Cystic Fibrosis
Conditions
Keywords
Cystic fibrosis (CF), Azithromycin, Tobramycin solution for inhalation (TIS), Pseudomonas aeruginosa (Pa), Early Pseudomonas aeruginosa infection, Pulmonary exacerbation, Standardized anti-pseudomonal therapy
Brief summary
The purpose of this trial is to compare the effects of treatment with tobramycin solution for inhalation (TIS) with and without azithromycin in people with cystic fibrosis (CF) age 6 months to 18 years who have early isolation of Pseudomonas aeruginosa (Pa) from a respiratory culture. Specimens of blood and sputum or throat swabs will be taken during the study along with pulmonary function testing. Participants will receive initial treatment with TIS followed additional treatment with TIS if quarterly respiratory cultures are positive for Pa in addition to either azithromycin or placebo for 18 months.
Detailed description
Cystic fibrosis (CF) lung disease begins in the first few months of life and follows a course of recurrent lower airway bacterial infection and inflammation and progression of disease over years and decades at a variable pace. With the development of chronic lung infection, obstructive disease progressively worsens, ultimately leading to respiratory failure. Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the CF lower airways, and its acquisition early in life is associated with a pro-inflammatory effect, lower lung function, poor nutritional outcomes, and decreased survival. Pseudomonas aeruginosa (Pa) infection of the cystic fibrosis (CF) airway typically proceeds from early infection to chronic infection. Although some studies have shown that a minority of individuals with CF spontaneously clear early Pseudomonas aeruginosa (Pa) infection, data from multiple studies suggest that antibiotics are superior to no treatment in clearing Pseudomonas aeruginosa (Pa) from respiratory cultures. Understanding the transition period from early to chronic Pseudomonas aeruginosa (Pa) infection is thus of critical importance in identifying strategies to prevent this progression. The study will assess the clinical and microbiologic efficacy and safety of azithromycin given three times weekly in combination with standardized tobramycin solution for inhalation (TIS) therapy among children with early Pseudomonas aeruginosa (Pa). TIS therapy is defined as an initial eradication treatment with 1-2 courses of 28 days TIS and subsequent 28 day treatments only at times a quarterly respiratory culture is positive for Pseudomonas aeruginosa (Pa). Eligible participants will be randomized within one month of their Pseudomonas aeruginosa (Pa) positive culture to receive one of the following two treatment strategies for 18 months: (1) oral placebo in addition to standardized TIS therapy, or (2) oral azithromycin in addition to standardized TIS therapy. At the first study visit, participants will undergo a physical examination and a review of their medical history. Lung function will be measured via spirometry (in children greater than four years of age who are able to perform spirometry), electrocardiogram (ECG) testing will be conducted, and hearing ability will be measured via audiometry. Blood will be drawn for laboratory tests and a specimen will be obtained for a respiratory culture before randomization and study drug dispensing occurs. Subsequent study visits will take place at Day 21, Weeks 13, 26, 39, 52, 65, and 78. At each visit, participants will undergo a physical examination, a spirometry test (as appropriate), a respiratory specimen for Pseudomonas aeruginosa (Pa) culture will be collected and study drug will be dispensed (except at Week 78). Participants will complete self-report or parent-completed respiratory symptom questionnaires and signs and symptoms evaluations will be performed at all visits. Repeat hearing and laboratory tests will be performed at Weeks 39 and 78 and ECG testing will be repeated at Day 21 and Week 78. Participants will be required to maintain a medication diary throughout the study.
