Trial Outcomes & Findings for Effect of Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Tiotropium: The HELIOS Study (BY217/M2-128) (NCT NCT00424268)

NCT ID: NCT00424268

Last Updated: 2016-12-05

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 743 participants
• Primary outcome timeframe: Change from baseline over 24 weeks of treatment
• Results posted on: 2016-12-05

Participant Flow

Participant milestones

Measure	Roflumilast Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled	Placebo Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled
Overall Study STARTED	371	372
Overall Study COMPLETED	309	333
Overall Study NOT COMPLETED	62	39

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effect of Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Tiotropium: The HELIOS Study (BY217/M2-128)

Baseline characteristics by cohort

Measure	Roflumilast n=371 Participants Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled	Placebo n=372 Participants Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled	Total n=743 Participants Total of all reporting groups
Age, Continuous	64.2 years STANDARD_DEVIATION 9.1 • n=5 Participants	64.0 years STANDARD_DEVIATION 9.3 • n=7 Participants	64.1 years STANDARD_DEVIATION 9.2 • n=5 Participants
Gender Female	109 Participants n=5 Participants	105 Participants n=7 Participants	214 Participants n=5 Participants
Gender Male	262 Participants n=5 Participants	267 Participants n=7 Participants	529 Participants n=5 Participants

PRIMARY outcome

Timeframe: Change from baseline over 24 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=365 Participants Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled	Placebo n=364 Participants Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled
Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)	65 mL Standard Error 12	-16 mL Standard Error 12

SECONDARY outcome

Timeframe: Change from baseline over 24 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=364 Participants Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled	Placebo n=363 Participants Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled
Post-bronchodilator FEV1	74 mL Standard Error 12	-7 mL Standard Error 11

SECONDARY outcome

Timeframe: 24 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=371 Participants Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled	Placebo n=372 Participants Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled
COPD Exacerbation Rate (Moderate or Severe)	0.262 exacerbations per patient per year Interval 0.184 to 0.375	0.342 exacerbations per patient per year Interval 0.248 to 0.472

SECONDARY outcome

Timeframe: Change from baseline over 24 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=364 Participants Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled	Placebo n=364 Participants Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled
Transition Dyspnea Index (TDI) Focal Score	1.4 scores on a scale Standard Error 0.1	0.9 scores on a scale Standard Error 0.1

SECONDARY outcome

Timeframe: Change from baseline over 24 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 SOBQ. This is a 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. The questions were administered at visits V0, V2, V3, V4, V5, V6 and Vend to assess the perceived shortness of breath of the patient. For each activity listed in the questionnaire the patient should rate his/her breathlessness on a scale between zero and five, where zero is "not at all breathless" and five is "maximally breathless or too breathless to do the activity".

Outcome measures

Measure	Roflumilast n=359 Participants Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled	Placebo n=359 Participants Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled
Shortness of Breath Questionnaire (SOBQ) Total Score	-3.4 scores on a scale Standard Error 0.7	-0.7 scores on a scale Standard Error 0.7

Adverse Events

Roflumilast

Serious events: 22 serious events

Other events: 106 other events

Deaths: 0 deaths

Placebo

Serious events: 21 serious events

Other events: 76 other events

Deaths: 0 deaths

Serious adverse events

Measure	Roflumilast n=374 participants at risk Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled	Placebo n=369 participants at risk Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled
General disorders Chest pain	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Hepatobiliary disorders Bile duct stone	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Investigations Weight decreased	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Musculoskeletal and connective tissue disorders Metatarsalgia	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Psychiatric disorders Confusional state	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Renal and urinary disorders Renal failure chronic	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Surgical and medical procedures Vascular operation	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Vascular disorders Aortic aneurysm	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three 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	1.1% 4/374 • Number of events 4 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	1.4% 5/369 • Number of events 5 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Haematochezia	0.53% 2/374 • Number of events 2 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Colitis	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Colonic polyp	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Duodenal ulcer	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Gastric ulcer	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Inguinal hernia	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Angina pectoris	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Atrioventricular block complete	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Cardiac failure	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Myocardial infarction	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Cardiac disorders Ventricular tachycardia	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three 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) B-cell lymphoma	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three 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	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three 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) Meningioma	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three 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 neoplasm	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three 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	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three 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) Pancreatic neoplasm	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Blood and lymphatic system disorders Anaemia	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Blood and lymphatic system disorders Lymphoid tissue hyperplasia	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Appendicitis	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Perianal abscess	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Pneumonia	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Contusion	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Post procedural myocardial infarction	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Injury, poisoning and procedural complications Spinal compression fracture	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Cerebral ischaemia	0.00% 0/374 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.27% 1/369 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Cerebrovascular accident	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Nervous system disorders Guillain-Barre syndrome	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Eye disorders Retinal artery embolism	0.27% 1/374 • Number of events 1 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.00% 0/369 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.

Other adverse events

Measure	Roflumilast n=374 participants at risk Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled	Placebo n=369 participants at risk Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	14.4% 54/374 • Number of events 64 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	17.1% 63/369 • Number of events 80 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Infections and infestations Nasopharyngitis	5.6% 21/374 • Number of events 24 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	5.4% 20/369 • Number of events 23 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Gastrointestinal disorders Diarrhoea	8.8% 33/374 • Number of events 38 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.54% 2/369 • Number of events 2 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.
Investigations Weight decreased	5.3% 20/374 • Number of events 20 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.	0.54% 2/369 • Number of events 2 • 24 weeks treatment period The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization. Three 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