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

Sponsor

Laval University (Other)

Overall Status

Terminated

CT.gov ID

NCT01701934

Collaborator

Innovair (Other), Takeda (Industry)

Enrollment

Locations

Arms

21.9

Duration (Months)

2.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease Metabolic Syndrome	Drug: Roflumilast Drug: Placebo	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

14 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Impact of Roflumilast on Visceral Adiposity and MetaBolic Profile in Chronic Obstructive Lung Disease: a Randomized and Controlled Trial: the RAMBO Trial.

Study Start Date :

Feb 1, 2013

Actual Primary Completion Date :

Oct 1, 2014

Anticipated Study Completion Date :

Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Roflumilast Roflumilast 500 mcg, once daily for 6 months	Drug: Roflumilast 500 mcg, oral, once daily for 6 months Other Names: DAXAS
Placebo Comparator: Placebo pill Placebo pill, once daily for 6 months	Drug: Placebo One placebo pill daily, for 6 months Other Names: Inactive comparator

Arm

Intervention/Treatment

Experimental: Roflumilast

Roflumilast 500 mcg, once daily for 6 months

Drug: Roflumilast

500 mcg, oral, once daily for 6 months

Other Names:

DAXAS

Placebo Comparator: Placebo pill

Placebo pill, once daily for 6 months

Drug: Placebo

One placebo pill daily, for 6 months

Other Names:

Inactive comparator

Outcome Measures

Primary Outcome Measures

Change in intrabdominal adiposity [At baseline and 6 months later]
Measured by CT scan.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 80 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Paul's Hospital	Vancouver	British Columbia	Canada	V6Z 1Y6
2	Centre hospitalier de l'Université de Montréal	Montréal	Quebec	Canada	H2W 1T8
3	Montreal Chest Institute	Montréal	Quebec	Canada	H2X 2P4
4	Institut universitaire de cardiologie et de pneumologie de Québec	Québec	Quebec	Canada	G1V 4G5
5	Hôpital régional de Saint-Jérôme	Saint-Jérôme	Quebec	Canada	J7Z 5T3