Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
This is a randomized, double-blind, placebo-controlled, parallel-group, multi-centre trial.The trial aims to evaluate efficacy of nebulized ipratropium bromide in Chinese peri-operative patients with COPD under general anaesthesia.
Interventions
DRUGplacebo
normal saline
DRUGipratropium bromide
ipratropium bromide
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* All patients must sign an informed consent. * Male or female patients aged \>= 40 years and \<= 80 years * All patients must be diagnosed with COPD and must meet the following spirometric criterion: post-bronchodilator forced expiratory volume in 1 second (FEV1) \< 70% of forced vital capacity (FVC) at Screening Visit (Visit 1). * All patients have relatively stable COPD (i.e. have no COPD exacerbation within 4 weeks prior to Screening Visit). * All patients are about to receive selective surgical procedures of lobectomy or right bilobectomy or segmentectomy under general anaesthesia, whilst the estimated time of surgical procedures lasts for not less than 2 hours, and the estimated time of general anaesthesia lasts for not less than 3 hours and not longer than 5 hours. * Patients must be able to perform all study related procedures including technically acceptable pulmonary function tests (PFTs).
Exclusion criteria
* Patients who need maintenance treatment of bronchodilators (including anticholinergics, ß-agonists, xanthines). * Patients with a recent history (i.e. six months or less) of myocardial infarction * Patients with any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the last year * Patients with symptomatic chronic heart failure (i.e. New York Heart Association functional class III-IV) * Known narrow angle glaucoma * Patients with prostatic hyperplasia or bladder neck obstruction with significant symptoms * Patients with a history of asthma, allergic rhinitis or who have a blood eosinophil count \>= 600 / mm3 (0.6×10\^9/L). A repeat eosinophil count will not be conducted in these patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Forced Expiratory Volume in 1 Second (FEV1) From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery | Baseline and Treatment day 3 | Change of forced expiratory volume in 1 second (FEV1) from pre-bronchodilator at baseline to post-nebulization one day before the surgery (Treatment day 3). Measurements of FEV1 were performed using calibrated electronic spirometers. Equipment and techniques should conform to American Thoracic Society (ATS) criteria (P05-12782). At screening visit, pulmonary function testing (PFT) was performed at baseline and repeated 30 minutes following inhalation of 4 puffs of salbutamol hydrofluoroalkanes metered-dose inhaler (HFA MDI). At treatment day 3, pulmonary function testing was performed 60 minutes following the inhalation of investigational drug. Spirometry was conducted with the patient in a seated position having abstained from medications. The best of three efforts was defined as the highest FEV1 each obtained on any of three efforts meeting the ATS criteria and it was selected regardless of whether they came from different spirometric manoeuvres or the same manoeuvre. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of Forced Vital Capacity (FVC) From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery | Baseline and Treatment day 3 | Change of forced vital capacity (FVC) from pre-bronchodilator at baseline to post-nebulization one day before the surgery (Treatment day 3). Measurements of FVC were performed using calibrated electronic spirometers. Equipment and techniques should conform to American Thoracic Society (ATS) criteria (P05-12782). At Visit 1, pulmonary function testing (PFT) was performed at baseline and repeated 30 minutes following inhalation of 4 puffs of salbutamol hydrofluoroalkanes metered-dose inhaler (HFA MDI). At Visit 3, pulmonary function testing was performed 60 minutes following the inhalation of investigational drug. Spirometry was conducted with the patient in a seated position having abstained from medications. The best of three efforts was defined as the highest FVC each obtained on any of three efforts meeting the ATS criteria and it was selected regardless of whether they came from different spirometric manoeuvres or the same manoeuvre. |
| Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Arterial Oxygen Pressure (PaO2) Value | Baseline and Treatment day 3 | Change of blood gas analyses from pre-bronchodilator at baseline to post-nebulization one day before the surgery (Treatment day 3): arterial oxygen pressure (PaO2) value |
| Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Oxygen Saturation | Baseline and Treatment day 3 | Change of blood gas analyses from pre-bronchodilator at baseline to post-nebulization one day before the surgery (Treatment day 3): Oxygen saturation |
| Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Arterial Carbon Dioxide Pressure (PaCO2) Value | Baseline and Treatment day 3 | Change of blood gas analyses from pre-bronchodilator at baseline to post-nebulization one day before the surgery (Treatment day 3): arterial carbon dioxide pressure (PaCO2) value |
| Main Post-operative Pulmonary Complications (Including Pneumonia, Atelectasis and Acute Respiratory Failure) Within Three Weeks After the Surgery | From surgery to 3 weeks post surgery, up to 21 days | Number of patients with at least one main post-operative pulmonary complications (including pneumonia, atelectasis and acute respiratory failure) within three weeks after the surgery. Post-operative pneumonia was defined by the presence of the following criteria: persistent lung infiltrate on chest X-ray or chest computerized tomography (CT)-scan, white blood cell count \>10,000 /mm3 and fever. Post-operative atelectasis was diagnosed by presence of atelectasis affecting one lobe or several lobes in chest X-ray test or chest CT-scan. Post-operative acute respiratory failure was defined by the presence of: PaO2 \< 60 mmHg and/or PaCO2 \> 50 mmHg while breathing air or other evidences which were considered as respiratory failure by investigators. |
Countries
China
Participant flow
Recruitment details
192 patients were randomized in a 1:1 ratio(96 patients in each group).1 patient each in both treatment groups did not receive the treatment.1 patient, who was randomized to the placebo group, but received nebulized ipratropium bromide, so the actual numbers of patients received nebulized ipratropium bromide and placebo were 96 and 94 respectively
Pre-assignment details
This was randomised, double-blind, placebo-controlled, parallel-group, multicentre trial which aims to evaluate efficacy and safety of nebulized ipratropium bromide in Chinese peri-operative patients with chronic obstructive pulmonary disease (COPD) under general anaesthesia.
