Bronchiectasis
Conditions
Keywords
Azithromycin, Bronchiectasis, Macrolide, Inflammation, Pulmonary
Brief summary
Bronchiectasis is a chronic lung condition characterised primarily by dilatation of the airways. Only a small number of clinical studies have been conducted investigating the use of macrolides to treat non-cystic fibrosis bronchiectasis. The purpose of this study is to determine the efficacy of 12 weeks treatment with azithromycin in adult patients with non-cystic fibrosis bronchiectasis.
Detailed description
Previous studies of various macrolides with small sample sizes have reported some benefit with the reduction of sputum volume in bronchiectasis patients. However, macrolide therapy could not yet be confidently used to treat bronchiectasis, given the diffuse nature of these findings. These studies have had a wide range of hypotheses, and have not necessarily focused on the anti-inflammatory effects of macrolides. Furthermore, these studies are few in number, and not all have been placebo-controlled or double-blinded. This, combined with the small sample sizes used, limits the reliability of these results. This study aims to expand on these limited published findings by investigating a larger sample population with different endpoints. Sputum volume and quality of life have been selected as important variables to aid in assessing efficacy. This study aims to be independent of previous studies in a number of ways. This is the only study of bronchiectasis patients to formally investigate quality of life after treatment with a macrolide, and the potential carryover effect of azithromycin therapy. This study will also expand on the findings of previous studies of macrolides in bronchiectasis by incorporating a larger sample size into the trial.
Interventions
DRUGAzithromycin
Azithromycin (C38H72N2O12 MW 749) is a 15-membered azalide, a subclass of macrolide antibiotics
In Part One of the study participants will be randomised to receive 12 weeks of either placebo or azithromycin in a 1:1 ratio in a double-blinded fashion. After 12 weeks, in Part Two of the study, all participants will receive placebo in a double-blinded fashion for an additional 12 weeks.
Sponsors
Penang Hospital, Malaysia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have provided written informed consent to participate in the study in accordance with the local ethics committee regulations * Have a confirmed diagnosis of bronchiectasis (by HRCT) Aged 18 years or over Have chronic sputum production, defined as a greater than 45 mililitres volume produced in the 1 week prior to study entry. * Be able to perform reproducible spirometry * Be in a relatively stable disease state in the 6 weeks prior to entry, as defined by the absence of the following: respiratory exacerbations requiring hospitalisation, change in cough and/or sputum production, new or increased hemoptysis, more than 10% weight loss, use of additional antibiotic courses
Exclusion criteria
* Subjects will be excluded if one or more of the following criteria occur. The subject: Is an investigator, or an immediate family member of an investigator * Has a confirmed diagnosis of cystic fibrosis, as evidenced by genetic analysis or a sweat test result more than 60mmol/L * Has a primary immunodeficiency Is a pregnant or lactating female Has had a respiratory exacerbation requiring hospitalisation or additional course of antibiotics in the 6 weeks prior to study entry * Has been prescribed or used oral steroids on any occasion for the 3 months prior to study entry. * Has been using mucolytic agents on any occasion for the 2 months prior to study entry Has active tuberculosis * Has an active malignancy, including melanoma (other skin carcinomas excluded) * Has a history of significant liver disease or insufficiency Has a significant history of drug abuse (including alcohol abuse) or mental illness Has a known intolerance or allergy to macrolides * Has been participating in another interventional drug study in the 3 months prior to enrolment into this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 24 Hour Sputum Volume | Visit 3 (Baseline); Visit 6 (Week 12); Visit 8 (Week 24) | Each participant must be instructed and enabled to collect 24 hour sputum volumes over the 24 hours prior to visits 3, 6 and 8, inclusive. As this is the primary endpoint of the study, it is critical that 24 hour sputum volumes are measured and recorded accurately, observing the following protocol: The subject should be given a sterile jar to collect the sputum, which has been weighed previously for convenience. Each jar will be labelled with subject name, start and finish time/date The collection should commence on rising in the morning and complete 24 hours later. Ensure that the sputum sample has minimal saliva in the collection Instruct subject to