Trial Outcomes & Findings for Effects of ROFLUMILAST on Subclinical Atherosclerosis in Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT01630200)
NCT ID: NCT01630200
Last Updated: 2019-04-12
Results Overview
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.
COMPLETED
PHASE4
80 participants
baseline, month 6
2019-04-12
Participant Flow
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).
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.
Participant milestones
| Measure |
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
|
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
|
|---|---|---|
|
Overall Study
STARTED
|
40
|
40
|
|
Overall Study
COMPLETED
|
33
|
34
|
|
Overall Study
NOT COMPLETED
|
7
|
6
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Effects of ROFLUMILAST on Subclinical Atherosclerosis in Chronic Obstructive Pulmonary Disease (COPD)
Baseline characteristics by cohort
| Measure |
Roflumilast
n=40 Participants
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
|
Placebo
n=40 Participants
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
n=80 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Age, Continuous
|
64.5 years
n=5 Participants
|
64.5 years
n=7 Participants
|
64.5 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
22 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
38 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
18 Participants
n=5 Participants
|
24 Participants
n=7 Participants
|
42 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
40 Participants
n=5 Participants
|
40 Participants
n=7 Participants
|
80 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Region of Enrollment
Austria
|
40 participants
n=5 Participants
|
40 participants
n=7 Participants
|
80 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: baseline, month 6Carotid 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.
Outcome measures
| Measure |
Roflumilast
n=33 Participants
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
|
Placebo
n=34 Participants
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
|
|---|---|---|
|
Change From Baseline in Carotid Femoral-Pulse Wave Velocity at Month 6
|
1.07 meters per second (m/s)
Interval 0.98 to 1.17
|
0.99 meters per second (m/s)
Interval 0.91 to 1.08
|
SECONDARY outcome
Timeframe: baseline, month 6Endothelial 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.
Outcome measures
| Measure |
Roflumilast
n=33 Participants
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
|
Placebo
n=34 Participants
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
|
|---|---|---|
|
Change From Baseline in Reactive Hyperemia Index at Month 6
|
0.99 Index
Interval 0.88 to 1.11
|
1.02 Index
Interval 0.91 to 1.15
|
SECONDARY outcome
Timeframe: baseline, month 6The 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.
Outcome measures
| Measure |
Roflumilast
n=33 Participants
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
|
Placebo
n=34 Participants
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
|
|---|---|---|
|
Change From Baseline in Augmentation Index at Month 6
|
-1.11 Index
Interval -5.33 to 3.11
|
-1.99 Index
Interval -6.12 to 2.14
|
SECONDARY outcome
Timeframe: baseline, month 6Circulating levels of Matrix Metalloproteinase-9 (MMP-9) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay
Outcome measures
| Measure |
Roflumilast
n=33 Participants
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
|
Placebo
n=34 Participants
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
|
|---|---|---|
|
Change From Baseline in Matrix Metalloproteinase-9
|
-143 ng/ml
Interval -370.0 to 84.6
|
-77 ng/ml
Interval -301.0 to 147.0
|
SECONDARY outcome
Timeframe: baseline, month 6Circulating levels of Asymmetric dimethylarginine (ADMA) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay
Outcome measures
| Measure |
Roflumilast
n=33 Participants
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
|
Placebo
n=34 Participants
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
|
|---|---|---|
|
Change From Baseline in Asymmetric Dimethylarginine at Month 6
|
0.97 µmol/l
Interval 0.88 to 1.06
|
0.91 µmol/l
Interval 0.83 to 1.0
|
SECONDARY outcome
Timeframe: baseline, month 6Circulating levels of Tumor Necrosis Factor-alpha (TNF-alpha) will be quantified from venous blood samples via Enzyme-linked Immunosorbent Assay
Outcome measures
| Measure |
Roflumilast
n=33 Participants
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
|
Placebo
n=34 Participants
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
|
|---|---|---|
|
Change From Baseline in Tumor Necrosis Factor-alpha at Month 6
|
0.95 pg/ml
Interval 0.82 to 1.08
|
1.06 pg/ml
Interval 0.92 to 1.22
|
SECONDARY outcome
Timeframe: baseline, month 6Forced Expiratory Volume in 1 second (FEV1) will be measured via standardized Spirometry
Outcome measures
| Measure |
Roflumilast
n=33 Participants
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
|
Placebo
n=34 Participants
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
|
|---|---|---|
|
Change From Baseline in Forced Expiratory Volume in 1 Second at Month 6
|
1.02 % predicted
Interval 0.96 to 1.08
|
1.01 % predicted
Interval 0.96 to 1.07
|
SECONDARY outcome
Timeframe: baseline, month 66-Minute Walk Test (6MWT) will be assessed to quantify functional exercise capacity following the standardized protocol of the American Thoracic Society
Outcome measures
| Measure |
Roflumilast
n=33 Participants
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
|
Placebo
n=34 Participants
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
|
|---|---|---|
|
Change From Baseline in 6-Minute Walk Test at Month 6
|
59.2 meters
Interval 18.3 to 100.0
|
0.69 meters
Interval -39.7 to 41.1
|
SECONDARY outcome
Timeframe: baseline, month 6COPD 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.
