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

• Sponsor: LudwLudwig Boltzmann Institute for COPD and Respiratory Epidemiology (Other)
• Overall Status: Completed
• CT.gov ID: NCT01630200
• Collaborator: Medical University of Vienna (Other)
• Enrollment: 80
• Location: 1
• Arms: 2
• Duration (Months): 44
• Patients Per Site Per Month: 1.8

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease and Allied Conditions	Drug: Roflumilast; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of ROFLUMILAST on Markers of Subclinical Atherosclerosis In Stable COPD; the ELASTIC-trial
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Roflumilast Active arm including patients who receive the study drug (500µg Roflumilast once daily)	Drug: Roflumilast; Roflumilast coated tablet, 500µg oral application, once daily in the morning; Other Names: Daxas
Placebo Comparator: Placebo Control arm including patients who receive the placebo tablet (once daily)	Drug: Placebo; Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Carotid Femoral-Pulse Wave Velocity at Month 6 [baseline, 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

1. Change From Baseline in Reactive Hyperemia Index at Month 6 [baseline, 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.

2. Change From Baseline in Augmentation Index at Month 6 [baseline, 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.

3. Change From Baseline in Matrix Metalloproteinase-9 [baseline, month 6]

   Circulating levels of Matrix Metalloproteinase-9 (MMP-9) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay

4. Change From Baseline in Asymmetric Dimethylarginine at Month 6 [baseline, month 6]

   Circulating levels of Asymmetric dimethylarginine (ADMA) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay

5. Change From Baseline in Tumor Necrosis Factor-alpha at Month 6 [baseline, month 6]

   Circulating levels of Tumor Necrosis Factor-alpha (TNF-alpha) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay

6. Change From Baseline in Forced Expiratory Volume in 1 Second at Month 6 [baseline, month 6]

   Forced Expiratory Volume in 1 second (FEV1) will be measured via standardized Spirometry

7. Change From Baseline in 6-Minute Walk Test at Month 6 [baseline, month 6]

   6-Minute Walk Test (6MWT) will be assessed to quantify functional exercise capacity following the standardized protocol of the American Thoracic Society

8. Change From Baseline in COPD Assessment Test at Month 6 [baseline, 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Deparment for Respiratory and Critical Care Medicine, Otto Wangner Hospital	Vienna		Austria	1140

Sponsors and Collaborators

• LudwLudwig Boltzmann Institute for COPD and Respiratory Epidemiology
• Medical University of Vienna

Investigators

• Principal Investigator: Otto C Burghuber, M.D., Department for Respiratory and Critical Care Medicine, Otto Wagner Hospital, Vienna

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: LudwLudwig Boltzmann Institute for COPD and Respiratory Epidemiology
• ClinicalTrials.gov Identifier: NCT01630200
• Other Study ID Numbers: ELASTIC2011
• First Posted: Jun 28, 2012
• Last Update Posted: Apr 12, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by LudwLudwig Boltzmann Institute for COPD and Respiratory Epidemiology: COPD; comorbidity; arterial stiffness; roflumilast
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Atherosclerosis

Study Results

Participant Flow

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 Detail	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
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

Baseline Characteristics

Arm/Group Title	Roflumilast	Placebo	Total
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 Participants	40	40	80
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	64.5	64.5	64.5
Sex: Female, Male (Count of Participants)
Female	22 55%	16 40%	38 47.5%
Male	18 45%	24 60%	42 52.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	40 100%	40 100%	80 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Austria	40 100%	40 100%	80 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Roflumilast	Placebo
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
Measure Participants	33	34
Least Squares Mean (95% Confidence Interval) [meters per second (m/s)]	1.07	0.99

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Roflumilast	Placebo
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
Measure Participants	33	34
Least Squares Mean (95% Confidence Interval) [Index]	0.99	1.02

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Roflumilast	Placebo
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
Measure Participants	33	34
Least Squares Mean (95% Confidence Interval) [Index]	-1.11	-1.99

