Trial Outcomes & Findings for Effect of Roflumilast on Exacerbation Rate in Patients With Chronic Obstructive Pulmonary Disease (COPD): The HERMES Study (BY217/M2-125) (NCT NCT00297115)

NCT ID: NCT00297115

Last Updated: 2016-11-07

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1568 participants
• Primary outcome timeframe: Change from baseline over 52 weeks of treatment
• Results posted on: 2016-11-07

Participant Flow

Participant milestones

Measure	Roflumilast 500 mcg, once daily, oral administration in the morning	Placebo once daily
Overall Study STARTED	772	796
Overall Study COMPLETED	527	550
Overall Study NOT COMPLETED	245	246

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effect of Roflumilast on Exacerbation Rate in Patients With Chronic Obstructive Pulmonary Disease (COPD): The HERMES Study (BY217/M2-125)

Baseline characteristics by cohort

Measure	Roflumilast n=772 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=796 Participants once daily	Total n=1568 Participants Total of all reporting groups
Age, Continuous	63.92 years STANDARD_DEVIATION 9.2 • n=5 Participants	64.31 years STANDARD_DEVIATION 9.0 • n=7 Participants	64.12 years STANDARD_DEVIATION 9.1 • n=5 Participants
Sex: Female, Male Female	162 Participants n=5 Participants	148 Participants n=7 Participants	310 Participants n=5 Participants
Sex: Female, Male Male	610 Participants n=5 Participants	648 Participants n=7 Participants	1258 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=730 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=766 Participants once daily
Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)	33 mL Standard Error 7	-25 mL Standard Error 7

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=772 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=796 Participants once daily
COPD Exacerbation Rate (Moderate or Severe)	1.210 exacerbations per patient per year Interval 1.074 to 1.364	1.485 exacerbations per patient per year Interval 1.333 to 1.655

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=724 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=764 Participants once daily
Post-bronchodilator FEV1 [L]	44 mL Standard Error 7	-17 mL Standard Error 7

SECONDARY outcome

Timeframe: 52 weeks treatment period

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

Outcome measures

Measure	Roflumilast n=25 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=25 Participants once daily
Time to Mortality Due to Any Reason	201.0 days Standard Deviation 116.9	214.6 days Standard Deviation 137.3

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=680 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=696 Participants once daily
Natural Log-transformed C-reactive Protein (CRP)	1.0840 mg/L Interval 0.9766 to 1.2033	1.0233 mg/L Interval 0.9228 to 1.1348

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=729 Participants 500 mcg, once daily, oral administration in the morning	Placebo n=769 Participants once daily
Mean Transition Dyspnea Index (TDI) Focal Score During the Treatment Period	0.662 scores on a scale Standard Error 0.087	0.376 scores on a scale Standard Error 0.084

