Trial Outcomes & Findings for Effect of Roflumilast on Exacerbation Rate in Patients With Chronic Obstructive Pulmonary Disease (COPD): The AURA Study (BY217/M2-124) (NCT NCT00297102)

NCT ID: NCT00297102

Last Updated: 2017-01-16

Results Overview

Mean rate of COPD exacerbations requiring oral or parenteral glucocorticosteroids (=moderate COPD exacerbations), or requiring hospitalization, or leading to death (=severe COPD exacerbations), per patient per year. A COPD exacerbation is an event in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management \[American Thoracic Society (ATS) / European Respiratory Society (ERS) 2005\].

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1523 participants
• Primary outcome timeframe: 52 weeks treatment period
• Results posted on: 2017-01-16

Participant Flow

Participant milestones

Measure	Roflumilast 500 mcg, once daily, oral administration in the morning	Placebo once daily
Overall Study STARTED	765	758
Overall Study COMPLETED	502	525
Overall Study NOT COMPLETED	263	233

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effect of Roflumilast on Exacerbation Rate in Patients With Chronic Obstructive Pulmonary Disease (COPD): The AURA Study (BY217/M2-124)

Baseline characteristics by cohort

Measure	Roflumilast n=765 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=758 Participants once daily	Total n=1523 Participants Total of all reporting groups
Age, Continuous	63.53 years STANDARD_DEVIATION 9.5 • n=5 Participants	63.36 years STANDARD_DEVIATION 9.2 • n=7 Participants	63.45 years STANDARD_DEVIATION 9.4 • n=5 Participants
Gender Female	225 Participants n=5 Participants	220 Participants n=7 Participants	445 Participants n=5 Participants
Gender Male	540 Participants n=5 Participants	538 Participants n=7 Participants	1078 Participants n=5 Participants

PRIMARY outcome

Timeframe: Change from baseline over 52 weeks of treatment

Population: ITT (Intention to Treat) analysis. Number of participants analyzed = number of participants with data available.

Mean change from baseline during the treatment period in pre-bronchodilator FEV1 [L]

Outcome measures

Measure	Roflumilast n=745 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=745 Participants once daily
Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)	46 mL Standard Error 8	8 mL Standard Error 8

PRIMARY outcome

Timeframe: 52 weeks treatment period

Population: ITT analysis.

Mean rate of COPD exacerbations requiring oral or parenteral glucocorticosteroids (=moderate COPD exacerbations), or requiring hospitalization, or leading to death (=severe COPD exacerbations), per patient per year. A COPD exacerbation is an event in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management [American Thoracic Society (ATS) / European Respiratory Society (ERS) 2005].

Outcome measures

Measure	Roflumilast n=765 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=758 Participants once daily
COPD Exacerbation Rate (Moderate or Severe)	1.077 exacerbations per patient per year Interval 0.96 to 1.207	1.266 exacerbations per patient per year Interval 1.141 to 1.404

SECONDARY outcome

Timeframe: Change from baseline over 52 weeks of treatment

Population: ITT analysis. Number of participants analyzed = number of participants with data available.

Mean change from baseline during the treatment period in post-bronchodilator FEV1 [L]

Outcome measures

Measure	Roflumilast n=729 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=736 Participants once daily
Post-bronchodilator FEV1 [L]	57 mL Standard Error 9	8 mL Standard Error 8

SECONDARY outcome

Timeframe: 52 weeks treatment period

Population: ITT analysis. Number of participants analyzed = number of participants who died.

Outcome measures

Measure	Roflumilast n=17 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=17 Participants once daily
Time to Mortality Due to Any Reason	213.8 days Standard Deviation 118.9	207.5 days Standard Deviation 108.5

SECONDARY outcome

Timeframe: Change from baseline to last post randomization measurement (52 weeks)

Population: ITT analysis. Number of participants analyzed = number of participants with data available.

Mean change from baseline to the last post randomization measurement in natural log-transformed CRP

Outcome measures

Measure	Roflumilast n=691 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=694 Participants once daily
Natural Log-transformed C-reactive Protein (CRP)	1.0475 mg/L Interval 0.9584 to 1.145	1.1003 mg/L Interval 1.0071 to 1.2021

SECONDARY outcome

Timeframe: Change from baseline over 52 weeks of treatment

Population: ITT analysis. Number of participants analyzed = number of participants with data available.

