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

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ClinicalTrials.gov Identifier: NCT01630200
Recruitment Status : Completed
First Posted : June 28, 2012
Results First Posted : April 12, 2019
Last Update Posted : April 12, 2019
Sponsor:
Collaborator:
Medical University of Vienna
Information provided by (Responsible Party):
LudwLudwig Boltzmann Institute for COPD and Respiratory Epidemiology

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Chronic Obstructive Pulmonary Disease and Allied Conditions
Interventions Drug: Roflumilast
Drug: Placebo
Enrollment 80
Recruitment Details Patients were recruited from the Department of Respiratory and Critical Care Medicine in the Otto Wagner Hospital in Vienna and supporting centres (hospitals, outpatient clinics, respiratory specialists).
Pre-assignment Details After inclusion, patients entered a 4 week, single-masked run-in period with placebo application. Given sufficient compliance to medication (≥70% of tablets) patients were randomized to receive either the study drug (Roflumilast 500 μg) or placebo in a double-masked manner.
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Period Title: Overall Study
Started 40 40
Completed 33 34
Not Completed 7 6
Arm/Group Title Roflumilast Placebo Total
Hide Arm/Group Description

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Total of all reporting groups
Overall Number of Baseline Participants 40 40 80
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 40 participants 40 participants 80 participants
64.5
(61 to 69.5)
64.5
(56 to 72)
64.5
(57 to 70)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 40 participants 80 participants
Female
22
  55.0%
16
  40.0%
38
  47.5%
Male
18
  45.0%
24
  60.0%
42
  52.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants 40 participants 80 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
40
 100.0%
40
 100.0%
80
 100.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Austria Number Analyzed 40 participants 40 participants 80 participants
40 40 80
1.Primary Outcome
Title Change From Baseline in Carotid Femoral-Pulse Wave Velocity at Month 6
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description:

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Overall Number of Participants Analyzed 33 34
Least Squares Mean (95% Confidence Interval)
Unit of Measure: meters per second (m/s)
1.07
(0.98 to 1.17)
0.99
(0.91 to 1.08)
2.Secondary Outcome
Title Change From Baseline in Reactive Hyperemia Index at Month 6
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description:

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Overall Number of Participants Analyzed 33 34
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Index
0.99
(0.88 to 1.11)
1.02
(0.91 to 1.15)
3.Secondary Outcome
Title Change From Baseline in Augmentation Index at Month 6
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description:

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Overall Number of Participants Analyzed 33 34
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Index
-1.11
(-5.33 to 3.11)
-1.99
(-6.12 to 2.14)
4.Secondary Outcome
Title Change From Baseline in Matrix Metalloproteinase-9
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description:

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Overall Number of Participants Analyzed 33 34
Least Squares Mean (95% Confidence Interval)
Unit of Measure: ng/ml
-143
(-370 to 84.6)
-77
(-301 to 147)
5.Secondary Outcome
Title Change From Baseline in Asymmetric Dimethylarginine at Month 6
Hide Description Circulating levels of Asymmetric dimethylarginine (ADMA) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay
Time Frame baseline, month 6
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description:

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Overall Number of Participants Analyzed 33 34
Least Squares Mean (95% Confidence Interval)
Unit of Measure: µmol/l
0.97
(0.88 to 1.06)
0.91
(0.83 to 1.00)
6.Secondary Outcome
Title Change From Baseline in Tumor Necrosis Factor-alpha at Month 6
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description:

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Overall Number of Participants Analyzed 33 34
Least Squares Mean (95% Confidence Interval)
Unit of Measure: pg/ml
0.95
(0.82 to 1.08)
1.06
(0.92 to 1.22)
7.Secondary Outcome
Title Change From Baseline in Forced Expiratory Volume in 1 Second at Month 6
Hide Description Forced Expiratory Volume in 1 second (FEV1) will be measured via standardized Spirometry
Time Frame baseline, month 6
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description:

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Overall Number of Participants Analyzed 33 34
Least Squares Mean (95% Confidence Interval)
Unit of Measure: % predicted
1.02
(0.96 to 1.08)
1.01
(0.96 to 1.07)
8.Secondary Outcome
Title Change From Baseline in 6-Minute Walk Test at Month 6
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description:

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Overall Number of Participants Analyzed 33 34
Least Squares Mean (95% Confidence Interval)
Unit of Measure: meters
59.2
(18.3 to 100)
0.69
(-39.7 to 41.1)
9.Secondary Outcome
Title Change From Baseline in COPD Assessment Test at Month 6
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description:

