Cystic Fibrosis
Conditions
Brief summary
This is a study to examine the effect of combining chronic oral azithromycin with inhaled tobramycin in adolescent and adult subjects with cystic fibrosis who are chronically infected with P. aeruginosa.
Detailed description
This study is a prospective, randomized, double-blinded, placebo-controlled trial of azithromycin 500mg taken orally thrice weekly vs. placebo in subjects with cystic fibrosis and chronic airway infection with P. aeruginosa who are utilizing chronic inhaled tobramycin therapy. It will include approximately 120 subjects able to complete a primary 6-week study phase. Subjects will be at least 12 years old with a baseline forced expiratory volume at one second (FEV1) between 25-100% predicted. Subjects will continue to use clinically prescribed inhaled tobramycin cycled on/off every 4 weeks. They will be provided over-encapsulated azithromycin 500mg tablets or placebo during the primary study phase. An optional extension phase will be offered to all subjects completing the primary 6-week study. This 8-week extension phase will include an initial 4 weeks without use of inhaled tobramycin or other inhaled antibiotics, followed by a 4-week period with inhaled tobramycin use. All subjects participating in the extension phase of the study will be provided azithromycin 500mg tablets to be taken thrice weekly for the entire 8-week period. This study will investigate how use of chronic oral azithromycin affects some of the previously demonstrated benefits to health when using inhaled tobramycin. The primary measurements will focus on lung function. Additional measurements will focus on disease-related quality of life as reported by subjects in the trial. Exploratory outcomes, including measurements of safety, are also planned.
Interventions
DRUGazithromycin
500mg tablet over-encapsulated to match placebo
DRUGplacebo (for azithromycin)
clinically prescribed inhaled tobramycin used by subjects participating in the study
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Cystic Fibrosis Foundation
CF Therapeutics Development Network Coordinating Center
Seattle Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 12 years old or older * documented diagnosis of cystic fibrosis * written informed consent (and assent when applicable) * at least two respiratory cultures growing P. aeruginosa within the last 12 months * FEV1% predicted between 25-100% * use of at least two cycles of inhaled tobramycin within the last 24 weeks * Off TISP and other inhaled anti-pseudomonal antibiotics for at least 2 weeks at Visit 1 and remain off of any inhaled antibiotics for an additional 2 weeks before starting inhaled tobramycin * most recent liver function test results less than 4 times the upper limit of normal, obtained within the last 12 months * prior or current use of azithromycin for at least four consecutive weeks * stable clinical status and therapeutic regimen
Exclusion criteria
* weight \<40 kg * positive pregnancy test, lactating, or unwillingness to practice a pre-defined form of contraception, which includes abstinence * inability to perform reproducible spirometry * inability or unwillingness to cycle off of inhaled tobramycin for one 4-week period and without use of any additional inhaled antibiotics * respiratory culture with Burkholderia cepacia complex species within 24 months or with nontuberculous mycobacteria within 18 months of screening * use of intravenous or oral anti-pseudomonal antibiotics within 4 weeks of screening * use of investigational therapy within 4 weeks of screening * use of systemic corticosteroids equivalent to a daily dose more than 10mg of prednisone * use of nelfinavir, warfarin, haloperidol, or methadone (concern of drug interaction with azithromycin) * initiation of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy within 30 days * ECG abnormality at screening requiring prompt further medical attention, or QTc interval \>480 msec for males and \>486 msec for females * any other condition that, in the opinion of the site investigator, would compromise the safety of the subject or quality of the data
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change in Lung Function | baseline (week 0) to week 6 (6 week period) | Relative change in FEV1 volume (L) from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change in Lung Function | week 2 to week 6 (4 week period) | Relative change in FEV1 (L) from the beginning of the 4-week period with inhaled tobramycin at week 2 to the end of the 4-week period with inhaled tobramycin at week 6 |
| Change in Cystic Fibrosis Respiratory Symptom Diary - Chronic Respiratory Infection Symptom Score (CFRSD-CRISS) | baseline (week 0) to week 6 (6 week period) | Absolute change in CFRSD-CRISS from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6. The Cystic Fibrosis Respiratory Symptoms Diary asks a participant to state the extent of 8 respiratory symptoms: difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest, and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present a great deal or extremely. A summed score (ranging from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where lower scores indicate improvement of symptoms. |
