Effect of Roflumilast at Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Effect of Roflumilast 500 μg Tablets Once Daily at Acute COPD Exacerbations Treated With Standard Therapy of Oral Steroids and Antibiotics. A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01473758

Acronym

TREAT

Enrollment

Registered

2011-11-17

Start date

2012-02-29

Completion date

2014-03-31

Last updated

2017-02-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Obstructive Pulmonary Disease With (Acute) Exacerbation

Keywords

COPD, Chronic obstructive pulmonary disease, Roflumilast

Brief summary

The purpose of this trial is to investigate if roflumilast can reduce the neutrophilic inflammation at acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD). In addition, the potential benefit of roflumilast on severity and recovery periods of acute COPD exacerbations will be assessed using patient diaries and questionnaires.

Detailed description

Participants will be asked whether they agree to participate in the measurements of arterial stiffness. Participants who agree will be included in the substudy, with the target of 60 patients with arterial stiffness measurements to complete the trial. Study was terminated due to difficulty in identifying further eligible patients for this exploratory study within a reasonable time.

Interventions

DRUGRoflumilast

500 µg tablet, od, oral administration in the morning after breakfast

DRUGPlacebo

tablet, od, oral administration in the morning after breakfast

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

40 Years to No maximum

Healthy volunteers

Inclusion criteria

* Written informed consent (IC) * Age ≥ 40 years * History of COPD for at least 12 months prior to enrollment (Visit V0) * Chronic productive cough for 3 months in each of the 2 years prior to enrollment (if other causes of productive cough have been excluded) and/or an exacerbation with predominantly bronchitic symptoms at enrollment * Presentation of an acute exacerbation of COPD that will be associated with increased sputum volume or change in sputum colour * Documented fixed airway obstruction determined by an FEV1/FVC ratio (post-bronchodilator) \< 70% (if a pulmonary function test is not possible at Visit V0 a previous measurement can be taken which must not be older than 6 months) * Former smoker (defined as: smoking cessation at least 1 year ago) or current smoker both with a smoking history of at least 10 pack years Main

Exclusion criteria

* Diagnosis of asthma and/or other relevant lung disease * Known alpha-1-antitrypsin deficiency * Recurrent exacerbations (within 8 weeks of a preceding exacerbation) * Treatment of current exacerbation with oral corticosteroids and/or antibiotics already started at enrollment * Treatment with PDE4 inhibitors within 3 months prior to Visit V0 * Other protocol-defined

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Initial Approach)	Baseline and Day 14	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. An Analysis of Covariance (ANCOVA) model was used with neutrophil count at Baseline and treatment as independent variables, fixed effects.
Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Extended Approach)	Baseline and Day 14	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. An Analysis of Covariance (ANCOVA) model was used with neutrophil count at Baseline and treatment as independent variables, fixed effects.

