Chronic Obstructive Pulmonary Disease and Allied Conditions
Conditions
Keywords
COPD, comorbidity, arterial stiffness, roflumilast
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.
Interventions
DRUGRoflumilast
Roflumilast coated tablet, 500µg oral application, once daily in the morning
DRUGPlacebo
Placebo coated tablet (visually identical to 500µg Roflumilast tablet), oral application, once daily in the morning
Sponsors
Medical University of Vienna
LudwLudwig Boltzmann Institute for COPD and Respiratory Epidemiology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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 |
| 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. |
| 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 |
| 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 |
| 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. |
| 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 |
Countries
Austria
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 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.
Participants by arm
| Arm | Count |
|---|---|
| Roflumilast 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 | 40 |
| Placebo 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 | 40 |
| Total | 80 |
Baseline characteristics
| Characteristic | Roflumilast | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 64.5 years | 64.5 years | 64.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 40 Participants | 80 Participants | 40 Participants |
| Region of Enrollment Austria | 40 participants | 80 participants | 40 participants |
| Sex: Female, Male Female | 22 Participants | 38 Participants | 16 Participants |
| Sex: Female, Male Male | 18 Participants | 42 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 40 | 1 / 40 |
| other Total, other adverse events | 27 / 40 | 22 / 40 |
| serious Total, serious adverse events | 13 / 40 | 9 / 40 |
Outcome results
Primary
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.
Time frame: baseline, month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Roflumilast | Change From Baseline in Carotid Femoral-Pulse Wave Velocity at Month 6 | 1.07 meters per second (m/s) |
| Placebo | Change From Baseline in Carotid Femoral-Pulse Wave Velocity at Month 6 | 0.99 meters per second (m/s) |
Secondary
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
Time frame: baseline, month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Roflumilast | Change From Baseline in 6-Minute Walk Test at Month 6 | 59.2 meters |
| Placebo | Change From Baseline in 6-Minute Walk Test at Month 6 | 0.69 meters |
Secondary
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
Time frame: baseline, month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Roflumilast | Change From Baseline in Asymmetric Dimethylarginine at Month 6 | 0.97 µmol/l |
| Placebo | Change From Baseline in Asymmetric Dimethylarginine at Month 6 | 0.91 µmol/l |
Secondary
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.
Time frame: baseline, month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Roflumilast | Change From Baseline in Augmentation Index at Month 6 | -1.11 Index |
| Placebo | Change From Baseline in Augmentation Index at Month 6 | -1.99 Index |
Secondary
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.
Time frame: baseline, month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Roflumilast | Change From Baseline in COPD Assessment Test at Month 6 | 0.42 units on a scale |
| Placebo | Change From Baseline in COPD Assessment Test at Month 6 | 1.2 units on a scale |
Secondary
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
Time frame: baseline, month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Roflumilast | Change From Baseline in Forced Expiratory Volume in 1 Second at Month 6 | 1.02 % predicted |
| Placebo | Change From Baseline in Forced Expiratory Volume in 1 Second at Month 6 | 1.01 % predicted |
Secondary
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
Time frame: baseline, month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Roflumilast | Change From Baseline in Matrix Metalloproteinase-9 | -143 ng/ml |
| Placebo | Change From Baseline in Matrix Metalloproteinase-9 | -77 ng/ml |
Secondary
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.
Time frame: baseline, month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Roflumilast | Change From Baseline in Reactive Hyperemia Index at Month 6 | 0.99 Index |
| Placebo | Change From Baseline in Reactive Hyperemia Index at Month 6 | 1.02 Index |
Secondary
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
Time frame: baseline, month 6
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Roflumilast | Change From Baseline in Tumor Necrosis Factor-alpha at Month 6 | 0.95 pg/ml |
| Placebo | Change From Baseline in Tumor Necrosis Factor-alpha at Month 6 | 1.06 pg/ml |