| Change in Cystic Fibrosis Questionnaire - Revised Respiratory Symptom Score (CFQ-R RSS) | baseline (week 0) to week 6 (6 week period) | Absolute change in the CFQ-R RSS from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6. Age appropriate versions of Cystic Fibrosis Questionnaire - Revised ask a participant from 4 to 6 questions related to respiratory symptoms. The Respiratory Domain Scaled Score is calculated as follows: 100\*\[sum of {responses-1}\] / \[{number of responses}\*3\] only if \[number of responses\] ≥ \[number of possible responses\]/2; otherwise the score is set to missing. The scaled score ranges from 0 to 100 and higher scores indicate improvement of symptoms. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Sputum Pseudomonas Aeruginosa Bacterial Density | baseline (week 0) to week 6 (6 week period) | Absolute change in log10 transformed quantitative Pseudomonas aeruginosa (Pa) bacterial density as measured by colony forming units (CFUs) per mL of sputum from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6. Culture results below the lower limit of detection of 1x10\^2 were set to 1/2 of that LLD prior to log transformation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azithromycin azithromycin 500mg tablet over-encapsulated to match placebo in appearance, taken by mouth thrice weekly for 6 weeks
azithromycin: 500mg tablet over-encapsulated to match placebo
inhaled tobramycin: clinically prescribed inhaled tobramycin used by subjects participating in the study | 61 |
| Placebo encapsulated placebo taken by mouth thrice weekly for 6 weeks
placebo (for azithromycin)
inhaled tobramycin: clinically prescribed inhaled tobramycin used by subjects participating in the study | 54 |
| Total | 115 |
Baseline characteristics
| Characteristic | Placebo | Azithromycin | Total |
|---|---|---|---|
| Age, Continuous | 26.5 years STANDARD_DEVIATION 9.7 | 26.1 years STANDARD_DEVIATION 9.9 | 26.3 years STANDARD_DEVIATION 9.8 |
| Age, Customized Age Distribution ≥ 12 to < 18 years | 12 Participants | 14 Participants | 26 Participants |
| Age, Customized Age Distribution ≥ 18 to < 30 years | 25 Participants | 28 Participants | 53 Participants |
| Age, Customized Age Distribution ≥ 30 years | 17 Participants | 19 Participants | 36 Participants |
| Current Tobramycin Formulation Tobramycin Inhaled Powder | 26 Participants | 28 Participants | 54 Participants |
| Current Tobramycin Formulation Tobramycin Inhaled Solution | 28 Participants | 33 Participants | 61 Participants |
| Cystic Fibrosis (CF) Genotype Delta F508 Heterozygous | 11 Participants | 17 Participants | 28 Participants |
| Cystic Fibrosis (CF) Genotype Delta F508 Homozygous | 35 Participants | 38 Participants | 73 Participants |
| Cystic Fibrosis (CF) Genotype Not Available | 1 Participants | 0 Participants | 1 Participants |
| Cystic Fibrosis (CF) Genotype Other | 7 Participants | 6 Participants | 13 Participants |
| Cystic Fibrosis (CF) Genotype Unidentified | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 9 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 52 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| FEV1 | 2.50 liters STANDARD_DEVIATION 0.85 | 2.59 liters STANDARD_DEVIATION 0.81 | 2.55 liters STANDARD_DEVIATION 0.83 |
| History of Azithromycin Use at Baseline Current User | 43 Participants | 51 Participants | 94 Participants |
| History of Azithromycin Use at Baseline Non-Current User | 11 Participants | 10 Participants | 21 Participants |
| ppFEV1 Category ≥ 25% to < 50% | 11 Participants | 11 Participants | 22 Participants |
| ppFEV1 Category ≥ 50% to < 75% | 16 Participants | 22 Participants | 38 Participants |
| ppFEV1 Category ≥ 75% | 27 Participants | 28 Participants | 55 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 49 Participants | 55 Participants | 104 Participants |
| Region of Enrollment United States | 54 participants | 61 participants | 115 participants |
| Sex: Female, Male Female | 26 Participants | 29 Participants | 55 Participants |
| Sex: Female, Male Male | 28 Participants | 32 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 54 |
| other Total, other adverse events | 22 / 61 | 32 / 54 |
| serious Total, serious adverse events | 4 / 61 | 3 / 54 |
Outcome results
Primary
Relative Change in Lung Function
Relative change in FEV1 volume (L) from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6
Time frame: baseline (week 0) to week 6 (6 week period)
Population: Participants in the m-ITT population with spirometry measurements of FEV1 liters at both baseline (week 0) and week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin | Relative Change in Lung Function | 1.69 percent change | Standard Deviation 10.39 |
| Placebo | Relative Change in Lung Function | -1.95 percent change | Standard Deviation 10.73 |
p-value: 0.084695% CI: [-0.48, 7.35]Regression, Linear
Secondary
Change in Cystic Fibrosis Questionnaire - Revised Respiratory Symptom Score (CFQ-R RSS)
Absolute change in the CFQ-R RSS from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6. Age appropriate versions of Cystic Fibrosis Questionnaire - Revised ask a participant from 4 to 6 questions related to respiratory symptoms. The Respiratory Domain Scaled Score is calculated as follows: 100\*\[sum of {responses-1}\] / \[{number of responses}\*3\] only if \[number of responses\] ≥ \[number of possible responses\]/2; otherwise the score is set to missing. The scaled score ranges from 0 to 100 and higher scores indicate improvement of symptoms.