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Roflumilast	Placebo
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
Measure Participants	33	34
Least Squares Mean (95% Confidence Interval) [ng/ml]	-143	-77

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Roflumilast	Placebo
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
Measure Participants	33	34
Least Squares Mean (95% Confidence Interval) [µmol/l]	0.97	0.91

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Roflumilast	Placebo
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
Measure Participants	33	34
Least Squares Mean (95% Confidence Interval) [pg/ml]	0.95	1.06

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Roflumilast	Placebo
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
Measure Participants	33	34
Least Squares Mean (95% Confidence Interval) [% predicted]	1.02	1.01

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Roflumilast	Placebo
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
Measure Participants	33	34
Least Squares Mean (95% Confidence Interval) [meters]	59.2	0.69

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Roflumilast	Placebo
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
Measure Participants	33	34
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.42	1.2

Adverse Events

Time Frame	6 months
Arm/Group Title	Roflumilast		Placebo
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	2/40 (5%)		1/40 (2.5%)
Serious Adverse Events
	Roflumilast		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/40 (32.5%)		9/40 (22.5%)
Cardiac disorders
Atrial fibrillation	1/40 (2.5%)	1	0/40 (0%)	0
Gastrointestinal disorders
Gastric ulcer	1/40 (2.5%)	1	0/40 (0%)	0
Polypectomy	0/40 (0%)	0	1/40 (2.5%)	1
Investigations
Death (unknown origin)	1/40 (2.5%)	1	0/40 (0%)	0
Metabolism and nutrition disorders
Hyponatremia	1/40 (2.5%)	1	0/40 (0%)	0
Nervous system disorders
Amyotrophic lateral sclerosis	0/40 (0%)	0	1/40 (2.5%)	1
insomnia	1/40 (2.5%)	1	0/40 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchoscopic lung volume reduction	1/40 (2.5%)	1	1/40 (2.5%)	1
Pulmonary nodule	0/40 (0%)	0	1/40 (2.5%)	1
Bronchoscopy for bronchiectasis	0/40 (0%)	0	1/40 (2.5%)	1
Hypercapnic decompensation	1/40 (2.5%)	1	0/40 (0%)	0
Pneumonia	3/40 (7.5%)	3	5/40 (12.5%)	5
COPD exacerbation	5/40 (12.5%)	6	1/40 (2.5%)	1
Vascular disorders
Carotid artery stenosis	1/40 (2.5%)	1	0/40 (0%)	0
Diabetic vasculopathy	1/40 (2.5%)	1	0/40 (0%)	0
Other (Not Including Serious) Adverse Events
	Roflumilast		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/40 (67.5%)		22/40 (55%)
Gastrointestinal disorders
Weight loss	6/40 (15%)	6	0/40 (0%)	0
Abdominal pain	1/40 (2.5%)	1	0/40 (0%)	0
Loss of appetite	1/40 (2.5%)	1	0/40 (0%)	0
Diarrhea	3/40 (7.5%)	3	0/40 (0%)	0
Obstipation	0/40 (0%)	0	1/40 (2.5%)	1
Infections and infestations
Influenca	0/40 (0%)	0	2/40 (5%)	2
Musculoskeletal and connective tissue disorders
Cramps in upper/lower extremities	4/40 (10%)	4	1/40 (2.5%)	1
Herniated vertebral disc	0/40 (0%)	0	1/40 (2.5%)	1
Nervous system disorders
Headache	2/40 (5%)	2	0/40 (0%)	0
Nausea	2/40 (5%)	2	0/40 (0%)	0
Insomnia	1/40 (2.5%)	1	0/40 (0%)	0
Tremor	0/40 (0%)	0	1/40 (2.5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/40 (0%)	0	2/40 (5%)	2
Common cold	5/40 (12.5%)	6	4/40 (10%)	6
COPD exacerbation	14/40 (35%)	19	16/40 (40%)	24
Pneumonia	1/40 (2.5%)	1	0/40 (0%)	0
Vascular disorders
Pulmonary embolism	0/40 (0%)	0	1/40 (2.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.