<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01701934</url>
  </required_header>
  <id_info>
    <org_study_id>RAMBO</org_study_id>
    <nct_id>NCT01701934</nct_id>
  </id_info>
  <brief_title>Impact of Roflumilast on Visceral Adiposity and Metabolic Profile in Chronic Obstructive Pulmonary Disease</brief_title>
  <acronym>RAMBO</acronym>
  <official_title>Impact of Roflumilast on Visceral Adiposity and MetaBolic Profile in Chronic Obstructive Lung Disease: a Randomized and Controlled Trial: the RAMBO Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Laval University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Innovair</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Takeda</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Laval University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether roflumilast can improve metabolic profile&#xD;
      and reduce visceral adiposity in patients with chronic obstructive pulmonary disease (COPD).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Although underweight has been the traditional nutritional concern in patients with COPD,&#xD;
      overweight and obesity are becoming important issues in this disease. In a rehabilitation&#xD;
      study, investigators found that 66% of patients with moderate to severe COPD were either&#xD;
      overweight or obese according to the WHO obesity classification (BMI ≥ 25 kg/m2). Obesity and&#xD;
      COPD being two frequent conditions, it is important to understand the nature of their&#xD;
      interactions.&#xD;
&#xD;
      Obesity, particularly in its visceral form is associated with a plethora of metabolic&#xD;
      consequences that increases the risk of cardiovascular diseases. This would seem relevant to&#xD;
      COPD which is in itself an important risk factor for cardiovascular diseases. The presence of&#xD;
      obesity, particularly visceral obesity, may thus define in patients with COPD a clinical&#xD;
      phenotype at high risk of cardiovascular diseases. In this context, it is relevant to note&#xD;
      that the prevalence of metabolic syndrome is increased in COPD. Although fat distribution has&#xD;
      not been precisely assessed in COPD studies, increased waist circumference is common in this&#xD;
      disease suggesting that visceral obesity is part of the obesity syndrome seen in COPD.&#xD;
&#xD;
      Given the relationship between COPD, obesity and the metabolic syndrome and cardiovascular&#xD;
      diseases, it is tempting to suggest that visceral obesity is likely to be frequent in COPD&#xD;
      (as in the general population) and that the profound metabolic and inflammatory perturbations&#xD;
      associated with this form of overweight/obesity could play a central role in the link between&#xD;
      COPD and cardiovascular diseases.&#xD;
&#xD;
      Roflumilast, a Phosphodiesterase-4 inhibitor, has been recently evaluated as an&#xD;
      anti-inflammatory medication in patients with COPD. Roflumilast, alone or in combination with&#xD;
      long-acting bronchodilators, provide modest but significant improvement in lung function&#xD;
      along with reductions in the rate of exacerbation in patients with moderate to severe COPD. A&#xD;
      very interesting observation that was made in these 12-month duration studies was that the&#xD;
      use of roflumilast was associated with an average reduction in body weight of 2 kg that took&#xD;
      place during the first 6 months of the trials and remained relatively stable throughout the&#xD;
      rest of the trials. The mechanisms and the precise effects of roflumilast on body composition&#xD;
      and adipose tissue distribution have not been studied in great detail. However, available&#xD;
      data suggest that roflumilast induces a preferential loss in body fat mass in comparison to&#xD;
      fat-free mass. It remains to be seen whether roflumilast specifically affects visceral versus&#xD;
      subcutaneous adipose tissue. The improved insulin sensitivity reported in one study in the&#xD;
      presence of an apparently trivial weight loss (0.7 kg compared to placebo) may suggest that a&#xD;
      selective loss of visceral adipose tissue may have been produced in response to roflumilast&#xD;
      therapy.&#xD;
&#xD;
      These observations, although not definitive, suggest that roflumilast could be used not only&#xD;
      to treat the respiratory component of COPD but also to modulate the metabolic aspect of this&#xD;
      disease including visceral adiposity, features of the metabolic syndrome and significant&#xD;
      co-morbidities of COPD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The recruitment of the study was prematurely stopped in July 2014 for the following reason; no&#xD;
    more study medication.&#xD;
  </why_stopped>
  <start_date>February 2013</start_date>
  <completion_date type="Anticipated">December 2014</completion_date>
  <primary_completion_date type="Actual">October 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in intrabdominal adiposity</measure>
    <time_frame>At baseline and 6 months later</time_frame>
    <description>Measured by CT scan.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in body mass index</measure>
    <time_frame>At baseline and 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in waist circumference</measure>
    <time_frame>At baseline and 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in waist-to-hip circumference ratio</measure>
    <time_frame>At baseline and 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in blood metabolic profile</measure>
    <time_frame>At baseline and 6 months later</time_frame>
    <description>Blood glucose, insulin, triglycerides, apolipoprotein B, LDL/HDL cholesterol, C-reactive protein will be measured.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in body composition</measure>
    <time_frame>At baseline and 6 months later</time_frame>
    <description>As measured by dual-energy X-ray absorptiometry (DEXA).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in subcutaneous adiposity</measure>
    <time_frame>At baseline and 6 months later</time_frame>
    <description>As measured by CT scan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in liver fat</measure>