collect all sputum produced spontaneously or after coughing over a single daytime 24 hour period. The sample should come from the lungs and should not be salivary. Encourage subject not to swallow sputum, but to collect. Each 24 hour collection period should be as similar as possible in terms of physiotherapy and exercise regimens |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Health Status: St George's Respiratory Questionnaire Score | Visit 3 (Baseline); Visit 6 (Week 12); Visit 8 (Week 24) | The St. George Respiratory Questionnaire is to be administered at visits 3, 6 and 8 inclusive. It should be administered in a quiet room where the participant can answer the questions without interruption, prior to any other protocol related procedures |
| Spirometry Value; Forced Expiratory Volume at 1 Second (FEV1) | Visit 3 (Baseline); Visit 6 (Week 12); Visit 8 (Week 24) | Pulmonary function testing using a spirometer will be carried out at visits 3, 6 and 8 inclusive. All testing should be done in the sitting position, except for obese patients, who commonly obtain deeper inspiration when tested in the standing position. Subjects should avoid the following prior to lung function testing: Smoking within 1 hour of testing Consuming alcohol within 4 hours of testing Performing vigorous exercise within 30 minutes of testing Wearing restrictive clothing around the chest or abdomen Eating a large meal within 2 hours of testing The following medications must be withheld prior to testing, with the minimum time from last dose indicated- short acting beta agonists (6 hours), long acting beta agonists (12 hours), ipratropium bromide (12 hours), antihistamines (12 hours), long acting bronchodilator combinations (12 hours) |
| Spirometric Values: Forced Vital Capacity (FVC) | Visit 3 (Baseline); Visit 6 (Week 12); Visit 8 (Week 24) | Pulmonary function testing using a spirometer will be carried out at visits 3, 6 and 8 inclusive. All testing should be done in the sitting position, except for obese patients, who commonly obtain deeper inspiration when tested in the standing position. Subjects should avoid the following prior to lung function testing: Smoking within 1 hour of testing Consuming alcohol within 4 hours of testing Performing vigorous exercise within 30 minutes of testing Wearing restrictive clothing around the chest or abdomen Eating a large meal within 2 hours of testing The following medications must be withheld prior to testing, with the minimum time from last dose indicated- short acting beta agonists (6 hours), long acting beta agonists (12 hours), ipratropium bromide (12 hours), antihistamines (12 hours), Iong acting bronchodilator combinations (12 hours) |
Countries
Malaysia
Participant flow
Recruitment details
A total of 90 subjects with a High Resolution CT scan diagnosis of pulmonary bronchiectasis was recruited from January - October 2011. Recruitment was done amongst patients in chest clinic, Hospital Taiping. A total of 78 subjects were selected based on the inclusion and exclusion criterias.
Pre-assignment details
12 subjects were excluded from randomization as they did not have chronic sputum production and were unable to perform spirometry.
Participants by arm
| Arm | Count |
|---|---|
| Azithromycin Patients randomised to the treatment arm received 1000mg of azithromycin once a week for 12 weeks followed by placebo for azithromycin once a week for another 12 weeks. | 33 |
| Placebo for Azithromycin Patients randomised to the control arm received placebo for azithromycin once a week for 12 weeks followed by placebo for azithromycin once a week for another 12 weeks. | 35 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Control Phase | Adverse Event | 0 | 1 |
| Control Phase | Death | 2 | 0 |
| Control Phase | Lost to Follow-up | 1 | 1 |
| Treatment vs. Placebo | Adverse Event | 3 | 0 |
| Treatment vs. Placebo | Lost to Follow-up | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo for Azithromycin | Total | Azithromycin |
|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 15.03 | 62.8 years STANDARD_DEVIATION 13.4 | 65.9 years STANDARD_DEVIATION 11.77 |
| Forced Expiratory Volume at 1 second (FEV1) | 1.17 Litres STANDARD_DEVIATION 0.54 | 1.13 Litres STANDARD_DEVIATION 0.48 | 1.08 Litres STANDARD_DEVIATION 0.41 |
| Forced Vital Capacity (FVC) | 1.69 Litres STANDARD_DEVIATION 0.74 | 1.63 Litres STANDARD_DEVIATION 0.7 | 1.56 Litres STANDARD_DEVIATION 0.65 |
| Sex: Female, Male Female | 22 Participants | 40 Participants | 18 Participants |
| Sex: Female, Male Male | 13 Participants | 28 Participants | 15 Participants |
| Sputum volume | 23.6 gram STANDARD_DEVIATION 20.67 | 32.4 gram STANDARD_DEVIATION 24.99 | 41.8 gram STANDARD_DEVIATION 26.05 |
