Testing the Effect of Adding Chronic Oral Azithromycin to Inhaled Tobramycin in People With Cystic Fibrosis (CF)

Study Overview
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Brief Summary
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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
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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.

Official Title
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TEACH Trial: Testing the Effect of Adding CHronic Azithromycin to Inhaled Tobramycin. A Randomized, Placebo-controlled, Double-blinded Trial of Azithromycin 500mg Thrice Weekly in Combination With Inhaled Tobramycin

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: azithromycin
* Drug: placebo (for azithromycin)
* Drug: inhaled tobramycin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: azithromycin<br>azithromycin 500mg tablet over-encapsulated to match placebo in appearance, taken by mouth thrice weekly for 6 weeks | Drug: azithromycin<br>* 500mg tablet over-encapsulated to match placebo<br>* Other names: Zithromax;Drug: inhaled tobramycin<br>* clinically prescribed inhaled tobramycin used by subjects participating in the study<br>|
| Placebo Comparator: placebo<br>encapsulated placebo taken by mouth thrice weekly for 6 weeks | Drug: placebo (for azithromycin)<br> <br> Drug: inhaled tobramycin<br>* clinically prescribed inhaled tobramycin used by subjects participating in the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | baseline (week 0) to week 6 (6 week period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | week 2 to week 6 (4 week period) | 
| 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. | baseline (week 0) to week 6 (6 week period) | 
| 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. | baseline (week 0) to week 6 (6 week period) |