Interventions
DRUGazithromycin
3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months
DRUGplacebo
3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months
300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Bonnie Ramsey
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥ 6 months to ≤ 18 years * Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype or positive CF Newborn Screening result for immunoreactive trypsinogen (IRT) IRT/DNA or IRT/IRT and one or more of the following criteria: * sweat chloride ≥ 60 milliequivalent (mEq)/liter by quantitative by pilocarpine iontophoresis test (QPIT) * two well-characterized mutations in the cystic fibrosis transmembrane conductive regulator (CFTR) gene * Abnormal nasal potential difference (NPD) (change in NPD in response to a low chloride solution and isoproteronol of less than - 5 mV) * Documented new positive oropharyngeal, sputum or lower respiratory tract culture for Pa within 30 days of the Baseline Visit (Visit 1), defined as: a) first lifetime documented Pa positive culture; or b) Pa recovered after at least a two-year history of Pa negative respiratory cultures (≥ 1 culture/ year) * Clinically stable with no evidence of any significant respiratory symptoms at the Baseline Visit that would require administration of intravenous anti- pseudomonal antibiotics, oxygen supplementation, and/or hospitalization as determined by the study physician * Written informed consent obtained from participant or participant's legal representative (and assent when applicable) and ability for participant to comply with the requirements of the study
Exclusion criteria
* Macrolide antibiotic use within 30 days of the Baseline Visit * Initiation of current course of treatment with TIS \>14 days prior to Baseline Visit * Weight \<6.0 kg at the Baseline Visit * History of aminoglycoside hypersensitivity or adverse reaction to inhaled aminoglycoside * History of azithromycin hypersensitivity or adverse reaction to azithromycin or allergy to macrolide antibiotics * History of positive respiratory culture for Non-tuberculous mycobacteria (NTM) or Burkholderia cepacia complex within 2 years of the Baseline Visit * History of unresolved, abnormal renal function (defined as serum creatinine greater than 1.5 times the upper limit of normal for age). * History of unresolved, abnormal liver function tests (defined as alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than 4 times the upper limit of normal range) or history of portal hypertension * History of unresolved, abnormal neutropenia (ANC ≤ 1000) * Abnormal ECG test at the Baseline Visit defined as a QT interval corrected (QTc) (B) of ≥460 msec or history of ventricular arrhythmia * History of abnormal hearing sensitivity defined as hearing threshold levels \>25 dB HL (decibels Hearing Level) for visual reinforcement audiometry (VRA) at any frequency (500-4000Hz) or \>20 Decibels Hearing Level (dBHL) for play or standard audiometry at any two frequencies (500-8000Hz) in either ear, not associated with middle ear disease (including infection) or a flat (Type B) tympanogram * New initiation of chronic therapy (greater than 21 days) with drugs known to prolong QT interval (refer to Appendix III) within 30 days prior to the Baseline Visit or coadministration of nelfinavir or oral anticoagulants * Positive serum or urine pregnancy test at the Baseline Visit (to be performed on all females of child-bearing potential) or for females of child bearing potential: pregnant, breastfeeding, or unwilling to use barrier contraception during participation in the study * Administration of any investigational drug within 30 days prior to the Baseline Visit * Presence of a condition or abnormality (e.g., pre-existing heart disease) that in the opinion of the site investigator would compromise the safety of the participant or the quality of the data
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to a Protocol-defined Pulmonary Exacerbation | Over the 18-month study period | Time to a protocol-defined pulmonary exacerbation requiring oral, inhaled, or intravenous antibiotics, using a prespecified definition available in the study protocol. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Pseudomonas Aeruginosa (Pa) Recurrence | Over the 18-month study period | Time to Pseudomonas aeruginosa (Pa) recurrence after the first quarter of treatment |
| Adverse Events (AEs) and Serious Adverse Events (SAEs) | Over the 18-month study period | The number and percentage of participants with at least one event over the 18-month study period. |
| Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Over the 18-month study period | Rate is defined as the number of events per participant follow-up month. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azithromycin azithromycin and tobramycin solution for inhalation (TIS) Azithromycin 3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months Tobramycin solution for inhalation (TIS), 300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months
azithromycin: 3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months
Tobramycin solution for inhalation: 300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months | 110 |
| Placebo placebo and tobramycin solution for inhalation (TIS) Placebo 3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months Tobramycin solution for inhalation (TIS), 300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months