| St George's Respiratory Questionnaire (SGRQ) score | 36.40 Scores on a scale STANDARD_DEVIATION 10.59 | 38.66 Scores on a scale STANDARD_DEVIATION 10.47 | 41.06 Scores on a scale STANDARD_DEVIATION 9.95 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 33 | 1 / 35 |
| serious Total, serious adverse events | 5 / 33 | 4 / 35 |
Outcome results
Primary
24 Hour Sputum Volume
Each participant must be instructed and enabled to collect 24 hour sputum volumes over the 24 hours prior to visits 3, 6 and 8, inclusive. As this is the primary endpoint of the study, it is critical that 24 hour sputum volumes are measured and recorded accurately, observing the following protocol: The subject should be given a sterile jar to collect the sputum, which has been weighed previously for convenience. Each jar will be labelled with subject name, start and finish time/date The collection should commence on rising in the morning and complete 24 hours later. Ensure that the sputum sample has minimal saliva in the collection Instruct subject to collect all sputum produced spontaneously or after coughing over a single daytime 24 hour period. The sample should come from the lungs and should not be salivary. Encourage subject not to swallow sputum, but to collect. Each 24 hour collection period should be as similar as possible in terms of physiotherapy and exercise regimens
Time frame: Visit 3 (Baseline); Visit 6 (Week 12); Visit 8 (Week 24)
Population: A total of 90 subjects were recruited. Among them, 78 subjects fulfilled the inclusion criteria and were randomized. Only 68 subjects completed the study and were subjected for analysis. We targeted to recruit 80 subjects and a dropout rate of 20% was anticipated as stated in the protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azithromycin | 24 Hour Sputum Volume | Visit 3(Baseline) | 41.8 gram | Standard Deviation 26.1 |
| Azithromycin | 24 Hour Sputum Volume | Visit 6(Week 12) | 29.9 gram | Standard Deviation 19.4 |
| Azithromycin | 24 Hour Sputum Volume | Visit 8(Week 24) | 30.4 gram | Standard Deviation 20.6 |
| Placebo for Azithromycin | 24 Hour Sputum Volume | Visit 3(Baseline) | 23.6 gram | Standard Deviation 20.7 |
| Placebo for Azithromycin | 24 Hour Sputum Volume | Visit 6(Week 12) | 26.2 gram | Standard Deviation 20.5 |
| Placebo for Azithromycin | 24 Hour Sputum Volume | Visit 8(Week 24) | 28.5 gram | Standard Deviation 21.6 |
Comparison: Sputum volume were compared between Visit 6 (Week 12) and Visit 3 (Baseline), Visit 8 (Week 24) and Visit 3 (Baseline), as well for Visit 8 (Week 24) and Visit 6 (Week 12).~Independent t-test was applied for study end points which were numerical variables.p-value: <0.01t-test, 1 sided
Comparison: Sputum volume were compared between Visit 6 (Week 12) and Visit 3 (Baseline), Visit 8 (Week 24) and Visit 3 (Baseline), as well for Visit 8 (Week 24) and Visit 6 (Week 12).~Independent t-test was applied for study end points which were numerical variables.p-value: <0.01t-test, 1 sided
Secondary
Health Status: St George's Respiratory Questionnaire Score
The St. George Respiratory Questionnaire is to be administered at visits 3, 6 and 8 inclusive. It should be administered in a quiet room where the participant can answer the questions without interruption, prior to any other protocol related procedures
Time frame: Visit 3 (Baseline); Visit 6 (Week 12); Visit 8 (Week 24)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azithromycin | Health Status: St George's Respiratory Questionnaire Score | Visit 3(Baseline) | 41.1 Units | Standard Deviation 9.9 |
| Azithromycin | Health Status: St George's Respiratory Questionnaire Score | Visit 6(Week 12) | 30.2 Units | Standard Deviation 8.5 |
| Azithromycin | Health Status: St George's Respiratory Questionnaire Score | Visit 8(Week 24) | 31.7 Units | Standard Deviation 8.1 |
| Placebo for Azithromycin | Health Status: St George's Respiratory Questionnaire Score | Visit 3(Baseline) | 36.4 Units | Standard Deviation 10.6 |
| Placebo for Azithromycin | Health Status: St George's Respiratory Questionnaire Score | Visit 6(Week 12) | 39.1 Units | Standard Deviation 9.3 |
| Placebo for Azithromycin | Health Status: St George's Respiratory Questionnaire Score | Visit 8(Week 24) | 41.1 Units | Standard Deviation 11.1 |
Comparison: SGRQ scores were compared between Visit 6 (Week 12) and Visit 3 (Baseline), Visit 8 (Week 24) and Visit 3 (Baseline), as well for Visit 8 (Week 24) and Visit 6 (Week 12).~Independent t-test was applied for study end points which were numerical variables.p-value: <0.01t-test, 1 sided
Comparison: SGRQ scores were compared between Visit 6 (Week 12) and Visit 3 (Baseline), Visit 8 (Week 24) and Visit 3 (Baseline), as well for Visit 8 (Week 24) and Visit 6 (Week 12).~Independent t-test was applied for study end points which were numerical variablesp-value: <0.01t-test, 1 sided
Secondary
Spirometric Values: Forced Vital Capacity (FVC)