    <time_frame>At baseline and 6 months later</time_frame>
    <description>As measured by CT scan</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <condition>Metabolic Syndrome</condition>
  <arm_group>
    <arm_group_label>Roflumilast</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Roflumilast 500 mcg, once daily for 6 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo pill</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo pill, once daily for 6 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Roflumilast</intervention_name>
    <description>500 mcg, oral, once daily for 6 months</description>
    <arm_group_label>Roflumilast</arm_group_label>
    <other_name>DAXAS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>One placebo pill daily, for 6 months</description>
    <arm_group_label>Placebo pill</arm_group_label>
    <other_name>Inactive comparator</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Gave an informed consent&#xD;
&#xD;
          -  Forced expiratory volume in 1 second &lt; 80% predicted&#xD;
&#xD;
          -  Forced expiratory volume in 1 second / Forced vital capacity &lt; 70%&#xD;
&#xD;
          -  No exacerbation in the last 4 weeks&#xD;
&#xD;
          -  Current or ex-smoker&#xD;
&#xD;
          -  Smoking history of at least 10 pack/year&#xD;
&#xD;
          -  Body mass index of at least 25 kg/m2&#xD;
&#xD;
          -  Waist circumference of at least 94 cm&#xD;
&#xD;
          -  Fasting blood triglycerides of at least 1.7 mmol/L&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any significant pulmonary pathology other than COPD&#xD;
&#xD;
          -  Under oxygen therapy more than 12 hours per day&#xD;
&#xD;
          -  More than 2 exacerbation episodes in the last 12 months&#xD;
&#xD;
          -  The patient is currently participating to the active phase of a rehabilitation program&#xD;
&#xD;
          -  Patient has been under roflumilast therapy prior to enrollment&#xD;
&#xD;
          -  Unstable hypertriglyceridemia or hypercholesterolemia&#xD;
&#xD;
          -  Under diabetes therapy (hypoglycemic agent or insulin)&#xD;
&#xD;
          -  Cancer history in the last 5 years (except basal cell carcinoma)&#xD;
&#xD;
          -  Moderate or severe hepatic impairment&#xD;
&#xD;
          -  Used prednisone or systemic corticosteroids in the last 4 weeks&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>François Maltais, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut universitaire de cardiologie et de pneumologie de Québec, University Laval</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>St. Paul's Hospital</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V6Z 1Y6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre hospitalier de l'Université de Montréal</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H2W 1T8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Montreal Chest Institute</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H2X 2P4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut universitaire de cardiologie et de pneumologie de Québec</name>
      <address>
        <city>Québec</city>
        <state>Quebec</state>
        <zip>G1V 4G5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital régional de Saint-Jérôme</name>
      <address>
        <city>Saint-Jérôme</city>
        <state>Quebec</state>
        <zip>J7Z 5T3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Sava F, Laviolette L, Bernard S, Breton MJ, Bourbeau J, Maltais F. The impact of obesity on walking and cycling performance and response to pulmonary rehabilitation in COPD. BMC Pulm Med. 2010 Nov 6;10:55. doi: 10.1186/1471-2466-10-55.</citation>
    <PMID>21054892</PMID>
  </reference>
  <reference>
    <citation>Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006 Dec 14;444(7121):881-7. doi: 10.1038/nature05488.</citation>
    <PMID>17167477</PMID>
  </reference>
  <reference>
    <citation>Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation. 2003 Mar 25;107(11):1514-9. doi: 10.1161/01.cir.0000056767.69054.b3.</citation>
    <PMID>12654609</PMID>
  </reference>
  <reference>
    <citation>Marquis K, Maltais F, Duguay V, Bezeau AM, LeBlanc P, Jobin J, Poirier P. The metabolic syndrome in patients with chronic obstructive pulmonary disease. J Cardiopulm Rehabil. 2005 Jul-Aug;25(4):226-32; discussion 233-4. doi: 10.1097/00008483-200507000-00010.</citation>
    <PMID>16056071</PMID>
  </reference>
  <reference>
    <citation>Lam KB, Jordan RE, Jiang CQ, Thomas GN, Miller MR, Zhang WS, Lam TH, Cheng KK, Adab P. Airflow obstruction and metabolic syndrome: the Guangzhou Biobank Cohort Study. Eur Respir J. 2010 Feb;35(2):317-23. doi: 10.1183/09031936.00024709. Epub 2009 Jul 2.</citation>
    <PMID>19574332</PMID>
  </reference>
  <reference>
    <citation>Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009 Aug 29;374(9691):695-703. doi: 10.1016/S0140-6736(09)61252-6.</citation>
    <PMID>19716961</PMID>
  </reference>
  <reference>
    <citation>Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009 Aug 29;374(9691):685-94. doi: 10.1016/S0140-6736(09)61255-1. Erratum In: Lancet. 2010 Oct 2;376(9747):1146.</citation>
    <PMID>19716960</PMID>
  </reference>
  <verification_date>November 2014</verification_date>
  <study_first_submitted>October 3, 2012</study_first_submitted>
  <study_first_submitted_qc>October 3, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 5, 2012</study_first_posted>
  <last_update_submitted>November 10, 2014</last_update_submitted>
  <last_update_submitted_qc>November 10, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 11, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COPD</keyword>
  <keyword>Intrabdominal adiposity</keyword>
  <keyword>Body composition</keyword>
  <keyword>Triglycerides</keyword>
  <keyword>Cholesterol</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
    <mesh_term>Metabolic Syndrome</mesh_term>
    <mesh_term>Obesity</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01701934
org study id: RAMBO
nct id: NCT01701934
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
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).