The TDI is a recognized questionnaire to measure dyspnea in an out patient COPD population. At baseline, 3 components of dyspnea, each graded with 4 questions, were asked: - Functional Impairment - Magnitude of Task - Magnitude of Effort At each of the post-randomization visits questions from the TDI were asked related to 3 components: Change in - Functional Impairment - Magnitude of Task - Magnitude of Effort Each question in the TDI is graded from -3 (major deterioration) to +3 (major improvement). This results in a TDI Focal Score ranging from -9 to +9.

Outcome measures

Measure	Roflumilast n=741 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=745 Participants once daily
Mean Transition Dyspnea Index (TDI) Focal Score During the Treatment Period	0.658 scores on a scale Standard Error 0.084	0.426 scores on a scale Standard Error 0.082

Adverse Events

Roflumilast

Serious events: 144 serious events

Other events: 232 other events

Deaths: 0 deaths

Placebo

Serious events: 153 serious events

Other events: 136 other events

Deaths: 0 deaths

Serious adverse events

Measure	Roflumilast n=769 participants at risk 500 mcg, once daily, oral administration in the morning	Placebo n=755 participants at risk once daily
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	9.1% 70/769 • Number of events 95 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	10.9% 82/755 • Number of events 108 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.39% 3/769 • Number of events 5 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.40% 3/755 • Number of events 3 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.26% 2/769 • Number of events 3 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.26% 2/769 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 3 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Emphysema	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Lung disorder	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Pleurisy	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Atrial fibrillation	0.91% 7/769 • Number of events 7 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Cardiac failure	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.53% 4/755 • Number of events 4 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Angina pectoris	0.26% 2/769 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Cardiac failure acute	0.26% 2/769 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Cardiac failure congestive	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.40% 3/755 • Number of events 3 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Acute myocardial infarction	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.40% 3/755 • Number of events 3 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Angina unstable	0.26% 2/769 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Cardiopulmonary failure	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Myocardial infarction	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Acute coronary syndrome	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Atrial tachycardia	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Cardiac arrest	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Left ventricular failure	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Palpitations	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Cardiac disorders Ventricular tachycardia	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Pneumonia	1.0% 8/769 • Number of events 8 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	1.5% 11/755 • Number of events 13 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Bronchitis	0.26% 2/769 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Cellulitis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Lower respiratory tract infection	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Bacteraemia	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Bronchopulmonary aspergillosis allergic	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Chronic sinusitis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Clostridial infection	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Diverticulitis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Gastroenteritis	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Lobar pneumonia	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Septic shock	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Staphylococcal bacteraemia	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Wound sepsis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Abdominal pain	0.26% 2/769 • Number of events 3 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Colonic polyp	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Haematochezia	0.26% 2/769 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Inguinal hernia	0.26% 2/769 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Pancreatitis acute	0.26% 2/769 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Abdominal hernia	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Colitis ulcerative	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Colonic pseudo-obstruction	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Constipation	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Diarrhoea	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Diverticulum	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Diverticulum intestinal	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Epigastric discomfort	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Flatulence	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Hiatus hernia	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Ileus	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Mesenteric artery thrombosis	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Nausea	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Oesophageal spasm	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Oesophageal ulcer	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Oesophageal varices haemorrhage	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Rectal haemorrhage	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Volvulus	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Vomiting	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Syncope	0.39% 3/769 • Number of events 3 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 4 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Transient ischaemic attack	0.26% 2/769 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Carotid artery stenosis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Cerebrovascular accident	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Carotid artery disease	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Cerebral haemorrhage	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Cerebral ischaemia	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Convulsion	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Dizziness	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Hypoaesthesia	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Ischaemic stroke	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Loss of consciousness	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Parkinson's disease	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Partial seizures	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Nervous system disorders Sciatica	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.26% 2/769 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung squamous cell carcinoma stage unspecified	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenoma benign	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder neoplasm	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bronchial carcinoma	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cervix neoplasm	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon adenoma	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic cancer metastatic	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung cancer metastatic	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic bronchial carcinoma	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer metastatic	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Hypertensive crisis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Aortic aneurysm	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Arterial disorder	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Arterial restenosis	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Arterial thrombosis limb	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Deep vein thrombosis	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Femoral arterial stenosis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Haematoma	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Hypertension	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Peripheral arterial occlusive disease	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Peripheral ischaemia	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Vascular disorders Venous thrombosis	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
