Effect of roflumilast on exacerbation rate in patients with Chronic Obstructive Pulmonary Disease (COPD): The HERMES Study (BY217/M2-125)

Study identifier:BY217/M2-125

ClinicalTrials.gov identifier:NCT00297115

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

Effect of roflumilast on exacerbation rate in patients with COPD. The HERMES Study

Medical condition

Chronic obstructive pulmonary disease (COPD)

Phase

Phase 3

Healthy volunteers

Study drug

Roflumilast, Placebo

Sex

All

Actual Enrollment

1568

Study type

Interventional

Age

40 Years +

Date

Study Start Date: 01 Mar 2006

Primary Completion Date: 01 Apr 2008

Study Completion Date: 01 Aug 2008

Study design

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

Verification:

Verified 01 Sept 2016 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

144

Location

Altana Pharma/Nycomed Investigational Site

Truro, NS, Canada, B2N 1L2

Location

Altana Pharma/Nycomed Investigational Site

Sainte-Foy, Quebec, Canada, G1V4G5

Location

Altana Pharma/Nycomed Investigational Site

Ste-Foy, QC, Canada, G1W 4R4

Location

Altana Pharma/Nycomed Investigational Site

St. Romuald, QC, Canada, G6W 5M6

Location

Altana Pharma/Nycomed Investigational Site

Montreal, Quebec, Canada, H1V 1X5

Location

Altana Pharma/Nycomed Investigational Site

Montreal, QC, Canada, H3S 2W1

Location

Altana Pharma/Nycomed Investigational Site

Sherbrooke, QC, Canada, J1H 4J6

Location

Altana Pharma/Nycomed Investigational Site

Ottawa, Ontario, Canada, K1Y 4E9

Arms	Assigned Interventions
Active Comparator: Roflumilast 500 mcg, once daily, oral administration in the morning	Drug: Roflumilast 500 mcg, once daily, oral administration in the morning
Placebo Comparator: Placebo once daily	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	500 mcg, once daily, oral administration in the morning
Placebo	once daily

Participant Flow: Overall Study

	Roflumilast	Placebo
STARTED	772^[1]	796^[2]
COMPLETED	527	550
NOT COMPLETED	245	246

[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	500 mcg, once daily, oral administration in the morning
Placebo	once daily

Baseline Measures

	Roflumilast	Placebo	Total
Number of Participants [units: Participants]	772	796	1568
Age Continuous [units: years] Mean ± Standard Deviation	63.92 ± 9.2	64.31 ± 9.0	64.12 ± 9.1
GenderNIH [units: participants]
Female	162	148	310
Male	610	648	1258

Outcome Measures

1. Primary Outcome Measure: Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) [ Time Frame: Change from baseline over 52 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 52 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	500 mcg, once daily, oral administration in the morning
Placebo	once daily

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	730	766
Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) [units: mL] Least Squares Mean (Standard Error)	33 (7)	-25 (7)

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]	58
Standard Error of the mean	± 9
95% Confidence Interval	( 41 to 75 )

[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 52 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 was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: COPD exacerbation rate (moderate or severe) [ Time Frame: 52 weeks treatment period ]

Measure Type	Primary
Measure Name	COPD exacerbation rate (moderate or severe)
Measure Description	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].
Time Frame	52 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	500 mcg, once daily, oral administration in the morning
Placebo	once daily

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	772	796
COPD exacerbation rate (moderate or severe) [units: exacerbations per patient per year] Mean (95% Confidence Interval)	1.210 (1.074 to 1.364)	1.485 (1.333 to 1.655)

Statistical Analysis 1 for COPD exacerbation rate (moderate or severe)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Poisson regression]
P-Value^[4]	0.0035
Other^[5]	0.815
Standard Error of the mean	± 0.057
95% Confidence Interval	( 0.710 to 0.935 )

[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 was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Post-bronchodilator FEV1 [L] [ Time Frame: Change from baseline over 52 weeks of treatment ]

