Effect of roflumilast on lung function in chronic obstructive pulmonary disease (COPD) patients treated with salmeterol: The EOS Study (BY217/M2-127) - EOS

Study identifier:BY217/M2-127

ClinicalTrials.gov identifier:NCT00313209

EudraCT identifier:2005-005080-28

CTIS identifier:N/A

Study Complete

Official Title

Effect of roflumilast in COPD patients treated with salmeterol. A 24-week, double-blind study with 500 μg roflumilast once daily versus placebo. The EOS Study

Medical condition

Chronic obstructive pulmonary disease (COPD)

Phase

Phase 3

Healthy volunteers

Study drug

Roflumilast, Placebo

Sex

All

Actual Enrollment

933

Study type

Interventional

Age

40 Years +

Date

Study Start Date: 01 Apr 2006

Primary Completion Date: 01 Jul 2007

Study Completion Date: 01 Feb 2008

Study design

Allocation: Randomized
Endpoint Classification: None
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Nov 2016 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

107

Location

Altana Pharma/Nycomed Investigational Site

Wien, Austria, 1030

Location

Altana Pharma/Nycomed Investigational Site

Wien, Austria, 1140

Location

Altana Pharma/Nycomed Investigational Site

Wien, Austria, 1150

Location

Altana Pharma/Nycomed Investigational Site

Wiener Neustadt, Austria, 2700

Location

Altana Pharma/Nycomed Investigational Site

St. Pölten, Austria, 3100

Location

Altana Pharma/Nycomed Investigational Site

Zwettl, Austria, 3910

Location

Altana Pharma/Nycomed Investigational Site

Linz, Austria, 4020

Location

Altana Pharma/Nycomed Investigational Site

Perg, Austria, 4320

Arms	Assigned Interventions
Active Comparator: Roflumilast Roflumilast 500 µg underlying medication: salmeterol 50 μg, twice daily, inhaled	Drug: Roflumilast 500 µg, once daily, oral administration in the morning
Placebo Comparator: Placebo Placebo underlying medication: salmeterol 50 μg, twice daily, inhaled	Drug: Placebo once daily

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 µg, once daily, oral and salmeterol 50 µg, twice daily, inhaled
Placebo	Placebo, once daily, oral and salmeterol 50 µg, twice daily, inhaled

Participant Flow: Overall Study

	Roflumilast	Placebo
STARTED	466^[1]	467^[2]
COMPLETED	359	385
NOT COMPLETED	107	82

[1]	Includes all randomized patients who took at least one dose of the investigational drug.
[2]	Includes all randomized patients who took at least one dose of the investigational drug.

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 µg, once daily, oral and salmeterol 50 µg, twice daily, inhaled
Placebo	Placebo, once daily, oral and salmeterol 50 µg, twice daily, inhaled

Baseline Measures

	Roflumilast	Placebo	Total
Number of Participants [units: Participants]	466	467	933
Age Continuous [units: years] Mean ± Standard Deviation	64.9 ± 8.7	64.9 ± 9.3	64.9 ± 9.0
Gender, Male/Female [units: participants]
Female	147	168	315
Male	319	299	618

Outcome Measures

1. Primary Outcome Measure: Pre-bronchodilator Forced expiratory volume in first second (FEV1) [ Time Frame: Change from baseline over 24 weeks of treatment ]

Measure Type	Primary
Measure Name	Pre-bronchodilator Forced expiratory volume in first second (FEV1)
Measure Description	Mean change from baseline during the treatment period in pre-bronchodilator FEV1 [L]
Time Frame	Change from baseline over 24 weeks of treatment
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT (Intention to Treat) analysis. Number of participants analyzed = number of participants with data available.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 µg, once daily, oral and salmeterol 50 µg, twice daily, inhaled
Placebo	Placebo, once daily, oral and salmeterol 50 µg, twice daily, inhaled

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	456	463
Pre-bronchodilator Forced expiratory volume in first second (FEV1) [units: mL] Least Squares Mean (Standard Error)	39 (9)	-10 (9)

Statistical Analysis 1 for Pre-bronchodilator Forced expiratory volume in first second (FEV1)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Net)^[5]	49
Standard Error of the mean	± 11
95% Confidence Interval	( 27 to 71 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Repeated measurements analysis (change from baseline over 24 weeks of treatment taking all post-randomization measurements into account).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustment of the significance level (0.05) was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Post-bronchodilator FEV1 [ Time Frame: Change from baseline over 24 weeks of treatment ]

Measure Type	Secondary
Measure Name	Post-bronchodilator FEV1
Measure Description	Mean change from baseline during the treatment period in post-bronchodilator FEV1 [L]
Time Frame	Change from baseline over 24 weeks of treatment
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT analysis. Number of participants analyzed = number of participants with data available.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 µg, once daily, oral and salmeterol 50 µg, twice daily, inhaled
Placebo	Placebo, once daily, oral and salmeterol 50 µg, twice daily, inhaled

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	452	460
Post-bronchodilator FEV1 [units: mL] Least Squares Mean (Standard Error)	68 (9)	8 (9)