Pulmonary function testing using a spirometer will be carried out at visits 3, 6 and 8 inclusive. All testing should be done in the sitting position, except for obese patients, who commonly obtain deeper inspiration when tested in the standing position. Subjects should avoid the following prior to lung function testing: Smoking within 1 hour of testing Consuming alcohol within 4 hours of testing Performing vigorous exercise within 30 minutes of testing Wearing restrictive clothing around the chest or abdomen Eating a large meal within 2 hours of testing The following medications must be withheld prior to testing, with the minimum time from last dose indicated- short acting beta agonists (6 hours), long acting beta agonists (12 hours), ipratropium bromide (12 hours), antihistamines (12 hours), Iong acting bronchodilator combinations (12 hours)
Time frame: Visit 3 (Baseline); Visit 6 (Week 12); Visit 8 (Week 24)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azithromycin | Spirometric Values: Forced Vital Capacity (FVC) | Visit 3(Baseline) | 1.56 Litres | Standard Deviation 0.65 |
| Azithromycin | Spirometric Values: Forced Vital Capacity (FVC) | Visit 6(Week 12) | 1.58 Litres | Standard Deviation 0.63 |
| Azithromycin | Spirometric Values: Forced Vital Capacity (FVC) | Visit 8(Week 24) | 1.55 Litres | Standard Deviation 0.66 |
| Placebo for Azithromycin | Spirometric Values: Forced Vital Capacity (FVC) | Visit 3(Baseline) | 1.69 Litres | Standard Deviation 0.74 |
| Placebo for Azithromycin | Spirometric Values: Forced Vital Capacity (FVC) | Visit 6(Week 12) | 1.60 Litres | Standard Deviation 0.7 |
| Placebo for Azithromycin | Spirometric Values: Forced Vital Capacity (FVC) | Visit 8(Week 24) | 1.58 Litres | Standard Deviation 0.72 |
Comparison: FVC values were compared between Visit 6 (Week 12) and Visit 3 (Baseline), Visit 8 (Week 24) and Visit 3 (Baseline), as well for Visit 8 (Week 24) and Visit 6 (Week 12).~Independent t-test was applied for study end points which were numerical variables.p-value: <0.01t-test, 1 sided
Comparison: FVC values were compared between Visit 6 (Week 12) and Visit 3 (Baseline), Visit 8 (Week 24) and Visit 3 (Baseline), as well for Visit 8 (Week 24) and Visit 6 (Week 12).~Independent t-test was applied for study end points which were numerical variables.p-value: <0.01t-test, 1 sided
Secondary
Spirometry Value; Forced Expiratory Volume at 1 Second (FEV1)
Pulmonary function testing using a spirometer will be carried out at visits 3, 6 and 8 inclusive. All testing should be done in the sitting position, except for obese patients, who commonly obtain deeper inspiration when tested in the standing position. Subjects should avoid the following prior to lung function testing: Smoking within 1 hour of testing Consuming alcohol within 4 hours of testing Performing vigorous exercise within 30 minutes of testing Wearing restrictive clothing around the chest or abdomen Eating a large meal within 2 hours of testing The following medications must be withheld prior to testing, with the minimum time from last dose indicated- short acting beta agonists (6 hours), long acting beta agonists (12 hours), ipratropium bromide (12 hours), antihistamines (12 hours), long acting bronchodilator combinations (12 hours)
Time frame: Visit 3 (Baseline); Visit 6 (Week 12); Visit 8 (Week 24)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azithromycin | Spirometry Value; Forced Expiratory Volume at 1 Second (FEV1) | Visit 3(Baseline) | 1.08 Litres | Standard Deviation 0.41 |
| Azithromycin | Spirometry Value; Forced Expiratory Volume at 1 Second (FEV1) | Visit 6(Week 12) | 1.09 Litres | Standard Deviation 0.4 |
| Azithromycin | Spirometry Value; Forced Expiratory Volume at 1 Second (FEV1) | Visit 8(Week 24) | 1.04 Litres | Standard Deviation 0.37 |
| Placebo for Azithromycin | Spirometry Value; Forced Expiratory Volume at 1 Second (FEV1) | Visit 3(Baseline) | 1.17 Litres | Standard Deviation 0.55 |
| Placebo for Azithromycin | Spirometry Value; Forced Expiratory Volume at 1 Second (FEV1) | Visit 6(Week 12) | 1.10 Litres | Standard Deviation 0.53 |
| Placebo for Azithromycin | Spirometry Value; Forced Expiratory Volume at 1 Second (FEV1) | Visit 8(Week 24) | 1.08 Litres | Standard Deviation 0.49 |
Comparison: FEV1 values were compared between Visit 6 (Week 12) and Visit 3 (Baseline), Visit 8 (Week 24) and Visit 3 (Baseline), as well for Visit 8 (Week 24) and Visit 6 (Week 12).~Independent t-test was applied for study end points which were numerical variables.p-value: <0.01t-test, 1 sided
Comparison: FEV1 values were compared between Visit 6 (Week 12) and Visit 3 (Baseline), Visit 8 (Week 24) and Visit 3 (Baseline), as well for Visit 8 (Week 24) and Visit 6 (Week 12).~Independent t-test was applied for study end points which were numerical variables.p-value: <0.01t-test, 1 sided