Measure Type	Secondary
Measure Name	Post-bronchodilator FEV1 [L]
Measure Description	Mean change from baseline during the treatment period in post-bronchodilator FEV1 [L]
Time Frame	Change from baseline over 52 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	500 mcg, once daily, oral administration in the morning
Placebo	once daily

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	724	764
Post-bronchodilator FEV1 [L] [units: mL] Least Squares Mean (Standard Error)	44 (7)	-17 (7)

Statistical Analysis 1 for Post-bronchodilator FEV1 [L]

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Net)^[5]	61
Standard Error of the mean	± 9
95% Confidence Interval	( 44 to 79 )

[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 52 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 was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Time to mortality due to any reason [ Time Frame: 52 weeks treatment period ]

Measure Type	Secondary
Measure Name	Time to mortality due to any reason
Measure Description
Time Frame	52 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. Number of participants analyzed = number of participants who died.

Reporting Groups

	Description
Roflumilast	500 mcg, once daily, oral administration in the morning
Placebo	once daily

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	25	25
Time to mortality due to any reason [units: days] Mean (Standard Deviation)	201.0 (116.9)	214.6 (137.3)

Statistical Analysis 1 for Time to mortality due to any reason

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Cox proportional hazards regression]
P-Value^[4]	0.5028
Hazard Ratio (HR)^[5]	1.213
Standard Error of the mean	± 0.350
95% Confidence Interval	( 0.689 to 2.137 )

[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 was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	The statistical analysis is based on the ITT Analysis Set (n= 772 in the roflumilast group, n= 796 in the placebo group).

5. Secondary Outcome Measure: Natural log-transformed C-reactive protein (CRP) [ Time Frame: Change from baseline to last post randomization measurement (52 weeks) ]

Measure Type	Secondary
Measure Name	Natural log-transformed C-reactive protein (CRP)
Measure Description	Mean change from baseline to the last post randomization measurement in natural log-transformed CRP
Time Frame	Change from baseline to last post randomization measurement (52 weeks)
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	500 mcg, once daily, oral administration in the morning
Placebo	once daily

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	680	696
Natural log-transformed C-reactive protein (CRP) [units: mg/L] Least Squares Mean (95% Confidence Interval)	1.0840 (0.9766 to 1.2033)	1.0233 (0.9228 to 1.1348)

Statistical Analysis 1 for Natural log-transformed C-reactive protein (CRP)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.3627
Other^[5]	1.0593
95% Confidence Interval	( 0.9356 to 1.1994 )

[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:
	ANCOVA model including last observation carried forward (LOCF) method
[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 was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Mean Transition dyspnea index (TDI) focal score during the treatment period [ Time Frame: Change from baseline over 52 weeks of treatment ]

Measure Type	Secondary
Measure Name	Mean Transition dyspnea index (TDI) focal score during the treatment period
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 52 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	500 mcg, once daily, oral administration in the morning
Placebo	once daily

Measured Values

	Roflumilast	Placebo
Number of Participants Analyzed [units:participants]	729	769
Mean Transition dyspnea index (TDI) focal score during the treatment period [units: scores on a scale] Least Squares Mean (Standard Error)	0.662 (0.087)	0.376 (0.084)

Statistical Analysis 1 for Mean Transition dyspnea index (TDI) focal score during the treatment period

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0059
Mean Difference (Final Values)^[5]	0.286
Standard Error of the mean	± 0.104
95% Confidence Interval	( 0.082 to 0.489 )

[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 52 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 was done as a hierarchical approach for hypotheses testing was used.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	52 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.