Adverse Events

Roflumilast

Serious events: 157 serious events

Other events: 145 other events

Deaths: 0 deaths

Placebo

Serious events: 183 serious events

Other events: 81 other events

Deaths: 0 deaths

Serious adverse events

Measure	Roflumilast n=778 participants at risk 500 mcg, once daily, oral administration in the morning	Placebo n=790 participants at risk once daily
Renal and urinary disorders Renal failure	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Ischaemic cardiomyopathy	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Mitral valve stenosis	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	11.2% 87/778 • Number of events 110 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	15.3% 121/790 • Number of events 160 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.51% 4/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.63% 5/790 • Number of events 6 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.51% 4/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Respiratory arrest	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Hyperventilation	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Hypoventilation	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Respiratory acidosis	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Pneumonia	2.3% 18/778 • Number of events 18 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	1.3% 10/790 • Number of events 10 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Bronchopneumonia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.38% 3/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Lower respiratory tract infection	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.38% 3/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Bronchitis	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Lobar pneumonia	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Viral infection	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Appendicitis	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Cellulitis	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Clostridium difficile colitis	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Localised infection	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Pneumonia primary atypical	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Pulmonary tuberculosis	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Septic shock	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Urinary tract infection	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Urosepsis	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Myocardial infarction	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.51% 4/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Angina pectoris	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.38% 3/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Atrial fibrillation	0.39% 3/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Cardiac failure congestive	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.38% 3/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Acute myocardial infarction	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Cardiopulmonary failure	0.39% 3/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Coronary artery disease	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.38% 3/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Right ventricular failure	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Bradycardia	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Cardiac arrest	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Cardiac failure	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Cardio-respiratory arrest	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Cor pulmonale	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Left ventricular failure	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Myocardial ischaemia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Ventricular extrasystoles	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Angina unstable	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Arteriosclerosis coronary artery	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Atrioventricular block	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Supraventricular tachyarrhythmia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Tachycardia	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Ventricular fibrillation	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Ventricular tachycardia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.51% 4/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Plasmacytoma	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute myeloid leukaemia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenoma benign	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder neoplasm	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bronchial carcinoma	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Carcinoid tumour of the small bowel	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Chronic lymphocytic leukaemia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer stage II	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastasis	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic carcinoma of the bladder	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neuroendocrine carcinoma	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer metastatic	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal neoplasm	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer stage unspecified	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Diarrhoea	0.51% 4/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Pancreatitis acute	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Abdominal pain upper	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Haemorrhoids	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Intestinal polyp	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Colitis	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Inguinal hernia	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Nausea	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Pancreatic cyst	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Vomiting	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
General disorders Sudden death	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.38% 3/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
General disorders Chest pain	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.38% 3/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
General disorders Non-cardiac chest pain	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
General disorders Death	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
General disorders Asthenia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
General disorders Malaise	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
General disorders Metaplasia	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
General disorders Pyrexia	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
General disorders Ulcer haemorrhage	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Cerebrovascular accident	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.38% 3/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Cerebral infarction	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Syncope	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Anoxic encephalopathy	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Dizziness	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Encephalopathy	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Hypoxic encephalopathy	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Optic neuritis	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Transient ischaemic attack	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Wernicke's encephalopathy	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Ankle fracture	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Cervical vertebral fracture	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Comminuted fracture	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Device dislocation	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Eye penetration	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Femur fracture	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Fibula fracture	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Foot fracture	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Foreign body trauma	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Humerus fracture	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Limb injury	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Procedural pain	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Tibia fracture	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Wound dehiscence	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Vascular disorders Arterial stenosis	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Vascular disorders Femoral artery occlusion	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Vascular disorders Haematoma	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Vascular disorders Hypertension	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Vascular disorders Hypotension	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Vascular disorders Ischaemia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Vascular disorders Peripheral artery aneurysm	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Blood and lymphatic system disorders Anaemia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.25% 2/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Blood and lymphatic system disorders Iron deficiency anaemia	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Blood and lymphatic system disorders Leukopenia	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Blood and lymphatic system disorders Polycythaemia	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Metabolism and nutrition disorders Hypokalaemia	0.39% 3/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Metabolism and nutrition disorders Dehydration	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Metabolism and nutrition disorders Diabetes mellitus	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Metabolism and nutrition disorders Diabetic ketoacidosis	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Metabolism and nutrition disorders Hyponatraemia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Metabolism and nutrition disorders Malnutrition	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Metabolism and nutrition disorders Metabolic acidosis	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Renal and urinary disorders Renal failure acute	0.39% 3/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Renal and urinary disorders Micturition disorder	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Psychiatric disorders Depression	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Psychiatric disorders Alcohol withdrawal syndrome	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Psychiatric disorders Completed suicide	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Psychiatric disorders Mental status changes	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Psychiatric disorders Suicidal ideation	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Skin and subcutaneous tissue disorders Eczema	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Skin and subcutaneous tissue disorders Leukocytoclastic vasculitis	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Skin and subcutaneous tissue disorders Rash	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Skin and subcutaneous tissue disorders Urticaria	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Hepatobiliary disorders Cholecystitis acute	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Hepatobiliary disorders Cholelithiasis	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Musculoskeletal and connective tissue disorders Arthralgia	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Musculoskeletal and connective tissue disorders Intervertebral disc degeneration	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Surgical and medical procedures Coronary artery bypass	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Surgical and medical procedures Endarterectomy	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Surgical and medical procedures Knee arthroplasty	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Eye disorders Cataract	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Investigations Blood creatine phosphokinase increased	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Investigations Blood creatinine increased	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Investigations Blood urea increased	0.13% 1/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.26% 2/778 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/790 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Immune system disorders Anti-neutrophil cytoplasmic antibody positive vasculitis	0.00% 0/778 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.13% 1/790 • 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.

Other adverse events

Measure	Roflumilast n=778 participants at risk 500 mcg, once daily, oral administration in the morning	Placebo n=790 participants at risk once daily
Gastrointestinal disorders Diarrhoea	8.2% 64/778 • Number of events 71 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	2.9% 23/790 • Number of events 25 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Investigations Weight decreased	8.4% 65/778 • Number of events 67 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	2.5% 20/790 • Number of events 20 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Nasopharyngitis	4.5% 35/778 • Number of events 43 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	5.9% 47/790 • Number of events 57 • 52 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.

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