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Effects of ROFLUMILAST on Subclinical Atherosclerosis in Chronic Obstructive Pulmonary Disease (COPD) (ELASTIC)

Primary Purpose

Chronic Obstructive Pulmonary Disease and Allied Conditions

Status
Completed
Phase
Phase 4
Locations
Austria
Study Type
Interventional
Intervention
Roflumilast
Placebo
Sponsored by
LudwLudwig Boltzmann Institute for COPD and Respiratory Epidemiology
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Obstructive Pulmonary Disease and Allied Conditions focused on measuring COPD, comorbidity, arterial stiffness, roflumilast

Eligibility Criteria

40 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Over 40 years of age
  • Smoking history of at least 10 pack years
  • Chronic obstructive pulmonary disease at Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II - IV diagnosed according to standard criteria.
  • History of at least one COPD exacerbation requiring systemic corticosteroid treatment or hospitalisation in the previous year

Exclusion Criteria:

  • Insufficient compliance to study medication (≤70% of tablets used) during 4 weeks run-in period
  • History of acute exacerbation 4 weeks prior to run-in period
  • Diagnosis of alpha-1-antitrypsin deficiency
  • Diagnosis of asthma
  • Acute respiratory infections (e.g. pneumonia)
  • Severe acute infectious diseases (e.g. active hepatitis, HIV)
  • Lung cancer
  • Bronchiectasis
  • Interstitial lung disease
  • Any other relevant lung disease
  • Acute myocardial infarction
  • Systolic left ventricular dysfunction
  • Congestive heart failure New York Heart Association Functional Classification (NYHA) severity grade IV
  • Haemodynamically significant cardiac arrhythmias or heart valve deformations
  • Peripheral arterial occlusive disease
  • Acute or chronic renal/hepatic failure
  • Active malignancy
  • Autoimmune disease
  • Pregnant or breastfeeding women
  • Women no using or not willing to use adequate contraceptive measures for the duration of the trial
  • Hypersensitivity to study medication or placebo
  • Severe psychiatric or neurological disorders or history of depression associated with suicidal ideation or behaviour
  • Galactose intolerance, lactase insufficiency or glucose-galactose malabsorption

Sites / Locations

  • Deparment for Respiratory and Critical Care Medicine, Otto Wangner Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Roflumilast

Placebo

Arm Description

Active arm including patients who receive the study drug (500µg Roflumilast once daily)

Control arm including patients who receive the placebo tablet (once daily)

Outcomes

Primary Outcome Measures

Change From Baseline in Carotid Femoral-Pulse Wave Velocity at Month 6
Carotid femoral-Pulse Wave Velocity (cf-PWV) will be measured non-invasively via applanation tonometry (AtCor Medical, Sydney, Australia). Wave propagation time will be calculated by the system software, using an ECG-gated reference frame. Aortic PWV is defined as the distance between two recording sites (i.e. common carotid- and femoral artery) divided by the wave propagation time.

Secondary Outcome Measures

Change From Baseline in Reactive Hyperemia Index at Month 6
Endothelial dysfunction will be assessed by Flow Mediated Dilation via the Endopat device. This validated system measures the pulse wave amplitudes at the tip of both index fingers. The dominant arm will be occluded for 5 minutes by a sphygmomanometric cuff. After cuff deflation the pulse wave amplitude will be assessed to finally calculate the ratio of pulse wave amplitude before and after cuff-induced hyperemia. The so called reactive hyperemia index represents endothelial dysfunction at the level of conduit as well as resistance vessels.
Change From Baseline in Augmentation Index at Month 6
The curve of the peripheral pressure wave will be recorded from the radial artery. Augmentation index (Aix) will be calculated from the generated central aortic pressure waveform via pulse wave analysis function. To correct for respective influences, Aix will be adjusted for a heart rate of 75 bpm. Appropriate intra observer validity will be assured via an operator index ≥ 80.
Change From Baseline in Matrix Metalloproteinase-9
Circulating levels of Matrix Metalloproteinase-9 (MMP-9) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay
Change From Baseline in Asymmetric Dimethylarginine at Month 6
Circulating levels of Asymmetric dimethylarginine (ADMA) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay
Change From Baseline in Tumor Necrosis Factor-alpha at Month 6
Circulating levels of Tumor Necrosis Factor-alpha (TNF-alpha) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay
Change From Baseline in Forced Expiratory Volume in 1 Second at Month 6
Forced Expiratory Volume in 1 second (FEV1) will be measured via standardized Spirometry
Change From Baseline in 6-Minute Walk Test at Month 6
6-Minute Walk Test (6MWT) will be assessed to quantify functional exercise capacity following the standardized protocol of the American Thoracic Society
Change From Baseline in COPD Assessment Test at Month 6
COPD Assessment Test (CAT) will be assessed to quantify patients disease related symptoms and to measure the impact of COPD on a patient's life, and how this changes over time. CAT is a standardised and validated patient questionaire comprising 8 distinct questions about different COPD-related symptoms. Each symptom is quantified by the patient on a numeric scale ranging from 0 to 5. Each symptom gives a number of points quantified as interval data without decimal places. The 8 different numbers of points are added to a total number expressed as the final points of the CAT score. The minimum achievable number of points is 0 and the maximum achievable number of points is 40. Higher values provide high symptoms and worse outcome, lower values provide low symptoms and better outcome.