Reporting Groups

	Description
Roflumilast	500 mcg, once daily, oral administration in the morning
Placebo	once daily

Serious Adverse Events

Roflumilast

Placebo

Total, serious adverse events

# participants affected / at risk

157/778 (20.18%)

183/790 (23.16%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

87/778 (11.18%)

121/790 (15.32%)

# events

110

160

Respiratory, thoracic and mediastinal disorders

Respiratory failure¹,^†

# participants affected / at risk

4/778 (0.51%)

5/790 (0.63%)

# events

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure¹,^†

# participants affected / at risk

2/778 (0.26%)

4/790 (0.51%)

# events

Respiratory, thoracic and mediastinal disorders

Bronchospasm¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Respiratory, thoracic and mediastinal disorders

Hypoxia¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

Respiratory, thoracic and mediastinal disorders

Respiratory arrest¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Respiratory, thoracic and mediastinal disorders

Hyperventilation¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Hypoventilation¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Respiratory, thoracic and mediastinal disorders

Pneumonia aspiration¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Respiratory, thoracic and mediastinal disorders

Pneumothorax¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Pulmonary oedema¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Respiratory acidosis¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Respiratory, thoracic and mediastinal disorders

Respiratory distress¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

18/778 (2.31%)

10/790 (1.27%)

# events

Infections and infestations

Bronchopneumonia¹,^†

# participants affected / at risk

1/778 (0.13%)

3/790 (0.38%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

0/778 (0.00%)

3/790 (0.38%)

# events

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

2/778 (0.26%)

0/790 (0.00%)

# events

Infections and infestations

Lobar pneumonia¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

Infections and infestations

Viral infection¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Infections and infestations

Appendicitis¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Infections and infestations

Cellulitis¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Infections and infestations

Clostridium difficile colitis¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Infections and infestations

Localised infection¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Infections and infestations

Pneumonia primary atypical¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Infections and infestations

Pulmonary tuberculosis¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Infections and infestations

Septic shock¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Infections and infestations

Urosepsis¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Cardiac disorders

Myocardial infarction¹,^†

# participants affected / at risk

2/778 (0.26%)

4/790 (0.51%)

# events

Cardiac disorders

Angina pectoris¹,^†

# participants affected / at risk

2/778 (0.26%)

3/790 (0.38%)

# events

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

3/778 (0.39%)

2/790 (0.25%)

# events

Cardiac disorders

Cardiac failure congestive¹,^†

# participants affected / at risk

2/778 (0.26%)

3/790 (0.38%)

# events

Cardiac disorders

Acute myocardial infarction¹,^†

# participants affected / at risk

1/778 (0.13%)

2/790 (0.25%)

# events

Cardiac disorders

Cardiopulmonary failure¹,^†

# participants affected / at risk

3/778 (0.39%)

0/790 (0.00%)

# events

Cardiac disorders

Coronary artery disease¹,^†

# participants affected / at risk

0/778 (0.00%)

3/790 (0.38%)

# events

Cardiac disorders

Right ventricular failure¹,^†

# participants affected / at risk

1/778 (0.13%)

2/790 (0.25%)

# events

Cardiac disorders

Bradycardia¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

Cardiac disorders

Cardiac arrest¹,^†

# participants affected / at risk

2/778 (0.26%)

0/790 (0.00%)

# events

Cardiac disorders

Cardiac failure¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Cardiac disorders

Cardio-respiratory arrest¹,^†

# participants affected / at risk

2/778 (0.26%)

0/790 (0.00%)

# events

Cardiac disorders

Cor pulmonale¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Cardiac disorders

Left ventricular failure¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Cardiac disorders

Myocardial ischaemia¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Cardiac disorders

Ventricular extrasystoles¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

Cardiac disorders

Angina unstable¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Cardiac disorders

Arteriosclerosis coronary artery¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Cardiac disorders

Atrioventricular block¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Cardiac disorders

Ischaemic cardiomyopathy¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Cardiac disorders

Mitral valve stenosis¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Cardiac disorders

Supraventricular tachyarrhythmia¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Cardiac disorders

Tachycardia¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Cardiac disorders

Ventricular fibrillation¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Cardiac disorders

Ventricular tachycardia¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

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

Prostate cancer¹,^†

# participants affected / at risk

4/778 (0.51%)

1/790 (0.13%)