Participants by arm
| Arm | Count |
|---|---|
| Nebulized Ipratropium Bromide 500 microgram (mcg) ipratropium bromide solution was administered orally via nebulizer four times a day up to 11 days. | 96 |
| Placebo 4 milliliter (ml) normal saline was administered orally via nebulizer four times a day up to 11 days. | 94 |
| Total | 190 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | Other Reasons | 16 | 17 |
| Overall Study | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Total | Nebulized Ipratropium Bromide | Placebo |
|---|---|---|---|
| Age, Continuous | 62.9 Years STANDARD_DEVIATION 6.5 | 63.4 Years STANDARD_DEVIATION 6.5 | 62.4 Years STANDARD_DEVIATION 6.4 |
| Sex: Female, Male Female | 22 Participants | 13 Participants | 9 Participants |
| Sex: Female, Male Male | 168 Participants | 83 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 96 | 16 / 94 |
| serious Total, serious adverse events | 5 / 96 | 4 / 94 |
Outcome results
Primary
Change of Forced Expiratory Volume in 1 Second (FEV1) From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery
Change of forced expiratory volume in 1 second (FEV1) from pre-bronchodilator at baseline to post-nebulization one day before the surgery (Treatment day 3). Measurements of FEV1 were performed using calibrated electronic spirometers. Equipment and techniques should conform to American Thoracic Society (ATS) criteria (P05-12782). At screening visit, pulmonary function testing (PFT) was performed at baseline and repeated 30 minutes following inhalation of 4 puffs of salbutamol hydrofluoroalkanes metered-dose inhaler (HFA MDI). At treatment day 3, pulmonary function testing was performed 60 minutes following the inhalation of investigational drug. Spirometry was conducted with the patient in a seated position having abstained from medications. The best of three efforts was defined as the highest FEV1 each obtained on any of three efforts meeting the ATS criteria and it was selected regardless of whether they came from different spirometric manoeuvres or the same manoeuvre.
Time frame: Baseline and Treatment day 3
Population: Full analysis set (FAS): All patients in the treated set who had observed analysable data in at least one efficacy endpoint. (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebulized Ipratropium Bromide | Change of Forced Expiratory Volume in 1 Second (FEV1) From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery | 169.9 ml | Standard Error 29.07 |
| Placebo | Change of Forced Expiratory Volume in 1 Second (FEV1) From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery | 15.0 ml | Standard Error 29.35 |
Comparison: The analysis of covariance (ANCOVA) method was used to compare the change of FEV1 from pre-bronchodilator at baseline to post-nebulization on treatment day 3 between the active arm and the placebo arm, with baseline value as covariate and two stratification factors based on acute bronchodilator responsiveness at baseline and age as main effects.p-value: <0.000195% CI: [91.08, 218.63]ANCOVA
Secondary
Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Arterial Carbon Dioxide Pressure (PaCO2) Value
Change of blood gas analyses from pre-bronchodilator at baseline to post-nebulization one day before the surgery (Treatment day 3): arterial carbon dioxide pressure (PaCO2) value
Time frame: Baseline and Treatment day 3
Population: Full analysis set (FAS). (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebulized Ipratropium Bromide | Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Arterial Carbon Dioxide Pressure (PaCO2) Value | -0.1 mmHg | Standard Error 0.51 |
| Placebo | Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Arterial Carbon Dioxide Pressure (PaCO2) Value | -0.5 mmHg | Standard Error 0.52 |
Comparison: The analysis of covariance (ANCOVA) method was used to compare the change of blood gas analyses from pre-bronchodilator at baseline to post-nebulization on treatment day 3 for PaCO2 between the active arm and the placebo arm, with baseline value as covariate and two stratification factors based on acute bronchodilator responsiveness at baseline and age as main effects.p-value: 0.475895% CI: [-0.72, 1.55]ANCOVA
Secondary
Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Arterial Oxygen Pressure (PaO2) Value
Change of blood gas analyses from pre-bronchodilator at baseline to post-nebulization one day before the surgery (Treatment day 3): arterial oxygen pressure (PaO2) value
Time frame: Baseline and Treatment day 3
Population: Full analysis set (FAS). (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebulized Ipratropium Bromide | Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Arterial Oxygen Pressure (PaO2) Value | 3.2 mmHg | Standard Error 1.92 |
| Placebo | Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Arterial Oxygen Pressure (PaO2) Value | 0.5 mmHg | Standard Error 1.92 |
Comparison: The analysis of covariance (ANCOVA) method was used to compare the change of blood gas analyses from pre-bronchodilator at baseline to post-nebulization on treatment day 3 for PaO2 between the active arm and the placebo arm, with baseline value as covariate and two stratification factors based on acute bronchodilator responsiveness at baseline and age as main effects.p-value: 0.206995% CI: [-1.54, 7.07]ANCOVA