Secondary

Measure	Time frame	Description
Change From Baseline in Sputum Marker Total Cells (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Total Cells (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Neutrophils (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of neutrophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Neutrophils (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of neutrophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction. A negative change from Baseline indicates improvement.
Change From Baseline in Sputum Marker Percentage of Macrophages (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of macrophages was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Macrophages (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of macrophages was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Eosinophils (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of eosinophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Eosinophils (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of eosinophils was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Lymphocyte (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of lymphocytes was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Percentage of Lymphocytes (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Aliquots of a cell suspension prepared from the sputum sample were used to prepare cytospin slides that were stained with Diff-Quik for differential cell counts. 100 cells were counted and the percentage of lymphocytes was determined. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-6 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Interleukin (IL)-6 (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-6 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-8 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Interleukin (IL)-8 (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker IL-8 was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker MPO was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Myeloperoxidase (MPO) (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker MPO was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Neutrophil Elastase (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker Neutrophil Elastase was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Sputum Marker Concentration of Neutrophil Elastase (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Sputum samples were collected and processed at the investigational site according to their standard procedures. Sputum inflammatory marker Neutrophil Elastase was quantified by commercial sandwich enzyme-linked immunosorbent assays (ELISA). A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Interleukin (IL)-6 (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker IL-6 was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Interleukin (IL)-6 (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker IL-6 was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Interleukin-1 Beta (IL-1β) (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker IL-1β was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker IL-1β (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker IL-1β was quantified using commercial sandwich ELISA. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker C-reactive Protein (CRP) (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker CRP was measured using Roche Modular Analytics E 170 Module. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker C-reactive Protein (CRP) (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and serum biomarker CRP was measured using Roche Modular Analytics E 170 Module. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Fibrinogen (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Biomarker Plasma fibrinogen was determined using the method described by Clauss. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Fibrinogen (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Biomarker Plasma fibrinogen was determined using the method described by Clauss. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Glucose (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and analyzed for serum glucose levels. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Blood Biomarker Glucose (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Blood was collected and analyzed for serum glucose levels. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Forced Expiratory Volume (FEV1) (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Change From Baseline in Forced Expiratory Volume (FEV1) (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Change From Baseline in Forced Vital Capacity (FVC) (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Change From Baseline in Forced Vital Capacity (FVC) (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using spirometry. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Change From Baseline in FEV1/FVC (Initial Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	FEV1/FVC is the percentage of the vital capacity which is expired in the first second of maximal expiration. In healthy patients the FEV1/FVC is usually around 70%. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Change From Baseline in FEV1/FVC (Extended Approach)	Baseline and Day 7, Day 14, Day 28 and Day 56	FEV1/FVC is the percentage of the vital capacity which is expired in the first second of maximal expiration. In healthy patients the FEV1/FVC is usually around 70%. A positive change from Baseline indicates an improvement. A Mixed Model Repeated Measurement (MMRM) was used for analysis with Baseline value, treatment, visit, and treatment by visit interaction as covariates.
Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Initial Approach)	Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients' health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient's wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst).
Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Extended Approach)	Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients' health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient's wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst).
Change From Stable State in Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients' health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient's wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst). A negative change from Baseline indicates improvement. Covariates for MMRM are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Chronic Obstructive Pulmonary Assessment Test (CAT) Weekly Averages (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The CAT is a short, validated, patient-completed questionnaire to assess the impact of COPD on health status. It comprises 8 questions that cover a broad range of effects of COPD on patients' health. Each question is scored in a range between 0 and 5, with the higher end indicating a higher impact of COPD on the patient's wellbeing. The CAT Total score ranges from 0 best) to 40 (Worst). A negative change from Baseline indicates improvement. Covariates for MMRM are stable state value, treatment, time point, and treatment by time point interaction.
Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Initial Approach)	Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status.
Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Extended Approach)	Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status.
Change From Stable State in Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, time point, treatment by time point and baseline by time point interaction.
Change From Stable State in Exacerbations of Chronic Pulmonary Disease Test (EXACT-PRO) Weekly Averages (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	The EXACT-PRO questionnaire is a new, validated, and standardized measure to evaluate the frequency, severity, and duration of COPD exacerbations. It is a 14-item daily diary, and scores range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, time point, treatment by time point and baseline by time point interaction.
Change From Stable State in Diaries Peak Expiratory Flow (PEF) Weekly Average (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Morning post-medication PEF (the best of 3 attempts measured with a mini-Wright peak-flow meter) was recorded in a daily diary. A positive change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Peak Expiratory Flow (PEF) Weekly Average (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Morning post-medication PEF (the best of 3 attempts measured with a mini-Wright peak-flow meter) was recorded in a daily diary. A positive change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Symptom Score Weekly Average (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Any increase in the following respiratory symptoms: dyspnea, sputum purulence, sputum amount, wheeze, sore throat, cough, fever, symptoms of a common cold, ie, nasal congestion and discharge over the previous 24 hours were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Symptom Score Weekly Average (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Any increase in the following respiratory symptoms: dyspnea, sputum purulence, sputum amount, wheeze, sore throat, cough, fever, symptoms of a common cold, ie, nasal congestion and discharge over the previous 24 hours were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Treatment Score Weekly Average (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Any changes in the participant's usual treatment were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Change From Stable State in Diaries Treatment Score Weekly Average (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Any changes in the participant's usual treatment were recorded in a daily diary. Diaries Symptom Score range from 0 to 100, with higher scores indicating worse health status. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Initial Approach)	Day 14	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) and were determined with a Neubauer hemocytometer.
Change From Stable State in Diaries Hours Out of the Home Weekly Average (Extended Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Estimates of the length of time the participants were out of their own home on the previous day were recorded in a daily diary. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Exacerbation Length (Initial Approach)	8 Weeks	Exacerbation length is the period from start of increased symptoms to end of increased symptoms; the last day of an exacerbation was to be followed by 2 days without symptom entries in the diary.
Exacerbation Length (Extended Approach)	8 Weeks	Exacerbation length is the period from start of increased symptoms to end of increased symptoms; the last day of an exacerbation was to be followed by 2 days without symptom entries in the diary.
Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Initial Approach)	Baseline and Days 14 and 28	Carotid-femoral aortic pulse wave velocity (aPWV) will be measured in a subset of participants to determine changes in arterial stiffness. A negative change from Baseline indicates improvement. Covariates for MMRM are baseline value, treatment, visit, and treatment by visit interaction.
Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Extended Approach)	Baseline and Days 14 and 28	Carotid-femoral aortic pulse wave velocity (aPWV) will be measured in a subset of participants to determine changes in arterial stiffness. A negative change from Baseline indicates improvement. Covariates for MMRM are baseline value, treatment, visit, and treatment by visit interaction.
Change From Stable State in Diaries Hours Out of the Home Weekly Average (Initial Approach)	Baseline and Weeks 1, 2, 3, 4, 5, 6, 7 and 8	Estimates of the length of time the participants were out of their own home on the previous day were recorded in a daily diary. A negative change from Baseline indicates improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are stable state value, treatment, time point, and treatment by time point interaction.
Percentage of Participants Whose Sputum Neutrophil Counts Returned to Stable State at Day 14 (Extended Approach)	Day 14	Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) and were determined with a Neubauer hemocytometer.

