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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.

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Official Title

Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.

Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.

The aim of this trial is to determine the efficacy, safety and tolerability of 500 µg Roflumilast tablets once daily in patients with COPD in China, Hong Kong, and Singapore.

A chronic obstructive pulmonary disease (COPD) trial investigating roflumilast on safety and effectiveness in China, Hong Kong and Singapore:

NCT ID

Therapeutic Area

Salbutamol (given by MDI and spacer) used as rescue medication on an ass needed basis throughout the trial, and was used for post-bronchodilator spirometry tests at all study visits.

A 6-month, double-blind, randomised, multicenter, multinational trial to investigate the effect of 500 µg roflumilast tablets once daily versus placebo on pulmonary function in patients with COPD. The ACROSS Trial

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 centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV1, time and a treatment-by-time interaction as independent variables.

Age Continuous

Gender, Male/Female

Race (NIH/OMB)

Height

Study Specific Characteristic

Weight

Body Mass Index (BMI)

COPD severity was classified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guideline (2009) as: - Very severe COPD: baseline post-bronchodilator FEV1 %predicted < 30% - Severe COPD: baseline post-bronchodilator FEV1 %predicted ≥ 30% to < 50% - Moderate COPD: baseline post-bronchodilator FEV1 %predicted ≥ 50% to < 80% - Mild COPD: baseline post-bronchodilator FEV1 %predicted ≥ 80%.

Chronic obstructive pulmonary disease (COPD) severity

COPD disease characteristics

Smoking status

Cigarette pack years

Pre-bronchodilator forced expiratory volume in the first second (FEV1)

Post-bronchodilator FEV1

Pre-bronchodilator FEV1 predicted

Post-bronchodilator FEV1 predicted

FEV1 reversibility increase

FEV reversibility (%) = (post-bronchodilator FEV minus pre-bronchodilator FEV) / pre-bronchodilator FEV * 100.

FEV1 reversibility % increase

Post-bronchodilator FEV1/forced vital capacity (FVC)

The primary endpoint was tested in a confirmatory manner with a 2-sided significance level of 5%.

Intent-to-treat population included all randomly assigned patients who took at least 1 dose of trial treatment after randomization. Patients were assigned to the treatment group based on the treatment to which they were randomly assigned. Only patients with available data at Baseline and with at least 1 post-baseline measurement are included.

Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)

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 centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV1, time and a treatment-by-time interaction as independent variables.

Intent-to-treat population with available data.

Change from Baseline in Post-bronchodilator FEV1

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 centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Change from baseline in Pre-bronchodilator Forced Vital Capacity (FVC)

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 centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Change from baseline in Post-bronchodilator Forced Vital Capacity (FVC)

Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Change from baseline in Pre-bronchodilator Forced expiratory flow 25-75%

Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Change from baseline in Post-bronchodilator Forced expiratory flow 25-75%

FEV3 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV3, time and a treatment-by-time interaction as independent variables.

Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3)

FEV3 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV3, time and a treatment-by-time interaction as independent variables.

Change from baseline in Post-bronchodilator Forced Expiratory Volume in First Three Seconds (FEV3)

FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first six seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of pre-bronchodilator FEV6, time and a treatment-by-time interaction as independent variables.

Change from baseline in Pre-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6)

FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first three seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value of post-bronchodilator FEV6, time and a treatment-by-time interaction as independent variables.

Change from baseline in Post-bronchodilator Forced Expiratory Volume in First Six Seconds (FEV6)

PEF is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Change from baseline in Pre-bronchodilator Peak expiratory flow rate (PEF)

PEF is the maximal flow (or speed) achieved during the maximally forced expiration initiated at full inspiration. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol. Change from baseline over 24 weeks of treatment was calculated from a repeated measures analysis of covariance (ANCOVA) model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Change from baseline in Post-bronchodilator Peak expiratory flow rate (PEF)

The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication.

Intent-to-treat population with available data; last observation carried forward (LOCF) was used.

Change from baseline in Pre-bronchodilator Ratio of forced expiratory volume after 1 second to forced vital capacity

The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol.

Change from baseline in Post-bronchodilator Ratio of forced expiratory volume after 1 second to forced vital capacity

The FEV1/FEV6 ratio represents the percentage of the volume of air expired in the first six seconds that is expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication.

Change from baseline in Pre-bronchodilator Ratio of forced expiratory volume after 1 second to forced expiratory volume after 6 seconds

The FEV1/FEV6 ratio represents the percentage of the volume of air expired in the first six seconds that is expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry prior to taking study medication. Post-bronchodilator measurements were taken 30 minutes after four inhalations of 100 μg salbutamol.

