, Quebec, Canada