# events

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

Non-small cell lung cancer¹,^†

# participants affected / at risk

2/778 (0.26%)

1/790 (0.13%)

# events

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

Bladder cancer¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

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

Gastric cancer¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

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

Lung neoplasm¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

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

Plasmacytoma¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

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

Renal cell carcinoma¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

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

Acute myeloid leukaemia¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

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

Adenoma benign¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

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

Bladder neoplasm¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

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

Breast cancer¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

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

Bronchial carcinoma¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

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

Carcinoid tumour of the small bowel¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

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

Chronic lymphocytic leukaemia¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

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

Colon cancer¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

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

Gastric cancer stage II¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

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

Lung adenocarcinoma¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

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

Lung neoplasm malignant¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

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

Metastases to liver¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

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

Metastasis¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

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

Metastatic carcinoma of the bladder¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

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

Neuroendocrine carcinoma¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

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

Non-small cell lung cancer metastatic¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

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

Oesophageal neoplasm¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

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

Small cell lung cancer stage unspecified¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

4/778 (0.51%)

0/790 (0.00%)

# events

Gastrointestinal disorders

Pancreatitis acute¹,^†

# participants affected / at risk

2/778 (0.26%)

1/790 (0.13%)

# events

Gastrointestinal disorders

Abdominal pain upper¹,^†

# participants affected / at risk

2/778 (0.26%)

0/790 (0.00%)

# events

Gastrointestinal disorders

Gastrointestinal haemorrhage¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

Gastrointestinal disorders

Haemorrhoids¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Gastrointestinal disorders

Intestinal polyp¹,^†

# participants affected / at risk

2/778 (0.26%)

0/790 (0.00%)

# events

Gastrointestinal disorders

Lower gastrointestinal haemorrhage¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

Gastrointestinal disorders

Colitis¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Gastrointestinal disorders

Haemorrhoidal haemorrhage¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Gastrointestinal disorders

Inguinal hernia¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Gastrointestinal disorders

Pancreatic cyst¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Gastrointestinal disorders

Small intestinal obstruction¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Gastrointestinal disorders

Upper gastrointestinal haemorrhage¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

General disorders and administration site conditions

Sudden death¹,^†

# participants affected / at risk

1/778 (0.13%)

3/790 (0.38%)

# events

General disorders and administration site conditions

Chest pain¹,^†

# participants affected / at risk

0/778 (0.00%)

3/790 (0.38%)

# events

General disorders and administration site conditions

Non-cardiac chest pain¹,^†

# participants affected / at risk

1/778 (0.13%)

2/790 (0.25%)

# events

General disorders and administration site conditions

Death¹,^†

# participants affected / at risk

0/778 (0.00%)

2/790 (0.25%)

# events

General disorders and administration site conditions

Asthenia¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

General disorders and administration site conditions

Malaise¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

General disorders and administration site conditions

Metaplasia¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

General disorders and administration site conditions

Pyrexia¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

General disorders and administration site conditions

Ulcer haemorrhage¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Nervous system disorders

Cerebrovascular accident¹,^†

# participants affected / at risk

1/778 (0.13%)

3/790 (0.38%)

# events

Nervous system disorders

Cerebral infarction¹,^†

# participants affected / at risk

2/778 (0.26%)

0/790 (0.00%)

# events

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Nervous system disorders

Anoxic encephalopathy¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Nervous system disorders

Encephalopathy¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Nervous system disorders

Hypoxic encephalopathy¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Nervous system disorders

Optic neuritis¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Nervous system disorders

Transient ischaemic attack¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Nervous system disorders

Wernicke's encephalopathy¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Ankle fracture¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Cervical vertebral fracture¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Comminuted fracture¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Device dislocation¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Eye penetration¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Femur fracture¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Fibula fracture¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Injury, poisoning and procedural complications

Foot fracture¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Foreign body trauma¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Injury, poisoning and procedural complications

Humerus fracture¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Limb injury¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Injury, poisoning and procedural complications