Full Information

First Posted
June 4, 2012
Last Updated
January 14, 2019
Sponsor
LudwLudwig Boltzmann Institute for COPD and Respiratory Epidemiology
Collaborators
Medical University of Vienna
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1. Study Identification

Unique Protocol Identification Number
NCT01630200
Brief Title
Effects of ROFLUMILAST on Subclinical Atherosclerosis in Chronic Obstructive Pulmonary Disease (COPD)
Acronym
ELASTIC
Official Title
Effects of ROFLUMILAST on Markers of Subclinical Atherosclerosis In Stable COPD; the ELASTIC-trial
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
May 2012 (undefined)
Primary Completion Date
January 2016 (Actual)
Study Completion Date
January 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
LudwLudwig Boltzmann Institute for COPD and Respiratory Epidemiology
Collaborators
Medical University of Vienna

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Chronic obstructive pulmonary disease is associated with a low grade systemic inflammatory process. Systemic inflammation is hypothesized to maintain cardiovascular morbidity and mortality in COPD. Early changes of vascular integrity can be detected via markers of subclinical atherosclerosis. Selective Inhibition of phosphodiesterase subtype 4 describes a promising therapeutic option in COPD with beneficial impact on lung function and exacerbation rate. Moreover, an anti-inflammatory effect of phosphodiesterase-4 inhibition was confirmed by recent data. The aim of this study is to assess the effects of the phosphodiesterase-4 inhibitor Roflumilast on firstly surrogates of subclinical atherosclerosis and secondly markers of systemic inflammation in the peripheral circulation of patients with stable chronic obstructive pulmonary disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Obstructive Pulmonary Disease and Allied Conditions
Keywords
COPD, comorbidity, arterial stiffness, roflumilast