Statistical Analysis 1 for Post-bronchodilator FEV1

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Net)^[5]	60
Standard Error of the mean	± 11
95% Confidence Interval	( 38 to 82 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Repeated measurements analysis (change from baseline over 24 weeks of treatment taking all post-randomization measurements into account).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustment of the significance level (0.05) was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: COPD Exacerbation Rate (mild, moderate or severe) [ Time Frame: 24 weeks treatment period ]

Measure Type	Secondary
Measure Name	COPD Exacerbation Rate (mild, moderate or severe)
Measure Description	Mean rate of COPD exacerbations requiring rescue medication of 3 or more puffs/day on at least 2 consecutive days (=mild COPD exacerbations), or 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 [ATS / ERS 2005].
Time Frame	24 weeks treatment period
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT analysis

Reporting Groups

	Description
Roflumilast	Roflumilast 500 µg, once daily, oral and salmeterol 50 µg, twice daily, inhaled
Placebo	Placebo, once daily, oral and salmeterol 50 µg, twice daily, inhaled

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	466	467
COPD Exacerbation Rate (mild, moderate or severe) [units: exacerbations per patient per year] Mean (95% Confidence Interval)	1.9 (1.5 to 2.5)	2.4 (1.9 to 3.1)

Statistical Analysis 1 for COPD Exacerbation Rate (mild, moderate or severe)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Poisson regression]
P-Value^[4]	0.1408
Other^[5]	0.79
Standard Error of the mean	± 0.12
95% Confidence Interval	( 0.58 to 1.08 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustment of the significance level (0.05) was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Transition dyspnea index (TDI) focal score [ Time Frame: Change from baseline over 24 weeks of treatment ]

Measure Type	Secondary
Measure Name	Transition dyspnea index (TDI) focal score
Measure Description	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.
Time Frame	Change from baseline over 24 weeks of treatment
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT analysis. Number of participants analyzed = number of participants with data available.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 µg, once daily, oral and salmeterol 50 µg, twice daily, inhaled
Placebo	Placebo, once daily, oral and salmeterol 50 µg, twice daily, inhaled

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	454	460
Transition dyspnea index (TDI) focal score [units: scores on a scale] Least Squares Mean (Standard Error)	1.2 (0.1)	1.1 (0.1)

Statistical Analysis 1 for Transition dyspnea index (TDI) focal score

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.4654
Mean Difference (Final Values)^[5]	0.1
Standard Error of the mean	± 0.2
95% Confidence Interval	( -0.2 to 0.4 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Repeated measurements analysis (change from baseline over 24 weeks of treatment taking all post-randomization measurements into account).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustment of the significance level (0.05) was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Shortness of Breath Questionnaire (SOBQ) Total Score [ Time Frame: Change from baseline over 24 weeks of treatment ]

Measure Type	Secondary
Measure Name	Shortness of Breath Questionnaire (SOBQ) Total Score
Measure Description	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".
Time Frame	Change from baseline over 24 weeks of treatment
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT analysis. Number of participants analyzed = number of participants with data available.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 µg, once daily, oral and salmeterol 50 µg, twice daily, inhaled
Placebo	Placebo, once daily, oral and salmeterol 50 µg, twice daily, inhaled

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	454	461
Shortness of Breath Questionnaire (SOBQ) Total Score [units: scores on a scale] Least Squares Mean (Standard Error)	-0.6 (0.7)	-1.1 (0.7)

Statistical Analysis 1 for Shortness of Breath Questionnaire (SOBQ) Total Score

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.5457
Mean Difference (Net)^[5]	0.5
Standard Error of the mean	± 0.9
95% Confidence Interval	( -1.2 to 2.2 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Repeated measurements analysis (change from baseline over 24 weeks of treatment taking all post-randomization measurements into account).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No adjustment of the significance level (0.05) was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	24 weeks treatment period
Additional Description	The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization.

Reporting Groups

	Description
Roflumilast	Roflumilast 500 µg, once daily, oral and salmeterol 50 µg, twice daily, inhaled
Placebo	Placebo, once daily, oral and salmeterol 50 µg, twice daily, inhaled

Serious Adverse Events

Roflumilast

Placebo

Total, serious adverse events

# participants affected / at risk

36/466 (7.73%)

42/467 (8.99%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

7/466 (1.50%)

11/467 (2.36%)

# events

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Respiratory, thoracic and mediastinal disorders

Bronchospasm¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Foreign body aspiration¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Respiratory, thoracic and mediastinal disorders

Pleural effusion¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Prostate cancer¹,^†

# participants affected / at risk

1/466 (0.21%)

2/467 (0.43%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Colon cancer¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Fibroadenoma of breast¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Gastric cancer¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Pancreatic carcinoma metastatic¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Papillary thyroid cancer¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Renal neoplasm¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Small cell lung cancer stage unspecified¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Squamous cell carcinoma¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Cardiac disorders

Myocardial infarction¹,^†

# participants affected / at risk

2/466 (0.43%)

1/467 (0.21%)