Time frame: baseline (week 0) to week 6 (6 week period)
Population: Participants in the m-ITT population with CFQ-R respiratory symptom scores at both baseline (week 0) and week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin | Change in Cystic Fibrosis Questionnaire - Revised Respiratory Symptom Score (CFQ-R RSS) | 1.0 score on a scale | Standard Deviation 14 |
| Placebo | Change in Cystic Fibrosis Questionnaire - Revised Respiratory Symptom Score (CFQ-R RSS) | -0.5 score on a scale | Standard Deviation 12.5 |
p-value: 0.5695% CI: [-3.7, 6.77]Regression, Linear
Secondary
Change in Cystic Fibrosis Respiratory Symptom Diary - Chronic Respiratory Infection Symptom Score (CFRSD-CRISS)
Absolute change in CFRSD-CRISS from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6. The Cystic Fibrosis Respiratory Symptoms Diary asks a participant to state the extent of 8 respiratory symptoms: difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest, and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present a great deal or extremely. A summed score (ranging from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where lower scores indicate improvement of symptoms.
Time frame: baseline (week 0) to week 6 (6 week period)
Population: Participants in the m-ITT population with CFRSD-CRISS diaries at both baseline (week 0) and week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin | Change in Cystic Fibrosis Respiratory Symptom Diary - Chronic Respiratory Infection Symptom Score (CFRSD-CRISS) | -2.3 score on a scale | Standard Deviation 11.4 |
| Placebo | Change in Cystic Fibrosis Respiratory Symptom Diary - Chronic Respiratory Infection Symptom Score (CFRSD-CRISS) | 0.6 score on a scale | Standard Deviation 9.8 |
p-value: 0.1795% CI: [-7.01, 1.22]Regression, Linear
Secondary
Relative Change in Lung Function
Relative change in FEV1 (L) from the beginning of the 4-week period with inhaled tobramycin at week 2 to the end of the 4-week period with inhaled tobramycin at week 6
Time frame: week 2 to week 6 (4 week period)
Population: Participants in the m-ITT population with spirometry measurements of FEV1 liters at both week 2 and week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin | Relative Change in Lung Function | 0.44 percent change | Standard Deviation 8.86 |
| Placebo | Relative Change in Lung Function | -0.91 percent change | Standard Deviation 11.41 |
p-value: 0.5195% CI: [-2.64, 5.26]Regression, Linear
Other Pre-specified
Change in Sputum Pseudomonas Aeruginosa Bacterial Density
Absolute change in log10 transformed quantitative Pseudomonas aeruginosa (Pa) bacterial density as measured by colony forming units (CFUs) per mL of sputum from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6. Culture results below the lower limit of detection of 1x10\^2 were set to 1/2 of that LLD prior to log transformation.
Time frame: baseline (week 0) to week 6 (6 week period)
Population: Participants in the m-ITT population with Pseudomonas aeruginosa sputum culture results at both baseline (week 0) and week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azithromycin | Change in Sputum Pseudomonas Aeruginosa Bacterial Density | 0.3 log10(CFUs/mL) | Standard Deviation 1.7 |
| Placebo | Change in Sputum Pseudomonas Aeruginosa Bacterial Density | -0.5 log10(CFUs/mL) | Standard Deviation 1.2 |
p-value: 0.04395% CI: [0.03, 1.47]Regression, Linear