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
80 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Roflumilast
Arm Type
Active Comparator
Arm Description
Active arm including patients who receive the study drug (500µg Roflumilast once daily)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Control arm including patients who receive the placebo tablet (once daily)
Intervention Type
Drug
Intervention Name(s)
Roflumilast
Other Intervention Name(s)
Daxas
Intervention Description
Roflumilast coated tablet, 500µg oral application, once daily in the morning
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning
Primary Outcome Measure Information:
Title
Change From Baseline in Carotid Femoral-Pulse Wave Velocity at Month 6
Description
Carotid femoral-Pulse Wave Velocity (cf-PWV) will be measured non-invasively via applanation tonometry (AtCor Medical, Sydney, Australia). Wave propagation time will be calculated by the system software, using an ECG-gated reference frame. Aortic PWV is defined as the distance between two recording sites (i.e. common carotid- and femoral artery) divided by the wave propagation time.
Time Frame
baseline, month 6
Secondary Outcome Measure Information:
Title
Change From Baseline in Reactive Hyperemia Index at Month 6
Description
Endothelial dysfunction will be assessed by Flow Mediated Dilation via the Endopat device. This validated system measures the pulse wave amplitudes at the tip of both index fingers. The dominant arm will be occluded for 5 minutes by a sphygmomanometric cuff. After cuff deflation the pulse wave amplitude will be assessed to finally calculate the ratio of pulse wave amplitude before and after cuff-induced hyperemia. The so called reactive hyperemia index represents endothelial dysfunction at the level of conduit as well as resistance vessels.
Time Frame
baseline, month 6
Title
Change From Baseline in Augmentation Index at Month 6
Description
The curve of the peripheral pressure wave will be recorded from the radial artery. Augmentation index (Aix) will be calculated from the generated central aortic pressure waveform via pulse wave analysis function. To correct for respective influences, Aix will be adjusted for a heart rate of 75 bpm. Appropriate intra observer validity will be assured via an operator index ≥ 80.
Time Frame
baseline, month 6
Title
Change From Baseline in Matrix Metalloproteinase-9
Description
Circulating levels of Matrix Metalloproteinase-9 (MMP-9) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay
Time Frame
baseline, month 6
Title
Change From Baseline in Asymmetric Dimethylarginine at Month 6
Description
Circulating levels of Asymmetric dimethylarginine (ADMA) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay
Time Frame
baseline, month 6
Title
Change From Baseline in Tumor Necrosis Factor-alpha at Month 6
Description
Circulating levels of Tumor Necrosis Factor-alpha (TNF-alpha) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay
Time Frame
baseline, month 6
Title
Change From Baseline in Forced Expiratory Volume in 1 Second at Month 6
Description
Forced Expiratory Volume in 1 second (FEV1) will be measured via standardized Spirometry
Time Frame
baseline, month 6
Title
Change From Baseline in 6-Minute Walk Test at Month 6
Description
6-Minute Walk Test (6MWT) will be assessed to quantify functional exercise capacity following the standardized protocol of the American Thoracic Society
Time Frame
baseline, month 6
Title
Change From Baseline in COPD Assessment Test at Month 6
Description
COPD Assessment Test (CAT) will be assessed to quantify patients disease related symptoms and to measure the impact of COPD on a patient's life, and how this changes over time. CAT is a standardised and validated patient questionaire comprising 8 distinct questions about different COPD-related symptoms. Each symptom is quantified by the patient on a numeric scale ranging from 0 to 5. Each symptom gives a number of points quantified as interval data without decimal places. The 8 different numbers of points are added to a total number expressed as the final points of the CAT score. The minimum achievable number of points is 0 and the maximum achievable number of points is 40. Higher values provide high symptoms and worse outcome, lower values provide low symptoms and better outcome.
Time Frame
baseline, month 6

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Over 40 years of age Smoking history of at least 10 pack years Chronic obstructive pulmonary disease at Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II - IV diagnosed according to standard criteria. History of at least one COPD exacerbation requiring systemic corticosteroid treatment or hospitalisation in the previous year Exclusion Criteria: Insufficient compliance to study medication (≤70% of tablets used) during 4 weeks run-in period History of acute exacerbation 4 weeks prior to run-in period Diagnosis of alpha-1-antitrypsin deficiency Diagnosis of asthma Acute respiratory infections (e.g. pneumonia) Severe acute infectious diseases (e.g. active hepatitis, HIV) Lung cancer Bronchiectasis Interstitial lung disease Any other relevant lung disease Acute myocardial infarction Systolic left ventricular dysfunction Congestive heart failure New York Heart Association Functional Classification (NYHA) severity grade IV Haemodynamically significant cardiac arrhythmias or heart valve deformations Peripheral arterial occlusive disease Acute or chronic renal/hepatic failure Active malignancy Autoimmune disease Pregnant or breastfeeding women Women no using or not willing to use adequate contraceptive measures for the duration of the trial Hypersensitivity to study medication or placebo Severe psychiatric or neurological disorders or history of depression associated with suicidal ideation or behaviour Galactose intolerance, lactase insufficiency or glucose-galactose malabsorption
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Otto C Burghuber, M.D.
Organizational Affiliation
Department for Respiratory and Critical Care Medicine, Otto Wagner Hospital, Vienna
Official's Role
Principal Investigator
Facility Information:
Facility Name
Deparment for Respiratory and Critical Care Medicine, Otto Wangner Hospital
City
Vienna
ZIP/Postal Code
1140
Country
Austria

12. IPD Sharing Statement

Citations:
PubMed Identifier
32725799
Citation
Urban MH, Kreibich N, Gleiss A, Funk GC, Hartl S, Burghuber OC. Effects of roflumilast on arterial stiffness in COPD (ELASTIC): A randomized trial. Respirology. 2021 Feb;26(2):153-160. doi: 10.1111/resp.13914. Epub 2020 Jul 28.
Results Reference
derived

Learn more about this trial

Effects of ROFLUMILAST on Subclinical Atherosclerosis in Chronic Obstructive Pulmonary Disease (COPD)

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