Change from baseline in Post-bronchodilator Ratio of forced expiratory volume after 1 second to forced expiratory volume after 6 seconds

Score Sum (n=282, 296)

Cough (n=284, 299)

Sputum (n=284, 296)

Symptoms of chronic bronchitis with respect to cough and sputum production were assessed daily by the patient and recorded in a diary. Symptoms were assessed on a 4-point scale as follows: Cough: 0: no cough; 1: mild cough (at some time during the day); 2: moderate cough (regularly during the day); 3: severe cough (never free of cough or feeling free of need to cough). Sputum production: 0: no sputum production (unnoticeable); 1: mild sputum production (noticeable as a problem); 2: moderate sputum production (frequent inconvenience); 3: severe sputum production (constant problem). Change from Baseline is reported for cough and sputum separately, and for the sum of the 2 scores (range 0 - 6). Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Change From Baseline in COPD Symptom Scores

Salbutamol (given by metered dose inhaler and spacer) was used as rescue medication according to the individual needs of a patient. Each use was documented in the patient’s paper diary. Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Change From Baseline in Use of Rescue Medication

The TDI is a recognized questionnaire to measure dyspnoea (shortness of breath) in patients with COPD. Questions from the TDI were used to assess the 3 components: "change in functional impairment", "change in magnitude of task" and "change in magnitude of effort". Transitions or changes from baseline are rated from -3 (major deterioration) to +3 (major improvement), and summed to give a total score ranging from -9 to +9. Least squares means (LSM) are from a repeated measures ANCOVA model with treatment, baseline value, time and a treatment-by-time interaction as independent variables.

Transition Dyspnoea Index (TDI) Total Score at Week 24

No exacerbations

One exacerbation

Two exacerbations

Three exacerbations

A COPD exacerbation is an event characterised by a worsening in the patient’s baseline dyspnoea, or cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management, and may be accompanied by increased wheeze, chest tightness, purulent sputum and symptoms of cold and/or fatigue. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.

Percentage of Participants with Moderate or Severe COPD Exacerbations

The mean rate of COPD exacerbations per patient per year rate = (number of exacerbations per treatment group/time to study withdrawal per treatment group) * 365. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.

Mean Rate of Moderate or Severe COPD Exacerbations per Patient per Year

Time to onset of a COPD exacerbation is defined as onset date of COPD exacerbation – date of first intake of study drug + 1 day. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.

Intent-to-treat population with at least one moderate or severe exacerbation

Time to onset of first moderate or severe COPD exacerbation

Time to onset of a COPD exacerbation is defined as onset date of COPD exacerbation – date of first intake of study drug + 1 day. At least 10 days between the stop date of an exacerbation and the start date of the following exacerbation was required for these to be be considered as two separate COPD exacerbations. COPD exacerbations were categorized as follows: - Severe: Requiring hospitalization and/or leading to death; - Moderate: Requiring oral or parenteral glucocorticosteroid therapy.

Intent-to-treat population who experienced a second moderate to severe COPD exacerbation.

Time to Onset of Second Moderate or Severe COPD Exacerbation

All AEs

Non-serious AEs

Serious AEs (including death)

Death

Serious AEs not including death

AEs with suggested relationship to trial treatment

AEs leading to withdrawal from the trial

AEs not recovered at trial termination

AEs with changes in concomitant medication

An adverse event (AE) is any untoward medical occurrence in a clinical trial participant regardless of causal relationship to study drug and regardless whether study drug has been administered. A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. A non-serious AE is any AE that does not meet the criteria above. Each AE was assessed by the Investigator as either 'related' or 'not related' to study drug.

Safety population, all randomized patients who took at least 1 dose of the trial treatment after randomization.

Number of participants with adverse events

Overall Study

Participants with a diagnosis of chronic obstructive pulmonary disease (COPD) were randomized in 1 of 2 treatment groups (placebo and roflumilast 500 μg once daily).

Arms	Assigned Interventions
Experimental: Roflumilast Roflumilast 500 μg, tablet, oral, once daily for up to 24 weeks.	Drug: Roflumilast Roflumilast tablets Drug: Salbutamol Salbutamol (given by MDI and spacer) used as rescue medication on an ass needed basis throughout the trial, and was used for post-bronchodilator spirometry tests at all study visits.
Placebo Comparator: Placebo Placebo to roflumilast, tablet, oral, once daily for up to 24 weeks.	Drug: Placebo Placebo tablets Drug: Salbutamol Salbutamol (given by MDI and spacer) used as rescue medication on an ass needed basis throughout the trial, and was used for post-bronchodilator spirometry tests at all study visits.

A chronic obstructive pulmonary disease (COPD) trial investigating roflumilast on safety and effectiveness in China, Hong Kong and Singapore: - ACROSS

Official Title

Medical condition

Phase

Healthy volunteers

Study drug

Sex

Actual Enrollment

Study type

Age

Date

Study design

Verification:

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Documents available

Trial Results Summaries

Contacts

Contact

Investigators

Principal Investigator