Procedural pain¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Tibia fracture¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Injury, poisoning and procedural complications

Wound dehiscence¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Vascular disorders

Arterial stenosis¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Vascular disorders

Femoral artery occlusion¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Vascular disorders

Haematoma¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Vascular disorders

Hypotension¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Vascular disorders

Ischaemia¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Vascular disorders

Peripheral artery aneurysm¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Blood and lymphatic system disorders

Anaemia¹,^†

# participants affected / at risk

1/778 (0.13%)

2/790 (0.25%)

# events

Blood and lymphatic system disorders

Iron deficiency anaemia¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Blood and lymphatic system disorders

Leukopenia¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Blood and lymphatic system disorders

Polycythaemia¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Metabolism and nutrition disorders

Hypokalaemia¹,^†

# participants affected / at risk

3/778 (0.39%)

0/790 (0.00%)

# events

Metabolism and nutrition disorders

Dehydration¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Metabolism and nutrition disorders

Diabetes mellitus¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Metabolism and nutrition disorders

Diabetic ketoacidosis¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Metabolism and nutrition disorders

Hyponatraemia¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Metabolism and nutrition disorders

Malnutrition¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Metabolism and nutrition disorders

Metabolic acidosis¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Renal and urinary disorders

Renal failure acute¹,^†

# participants affected / at risk

3/778 (0.39%)

1/790 (0.13%)

# events

Renal and urinary disorders

Micturition disorder¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Renal and urinary disorders

Renal failure¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Psychiatric disorders

Depression¹,^†

# participants affected / at risk

2/778 (0.26%)

1/790 (0.13%)

# events

Psychiatric disorders

Alcohol withdrawal syndrome¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Psychiatric disorders

Completed suicide¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Psychiatric disorders

Mental status changes¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Psychiatric disorders

Suicidal ideation¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Skin and subcutaneous tissue disorders

Eczema¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Skin and subcutaneous tissue disorders

Leukocytoclastic vasculitis¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Skin and subcutaneous tissue disorders

Rash¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Skin and subcutaneous tissue disorders

Urticaria¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Hepatobiliary disorders

Cholecystitis acute¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Hepatobiliary disorders

Cholelithiasis¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Intervertebral disc degeneration¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Musculoskeletal and connective tissue disorders

Rotator cuff syndrome¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Surgical and medical procedures

Coronary artery bypass¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Surgical and medical procedures

Endarterectomy¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Surgical and medical procedures

Knee arthroplasty¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Eye disorders

Cataract¹,^†

# participants affected / at risk

1/778 (0.13%)

1/790 (0.13%)

# events

Investigations

Blood creatine phosphokinase increased¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

Investigations

Blood creatinine increased¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Investigations

Blood urea increased¹,^†

# participants affected / at risk

1/778 (0.13%)

0/790 (0.00%)

# events

Reproductive system and breast disorders

Benign prostatic hyperplasia¹,^†

# participants affected / at risk

2/778 (0.26%)

0/790 (0.00%)

# events

Immune system disorders

Anti-neutrophil cytoplasmic antibody positive vasculitis¹,^†

# participants affected / at risk

0/778 (0.00%)

1/790 (0.13%)

# events

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

Other Adverse Events

Time Frame	52 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. Six patients randomized to placebo received roflumilast instead and were included in the roflumilast group for safety analyses.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Roflumilast	500 mcg, once daily, oral administration in the morning
Placebo	once daily

Other Adverse Events

Roflumilast

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

145/778 (18.64%)

81/790 (10.25%)

Gastrointestinal disorders

Diarrhoea¹,^†
non-serious

# participants affected / at risk

64/778 (8.23%)

23/790 (2.91%)

# events

Investigations

Weight decreased¹,^†

# participants affected / at risk

65/778 (8.35%)

20/790 (2.53%)

# events

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

35/778 (4.50%)

47/790 (5.95%)

# events

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

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
No text entered.

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