# events

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

2/466 (0.43%)

0/467 (0.00%)

# events

Cardiac disorders

Cardiac failure¹,^†

# participants affected / at risk

0/466 (0.00%)

2/467 (0.43%)

# events

Cardiac disorders

Acute myocardial infarction¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Cardiac disorders

Angina pectoris¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Cardiac disorders

Atrioventricular block complete¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Cardiac disorders

Cardiac failure congestive¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Cardiac disorders

Tachycardia¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

1/466 (0.21%)

2/467 (0.43%)

# events

Infections and infestations

Abdominal abscess¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Infections and infestations

Bronchopneumonia¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Infections and infestations

Cellulitis¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Infections and infestations

Gastroenteritis¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Infections and infestations

Lobar pneumonia¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Infections and infestations

Tooth abscess¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Vascular disorders

Aortic aneurysm¹,^†

# participants affected / at risk

2/466 (0.43%)

1/467 (0.21%)

# events

Vascular disorders

Intermittent claudication¹,^†

# participants affected / at risk

1/466 (0.21%)

1/467 (0.21%)

# events

Vascular disorders

Arterial occlusive disease¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Vascular disorders

Arterial restenosis¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Vascular disorders

Peripheral ischaemia¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Renal and urinary disorders

Renal failure acute¹,^†

# participants affected / at risk

1/466 (0.21%)

2/467 (0.43%)

# events

Renal and urinary disorders

Renal failure¹,^†

# participants affected / at risk

0/466 (0.00%)

2/467 (0.43%)

# events

Renal and urinary disorders

Dysuria¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Renal and urinary disorders

Urinary tract obstruction¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Gastrointestinal disorders

Crohn's disease¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Gastrointestinal disorders

Haematemesis¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Gastrointestinal disorders

Oesophageal varices haemorrhage¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Gastrointestinal disorders

Peptic ulcer perforation¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

General disorders and administration site conditions

Asthenia¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

General disorders and administration site conditions

General physical health deterioration¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

General disorders and administration site conditions

Hyperthermia¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

General disorders and administration site conditions

Nodule¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

General disorders and administration site conditions

Pyrexia¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Injury, poisoning and procedural complications

Fracture¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Injury, poisoning and procedural complications

Injury¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Injury, poisoning and procedural complications

Radius fracture¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Nervous system disorders

Carotid artery stenosis¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Nervous system disorders

Cerebrovascular accident¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Nervous system disorders

Loss of consciousness¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Nervous system disorders

Meningorrhagia¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Ear and labyrinth disorders

Tympanic membrane perforation¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Ear and labyrinth disorders

Vertigo¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Investigations

Investigation¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Investigations

Weight decreased¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Psychiatric disorders

Mental disorder¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Psychiatric disorders

Suicide attempt¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Skin and subcutaneous tissue disorders

Rash papular¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Skin and subcutaneous tissue disorders

Skin lesion¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Blood and lymphatic system disorders

Anaemia¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Congenital, familial and genetic disorders

Retinitis pigmentosa¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Metabolism and nutrition disorders

Anorexia¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

Reproductive system and breast disorders

Benign prostatic hyperplasia¹,^†

# participants affected / at risk

0/466 (0.00%)

1/467 (0.21%)

# events

Surgical and medical procedures

Finger amputation¹,^†

# participants affected / at risk

1/466 (0.21%)

0/467 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (11.0)
2	Term from vocabulary, MedDRA (10.1)

Other Adverse Events

Time Frame	24 weeks treatment period
Additional Description	The Safety Set was based on all randomized patients who took at least one dose of the investigational drug after randomization.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Roflumilast	Roflumilast 500 µg, once daily, oral and salmeterol 50 µg, twice daily, inhaled
Placebo	Placebo, once daily, oral and salmeterol 50 µg, twice daily, inhaled

Other Adverse Events

Roflumilast

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

165/466 (35.41%)

143/467 (30.62%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†
non-serious

# participants affected / at risk

70/466 (15.02%)

103/467 (22.06%)

# events

126

Gastrointestinal disorders

Diarrhoea¹,^†
non-serious

# participants affected / at risk

38/466 (8.15%)

15/467 (3.21%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

25/466 (5.36%)

1/467 (0.21%)

# events

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

33/466 (7.08%)

35/467 (7.49%)

# events

Investigations

Weight decreased¹,^†
non-serious

# participants affected / at risk

39/466 (8.37%)

5/467 (1.07%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (11.0)
2	Term from vocabulary, MedDRA (10.1)

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact

Name/Title:	AstraZeneca Clinical Study Information Center
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

AstraZeneca AstraZeneca

AstraZeneca

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Altana Pharma/Nycomed Investigational Site

Altana Pharma/Nycomed Investigational Site

Altana Pharma/Nycomed Investigational Site

Altana Pharma/Nycomed Investigational Site

Altana Pharma/Nycomed Investigational Site

Altana Pharma/Nycomed Investigational Site

Altana Pharma/Nycomed Investigational Site

Altana Pharma/Nycomed Investigational Site

Trial Results Summaries