placebo: 3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months
Tobramycin solution for inhalation: 300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months | 111 |
| Total | 221 |
Baseline characteristics
| Characteristic | Azithromycin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 7.1 years STANDARD_DEVIATION 5.1 | 6.8 years STANDARD_DEVIATION 5 | 6.9 years STANDARD_DEVIATION 5 |
| Age, Customized Age Distribution > 12 years | 19 Participants | 18 Participants | 37 Participants |
| Age, Customized Age Distribution > 3 years - 6 years | 22 Participants | 23 Participants | 45 Participants |
| Age, Customized Age Distribution >= 6 months - 3 years | 39 Participants | 41 Participants | 80 Participants |
| Age, Customized Age Distribution > 6 years - 12 years | 30 Participants | 29 Participants | 59 Participants |
| Cystic Fibrosis (CF) Genotype F508 del Heterozygous | 35 Participants | 44 Participants | 79 Participants |
| Cystic Fibrosis (CF) Genotype F508 del Homozygous | 59 Participants | 57 Participants | 116 Participants |
| Cystic Fibrosis (CF) Genotype Not Available | 5 Participants | 1 Participants | 6 Participants |
| Cystic Fibrosis (CF) Genotype Other | 11 Participants | 9 Participants | 20 Participants |
| Cystic Fibrosis (CF) Genotype Unidentified | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian or Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African-American | 4 Participants | 6 Participants | 10 Participants |
| Race/Ethnicity, Customized Race Hispanic or Latino | 5 Participants | 10 Participants | 15 Participants |
| Race/Ethnicity, Customized Race Unknown/Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 100 Participants | 94 Participants | 194 Participants |
| Region of Enrollment United States | 110 participants | 111 participants | 221 participants |
| Sex: Female, Male Female | 55 Participants | 49 Participants | 104 Participants |
| Sex: Female, Male Male | 55 Participants | 62 Participants | 117 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 110 | 0 / 111 |
| other Total, other adverse events | 99 / 110 | 92 / 111 |
| serious Total, serious adverse events | 25 / 110 | 28 / 111 |
Outcome results
Primary
Time to a Protocol-defined Pulmonary Exacerbation
Time to a protocol-defined pulmonary exacerbation requiring oral, inhaled, or intravenous antibiotics, using a prespecified definition available in the study protocol.
Time frame: Over the 18-month study period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azithromycin | Time to a Protocol-defined Pulmonary Exacerbation | 1.350 years |
| Placebo | Time to a Protocol-defined Pulmonary Exacerbation | 0.758 years |
p-value: 0.004395% CI: [0.37, 0.83]Cox Proportional Hazards Model
Secondary
Adverse Events (AEs) and Serious Adverse Events (SAEs)
The number and percentage of participants with at least one event over the 18-month study period.
Time frame: Over the 18-month study period
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Azithromycin | Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of Participants with AE | 102 Participants |
| Azithromycin | Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of Participants with SAE | 25 Participants |
| Placebo | Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of Participants with AE | 98 Participants |
| Placebo | Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of Participants with SAE | 28 Participants |
p-value: 0.753195% CI: [-13.7, 8.7]Fisher Exact
p-value: 0.359395% CI: [-3.5, 12.6]Fisher Exact
Secondary
Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Rate is defined as the number of events per participant follow-up month.
Time frame: Over the 18-month study period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azithromycin | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of AEs per participant month | 0.92 events per participant-month |
| Azithromycin | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of SAEs per participant month | 0.06 events per participant-month |
| Placebo | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of AEs per participant month | 1.06 events per participant-month |
| Placebo | Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of SAEs per participant month | 0.05 events per participant-month |
Comparison: Rate Ratio for Adverse Events calculated using Poisson Regression with an offset for the log of follow-up time in months. The total number of follow-up months of all participants (not per participant) in the trial was as follows: in the Azithromycin group was 1267.73 and in the Placebo group was 1193.72.p-value: 0.000495% CI: [0.8, 0.94]Poisson Regression
Comparison: Rate Ratio for Serious Adverse Events calculated using Poisson Regression with an offset for the log of follow-up time in months. The total number of follow-up months of all participants (not per participant) in the trial was as follows: in the Azithromycin group was 1267.73 and in the Placebo group was 1193.72.p-value: 0.209895% CI: [0.88, 1.78]Poisson Regression
Secondary
Time to Pseudomonas Aeruginosa (Pa) Recurrence
Time to Pseudomonas aeruginosa (Pa) recurrence after the first quarter of treatment
Time frame: Over the 18-month study period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azithromycin | Time to Pseudomonas Aeruginosa (Pa) Recurrence | 1.51 years |
| Placebo | Time to Pseudomonas Aeruginosa (Pa) Recurrence | 1.46 years |
p-value: 0.991595% CI: [0.64, 1.55]Cox Proportional Hazards Model