General disorders Chest pain	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
General disorders Sudden death	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
General disorders Asthenia	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
General disorders Chest discomfort	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
General disorders Death	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
General disorders Injection site inflammation	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
General disorders Malaise	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
General disorders Non-cardiac chest pain	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Injury, poisoning and procedural complications Ankle fracture	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Injury, poisoning and procedural complications Chemical eye injury	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Injury, poisoning and procedural complications Meniscus lesion	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Injury, poisoning and procedural complications Rib fracture	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Injury, poisoning and procedural complications Vascular graft complication	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Musculoskeletal and connective tissue disorders Bursitis	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Musculoskeletal and connective tissue disorders Gouty arthritis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Musculoskeletal and connective tissue disorders Intervertebral disc degeneration	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Musculoskeletal and connective tissue disorders Muscoloskeletal pain	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Musculoskeletal and connective tissue disorders Neck mass	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Musculoskeletal and connective tissue disorders Polyarthritis	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Psychiatric disorders Depression	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.26% 2/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Psychiatric disorders Acute psychosis	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Psychiatric disorders Confusional state	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Psychiatric disorders Panic attack	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Psychiatric disorders Suicide attempt	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Renal and urinary disorders Calculus urinary	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Renal and urinary disorders Haematuria	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Renal and urinary disorders Nephrolithiasis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Renal and urinary disorders Renal artery stenosis	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Renal and urinary disorders Renal colic	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Renal and urinary disorders Renal failure acute	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Eye disorders Blepharochalasis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Eye disorders Glaucoma	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Eye disorders Retinal detachment	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Investigations Anticoagulation drug level above therapeutic	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Investigations Bronchoscopy	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Investigations Computerised tomogram thorax abnormal	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 2 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Skin and subcutaneous tissue disorders Angioedema	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Skin and subcutaneous tissue disorders Eczema	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Skin and subcutaneous tissue disorders Skin ulcer	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Surgical and medical procedures Hip arthroplasty	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Surgical and medical procedures Cataract operation	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Hepatobiliary disorders Hepatitis	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Hepatobiliary disorders Hepatitis toxic	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Metabolism and nutrition disorders Dehydration	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Metabolism and nutrition disorders Malnutrition	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Reproductive system and breast disorders Metrorrhagia	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Reproductive system and breast disorders Uterine haemorrhage	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Congenital, familial and genetic disorders Adenomatous polyposis coli	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Endocrine disorders Hyperthyroidism	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Immune system disorders Drug hypersensitivity	0.00% 0/769 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.13% 1/755 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Social circumstances Physical assault	0.13% 1/769 • Number of events 1 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	0.00% 0/755 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.

Other adverse events

Measure	Roflumilast n=769 participants at risk 500 mcg, once daily, oral administration in the morning	Placebo n=755 participants at risk once daily
Infections and infestations Nasopharyngitis	7.4% 57/769 • Number of events 76 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	6.6% 50/755 • Number of events 65 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Infections and infestations Bronchitis	4.3% 33/769 • Number of events 41 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	5.2% 39/755 • Number of events 49 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Diarrhoea	8.1% 62/769 • Number of events 72 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	3.4% 26/755 • Number of events 30 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Gastrointestinal disorders Nausea	5.2% 40/769 • Number of events 44 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	2.0% 15/755 • Number of events 15 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.
Investigations Weight decreased	12.0% 92/769 • Number of events 94 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.	3.2% 24/755 • Number of events 24 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. 4 patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses. 1 patient was randomized twice. The second randomization is only included in the Safety Set.

Additional Information

AstraZeneca Clinical Study Information Center

AstraZeneca

Phone: 1-877-240-9479

Email: information.center@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee The study results may be published and/or presented at scientific meetings. Prior to any submission, all manuscripts/abstracts must be presented to the sponsor for possible comments.
• Publication restrictions are in place

Restriction type: OTHER