Countries

United Kingdom

Participant flow

Recruitment details

Participants took part in the study at 1 investigative site in the United Kingdom from 16 February 2012 to 25 March 2014.

Pre-assignment details

Participants with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) were enrolled equally in 1 of 2 treatment groups, once a day placebo or roflumilast 500 µg in Cycle 1. Participants were re-randomized in Cycle 2 to once a day placebo or roflumilast 500 µg and are counted as new participants.

Participants by arm

Arm	Count
Roflumilast 500 μg Roflumilast 500 µg tablet, once daily, orally in the morning after breakfast for 4 weeks added on to standard therapy for acute COPD exacerbations.	38
Placebo Placebo matching roflumilast tablet, once daily, orally in the morning after breakfast for 4 weeks added on to standard therapy for acute COPD exacerbations.	43
Total	81

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Cycle 1	Adverse Event	10	2	0
Cycle 1	Withdrawal by Subject	1	1	0
Cycle 2	Adverse Event	0	0	5

Baseline characteristics

Characteristic	Roflumilast 500 μg	Placebo	Total
Age, Customized ≤ 65 years	7 participants	11 participants	18 participants
Age, Customized > 65 years	31 participants	32 participants	63 participants
Baseline COPD Assessment Test (CAT) Total Score < 10	2 participants	3 participants	5 participants
Baseline COPD Assessment Test (CAT) Total Score ≥ 10	16 participants	25 participants	41 participants
Baseline COPD Assessment Test (CAT) Total Score Missing	20 participants	15 participants	35 participants
Chronic Bronchitis No	14 participants	17 participants	31 participants
Chronic Bronchitis Yes	24 participants	26 participants	50 participants
Gender Female	16 Participants	15 Participants	31 Participants
Gender Male	22 Participants	28 Participants	50 Participants
Historical Chronic Obstructive Pulmonary Disease (COPD) Exacerbations < 2	28 participants	28 participants	56 participants
Historical Chronic Obstructive Pulmonary Disease (COPD) Exacerbations ≥ 2	10 participants	15 participants	25 participants
Race/Ethnicity, Customized Asian	2 participants	1 participants	3 participants
Race/Ethnicity, Customized White	36 participants	42 participants	78 participants
Smoking status Current smoker	8 participants	11 participants	19 participants
Smoking status Former smoker	30 participants	32 participants	62 participants
Smoking status Non-smoker	0 participants	0 participants	0 participants
Weight Category by Body Mass Index (BMI) Missing	0 participants	1 participants	1 participants
Weight Category by Body Mass Index (BMI) Normal Weight	15 participants	18 participants	33 participants
Weight Category by Body Mass Index (BMI) Obese	9 participants	9 participants	18 participants
Weight Category by Body Mass Index (BMI) Overweight	11 participants	15 participants	26 participants
Weight Category by Body Mass Index (BMI) Underweight	3 participants	0 participants	3 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	35 / 38	25 / 43	44 / 48	28 / 47
serious Total, serious adverse events	4 / 38	1 / 43	4 / 48	1 / 47