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Change in intrabdominal adiposity
time frame: At baseline and 6 months later
description: Measured by CT scan.
measure: Change in body mass index
time frame: At baseline and 6 months later
measure: Change in waist circumference
time frame: At baseline and 6 months later
measure: Change in waist-to-hip circumference ratio
time frame: At baseline and 6 months later
measure: Change in blood metabolic profile
time frame: At baseline and 6 months later
description: Blood glucose, insulin, triglycerides, apolipoprotein B, LDL/HDL cholesterol, C-reactive protein will be measured.
measure: Change in body composition
time frame: At baseline and 6 months later
description: As measured by dual-energy X-ray absorptiometry (DEXA).
measure: Change in subcutaneous adiposity
time frame: At baseline and 6 months later
description: As measured by CT scan.
measure: Change in liver fat
time frame: At baseline and 6 months later
description: As measured by CT scan
arm group label: Roflumilast
arm group type: Experimental
description: Roflumilast 500 mcg, once daily for 6 months
arm group label: Placebo pill
arm group type: Placebo Comparator
description: Placebo pill, once daily for 6 months
intervention type: Drug
intervention name: Roflumilast
description: 500 mcg, oral, once daily for 6 months
arm group label: Roflumilast
other name: DAXAS
intervention type: Drug
intervention name: Placebo
description: One placebo pill daily, for 6 months
arm group label: Placebo pill
other name: Inactive comparator
criteria: 
gender: Male
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
last name: François Maltais, MD
role: Principal Investigator
affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, University Laval
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
citation: Sava F, Laviolette L, Bernard S, Breton MJ, Bourbeau J, Maltais F. The impact of obesity on walking and cycling performance and response to pulmonary rehabilitation in COPD. BMC Pulm Med. 2010 Nov 6;10:55. doi: 10.1186/1471-2466-10-55.
PMID: 21054892
citation: Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006 Dec 14;444(7121):881-7. doi: 10.1038/nature05488.
PMID: 17167477
citation: Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation. 2003 Mar 25;107(11):1514-9. doi: 10.1161/01.cir.0000056767.69054.b3.
PMID: 12654609
citation: Marquis K, Maltais F, Duguay V, Bezeau AM, LeBlanc P, Jobin J, Poirier P. The metabolic syndrome in patients with chronic obstructive pulmonary disease. J Cardiopulm Rehabil. 2005 Jul-Aug;25(4):226-32; discussion 233-4. doi: 10.1097/00008483-200507000-00010.
PMID: 16056071
citation: Lam KB, Jordan RE, Jiang CQ, Thomas GN, Miller MR, Zhang WS, Lam TH, Cheng KK, Adab P. Airflow obstruction and metabolic syndrome: the Guangzhou Biobank Cohort Study. Eur Respir J. 2010 Feb;35(2):317-23. doi: 10.1183/09031936.00024709. Epub 2009 Jul 2.
PMID: 19574332
citation: Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009 Aug 29;374(9691):695-703. doi: 10.1016/S0140-6736(09)61252-6.
PMID: 19716961
citation: Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009 Aug 29;374(9691):685-94. doi: 10.1016/S0140-6736(09)61255-1. Erratum In: Lancet. 2010 Oct 2;376(9747):1146.
PMID: 19716960
responsible party type: Sponsor
mesh term: Lung Diseases
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Metabolic Syndrome
mesh term: Obesity