Outcome measures
| Measure |
Roflumilast
n=33 Participants
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
|
Placebo
n=34 Participants
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
|
|---|---|---|
|
Change From Baseline in COPD Assessment Test at Month 6
|
0.42 units on a scale
Interval -1.36 to 2.19
|
1.2 units on a scale
Interval -0.57 to 2.98
|
Adverse Events
Roflumilast
Placebo
Serious adverse events
| Measure |
Roflumilast
n=40 participants at risk
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
|
Placebo
n=40 participants at risk
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
|
|---|---|---|
|
Nervous system disorders
Amyotrophic lateral sclerosis
|
0.00%
0/40 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
|
Cardiac disorders
Atrial fibrillation
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Bronchoscopic lung volume reduction
|
2.5%
1/40 • Number of events 1 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary nodule
|
0.00%
0/40 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
|
Vascular disorders
Carotid artery stenosis
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Vascular disorders
Diabetic vasculopathy
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Bronchoscopy for bronchiectasis
|
0.00%
0/40 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
|
Investigations
Death (unknown origin)
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Gastrointestinal disorders
Gastric ulcer
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Hypercapnic decompensation
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Pneumonia
|
7.5%
3/40 • Number of events 3 • 6 months
|
12.5%
5/40 • Number of events 5 • 6 months
|
|
Metabolism and nutrition disorders
Hyponatremia
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Nervous system disorders
insomnia
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Gastrointestinal disorders
Polypectomy
|
0.00%
0/40 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
COPD exacerbation
|
12.5%
5/40 • Number of events 6 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
Other adverse events
| Measure |
Roflumilast
n=40 participants at risk
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
|
Placebo
n=40 participants at risk
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
|
|---|---|---|
|
Gastrointestinal disorders
Weight loss
|
15.0%
6/40 • Number of events 6 • 6 months
|
0.00%
0/40 • 6 months
|
|
Nervous system disorders
Headache
|
5.0%
2/40 • Number of events 2 • 6 months
|
0.00%
0/40 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
0.00%
0/40 • 6 months
|
5.0%
2/40 • Number of events 2 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Common cold
|
12.5%
5/40 • Number of events 6 • 6 months
|
10.0%
4/40 • Number of events 6 • 6 months
|
|
Gastrointestinal disorders
Abdominal pain
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Gastrointestinal disorders
Loss of appetite
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Musculoskeletal and connective tissue disorders
Cramps in upper/lower extremities
|
10.0%
4/40 • Number of events 4 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
|
Gastrointestinal disorders
Diarrhea
|
7.5%
3/40 • Number of events 3 • 6 months
|
0.00%
0/40 • 6 months
|
|
Nervous system disorders
Nausea
|
5.0%
2/40 • Number of events 2 • 6 months
|
0.00%
0/40 • 6 months
|
|
Nervous system disorders
Insomnia
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Nervous system disorders
Tremor
|
0.00%
0/40 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
|
Vascular disorders
Pulmonary embolism
|
0.00%
0/40 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
|
Infections and infestations
Influenca
|
0.00%
0/40 • 6 months
|
5.0%
2/40 • Number of events 2 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
COPD exacerbation
|
35.0%
14/40 • Number of events 19 • 6 months
|
40.0%
16/40 • Number of events 24 • 6 months
|
|
Respiratory, thoracic and mediastinal disorders
Pneumonia
|
2.5%
1/40 • Number of events 1 • 6 months
|
0.00%
0/40 • 6 months
|
|
Gastrointestinal disorders
Obstipation
|
0.00%
0/40 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
|
Musculoskeletal and connective tissue disorders
Herniated vertebral disc
|
0.00%
0/40 • 6 months
|
2.5%
1/40 • Number of events 1 • 6 months
|
Additional Information
Dr. Matthias Urban
Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place