Outcome results

Primary

Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Extended Approach)

Sputum samples were collected and processed at the investigational site according to their standard procedures. Total cell count (absolute number of nonsquamous cells per gram of the original sputum sample) were determined using a Neubauer hemocytometer. A negative change from Baseline indicates improvement. An Analysis of Covariance (ANCOVA) model was used with neutrophil count at Baseline and treatment as independent variables, fixed effects.

Time frame: Baseline and Day 14

Population: Participants from the Intent-to-treat population, all randomized participants, with data available at the given time-point. Extended Approach Analysis included all participants who received treatment in Cycle 1 and participants who were re-randomized and received treatment in Cycle 2.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Roflumilast 500 μg	Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Extended Approach)	-19.569 10^6 cells/gram sputum	Standard Error 1.906
Placebo	Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Extended Approach)	-19.157 10^6 cells/gram sputum	Standard Error 1.855

p-value: 0.878695% CI: [-5.766, 4.943]ANCOVA

Primary

Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Initial Approach)

Time frame: Baseline and Day 14

Population: Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Analysis included all participants who received treatment in Cycle 1.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Roflumilast 500 μg	Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Initial Approach)	-18.705 10^6 cells/gram sputum	Standard Error 2.263
Placebo	Change From Baseline in Sputum Neutrophil Counts at Day 14 Post Exacerbation (Initial Approach)	-20.109 10^6 cells/gram sputum	Standard Error 1.995

p-value: 0.649195% CI: [-4.731, 7.538]ANCOVA

Secondary

Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Extended Approach)

Carotid-femoral aortic pulse wave velocity (aPWV) will be measured in a subset of participants to determine changes in arterial stiffness. A negative change from Baseline indicates improvement. Covariates for MMRM are baseline value, treatment, visit, and treatment by visit interaction.

Time frame: Baseline and Days 14 and 28

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Roflumilast 500 μg	Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Extended Approach)	Change at Day 14 (n=28, 28)	-0.128 meters/second	Standard Error 0.247
Roflumilast 500 μg	Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Extended Approach)	Change at Day 28 (n=19, 28)	-0.316 meters/second	Standard Error 0.323
Placebo	Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Extended Approach)	Change at Day 28 (n=19, 28)	-0.511 meters/second	Standard Error 0.273
Placebo	Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Extended Approach)	Change at Day 14 (n=28, 28)	-0.326 meters/second	Standard Error 0.245

Secondary

Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Initial Approach)

Time frame: Baseline and Days 14 and 28

Population: Participants from the Intent-to-treat (ITT) population, all randomized participants, with data available at the given time-point. Initial Approach Analysis included all participants who received treatment in Cycle 1.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Roflumilast 500 μg	Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Initial Approach)	Change at Day 28 (n=14, 24)	-0.380 meters/second	Standard Error 0.413
Roflumilast 500 μg	Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Initial Approach)	Change at Day 14 (n=18, 24)	-0.047 meters/second	Standard Error 0.337
Placebo	Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Initial Approach)	Change at Day 28 (n=14, 24)	-0.474 meters/second	Standard Error 0.321
Placebo	Change From Baseline in Aortic Pulse Wave Velocity in a Subset of Participants (Initial Approach)	Change at Day 14 (n=18, 24)	-0.343 meters/second	Standard Error 0.29

Secondary

Change From Baseline in Blood Biomarker C-reactive Protein (CRP) (Extended Approach)

Blood was collected and serum biomarker CRP was measured using Roche Modular Analytics E 170 Module. A negative change from Baseline indicated improvement. Covariates for Mixed Model Repeated Measurement (MMRM) are baseline value, treatment, visit, and treatment by visit interaction.