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Overall Number of Participants Analyzed 33 34
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
0.42
(-1.36 to 2.19)
1.2
(-0.57 to 2.98)
Time Frame 6 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Roflumilast Placebo
Hide Arm/Group Description

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

Roflumilast: Roflumilast coated tablet, 500µg oral application, once daily in the morning

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

Placebo: Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

All-Cause Mortality
Roflumilast Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   2/40 (5.00%)      1/40 (2.50%)    
Hide Serious Adverse Events
Roflumilast Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   13/40 (32.50%)      9/40 (22.50%)    
Cardiac disorders     
Atrial fibrillation *  1/40 (2.50%)  1 0/40 (0.00%)  0
Gastrointestinal disorders     
Gastric ulcer *  1/40 (2.50%)  1 0/40 (0.00%)  0
Polypectomy *  0/40 (0.00%)  0 1/40 (2.50%)  1
Investigations     
Death (unknown origin) *  1/40 (2.50%)  1 0/40 (0.00%)  0
Metabolism and nutrition disorders     
Hyponatremia *  1/40 (2.50%)  1 0/40 (0.00%)  0
Nervous system disorders     
Amyotrophic lateral sclerosis *  0/40 (0.00%)  0 1/40 (2.50%)  1
insomnia *  1/40 (2.50%)  1 0/40 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Bronchoscopic lung volume reduction *  1/40 (2.50%)  1 1/40 (2.50%)  1
Pulmonary nodule *  0/40 (0.00%)  0 1/40 (2.50%)  1
Bronchoscopy for bronchiectasis *  0/40 (0.00%)  0 1/40 (2.50%)  1
Hypercapnic decompensation *  1/40 (2.50%)  1 0/40 (0.00%)  0
Pneumonia *  3/40 (7.50%)  3 5/40 (12.50%)  5
COPD exacerbation *  5/40 (12.50%)  6 1/40 (2.50%)  1
Vascular disorders     
Carotid artery stenosis *  1/40 (2.50%)  1 0/40 (0.00%)  0
Diabetic vasculopathy *  1/40 (2.50%)  1 0/40 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Roflumilast Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   27/40 (67.50%)      22/40 (55.00%)    
Gastrointestinal disorders     
Weight loss *  6/40 (15.00%)  6 0/40 (0.00%)  0
Abdominal pain *  1/40 (2.50%)  1 0/40 (0.00%)  0
Loss of appetite *  1/40 (2.50%)  1 0/40 (0.00%)  0
Diarrhea *  3/40 (7.50%)  3 0/40 (0.00%)  0
Obstipation *  0/40 (0.00%)  0 1/40 (2.50%)  1
Infections and infestations     
Influenca *  0/40 (0.00%)  0 2/40 (5.00%)  2
Musculoskeletal and connective tissue disorders     
Cramps in upper/lower extremities *  4/40 (10.00%)  4 1/40 (2.50%)  1
Herniated vertebral disc *  0/40 (0.00%)  0 1/40 (2.50%)  1
Nervous system disorders     
Headache *  2/40 (5.00%)  2 0/40 (0.00%)  0
Nausea *  2/40 (5.00%)  2 0/40 (0.00%)  0
Insomnia *  1/40 (2.50%)  1 0/40 (0.00%)  0
Tremor *  0/40 (0.00%)  0 1/40 (2.50%)  1
Respiratory, thoracic and mediastinal disorders     
Cough *  0/40 (0.00%)  0 2/40 (5.00%)  2
Common cold *  5/40 (12.50%)  6 4/40 (10.00%)  6
COPD exacerbation *  14/40 (35.00%)  19 16/40 (40.00%)  24
Pneumonia *  1/40 (2.50%)  1 0/40 (0.00%)  0
Vascular disorders     
Pulmonary embolism *  0/40 (0.00%)  0 1/40 (2.50%)  1
*
Indicates events were collected by non-systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Matthias Urban
Organization: Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology
Phone: +43(0)6508125980
EMail: matthias.urban1@gmx.net
Layout table for additonal information
Responsible Party: LudwLudwig Boltzmann Institute for COPD and Respiratory Epidemiology
ClinicalTrials.gov Identifier: NCT01630200    
Other Study ID Numbers: ELASTIC2011
First Submitted: June 4, 2012
First Posted: June 28, 2012
Results First Submitted: August 26, 2017
Results First Posted: April 12, 2019
Last Update Posted: April 12, 2019