Secondary
Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Oxygen Saturation
Change of blood gas analyses from pre-bronchodilator at baseline to post-nebulization one day before the surgery (Treatment day 3): Oxygen saturation
Time frame: Baseline and Treatment day 3
Population: Full analysis set (FAS). (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebulized Ipratropium Bromide | Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Oxygen Saturation | 0.6 Percentage of Oxygen | Standard Error 0.25 |
| Placebo | Change of Blood Gas Analyses From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery: Oxygen Saturation | 0.3 Percentage of Oxygen | Standard Error 0.25 |
Comparison: The analysis of covariance (ANCOVA) method was used to compare the change of blood gas analyses from pre-bronchodilator at baseline to post-nebulization on treatment day 3 for Oxygen saturation between the active arm and the placebo arm, with baseline value as covariate and two stratification factors based on acute bronchodilator responsiveness at baseline and age as main effects.p-value: 0.189995% CI: [-0.19, 0.93]ANCOVA
Secondary
Change of Forced Vital Capacity (FVC) From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery
Change of forced vital capacity (FVC) from pre-bronchodilator at baseline to post-nebulization one day before the surgery (Treatment day 3). Measurements of FVC were performed using calibrated electronic spirometers. Equipment and techniques should conform to American Thoracic Society (ATS) criteria (P05-12782). At Visit 1, pulmonary function testing (PFT) was performed at baseline and repeated 30 minutes following inhalation of 4 puffs of salbutamol hydrofluoroalkanes metered-dose inhaler (HFA MDI). At Visit 3, pulmonary function testing was performed 60 minutes following the inhalation of investigational drug. Spirometry was conducted with the patient in a seated position having abstained from medications. The best of three efforts was defined as the highest FVC each obtained on any of three efforts meeting the ATS criteria and it was selected regardless of whether they came from different spirometric manoeuvres or the same manoeuvre.
Time frame: Baseline and Treatment day 3
Population: Full analysis set (FAS). (Only patients with observed cases (OC) values were analysed)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nebulized Ipratropium Bromide | Change of Forced Vital Capacity (FVC) From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery | 59.4 ml | Standard Error 48.76 |
| Placebo | Change of Forced Vital Capacity (FVC) From Pre-bronchodilator at Baseline to Post-nebulization One Day Before the Surgery | 8.5 ml | Standard Error 49.27 |
Comparison: The analysis of covariance (ANCOVA) method was used to compare the change of forced vital capacity (FVC) from pre-bronchodilator at baseline to post-nebulization on treatment day 3 between the active arm and the placebo arm, with baseline value as covariate and two stratification factors based on acute bronchodilator responsiveness at baseline and age as main effects.p-value: 0.350995% CI: [-56.55, 158.46]ANCOVA
Secondary
Main Post-operative Pulmonary Complications (Including Pneumonia, Atelectasis and Acute Respiratory Failure) Within Three Weeks After the Surgery
Number of patients with at least one main post-operative pulmonary complications (including pneumonia, atelectasis and acute respiratory failure) within three weeks after the surgery. Post-operative pneumonia was defined by the presence of the following criteria: persistent lung infiltrate on chest X-ray or chest computerized tomography (CT)-scan, white blood cell count \>10,000 /mm3 and fever. Post-operative atelectasis was diagnosed by presence of atelectasis affecting one lobe or several lobes in chest X-ray test or chest CT-scan. Post-operative acute respiratory failure was defined by the presence of: PaO2 \< 60 mmHg and/or PaCO2 \> 50 mmHg while breathing air or other evidences which were considered as respiratory failure by investigators.
Time frame: From surgery to 3 weeks post surgery, up to 21 days
Population: Surgery complete set (SCS): All patients who completed surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nebulized Ipratropium Bromide | Main Post-operative Pulmonary Complications (Including Pneumonia, Atelectasis and Acute Respiratory Failure) Within Three Weeks After the Surgery | 8 Participants |
| Placebo | Main Post-operative Pulmonary Complications (Including Pneumonia, Atelectasis and Acute Respiratory Failure) Within Three Weeks After the Surgery | 14 Participants |
Comparison: For main post-operative pulmonary complications, the Cochran-Mantel-Haenszel analysis was performed on the SCS. Mantel-Haenszel test with strata based on acute bronchodilator responsiveness at baseline and age was used to compare the number of patients with main post-operative pulmonary complications between the two arms.p-value: 0.1779Cochran-Mantel-Haenszel