Cystic Fibrosis
Conditions
Keywords
aztreonam lysine, tobramycin inhalation solution, tobramycin nebuliser solution, cystic fibrosis, pseudomonas aeruginosa, lung infection, CFQ-R, inhaled antibiotic
Brief summary
The purpose of this study was to assess the comparative safety and effectiveness of aztreonam for inhalation solution versus tobramycin inhalation solution in adult and pediatric patients with cystic fibrosis (CF) and pulmonary Pseudomonas aeruginosa (PA) infection.
Detailed description
Number of Subjects Planned: Approximately 240 randomized patients Target Population: CF patients \>= 6 years of age with stable pulmonary disease, who at study entry had a recent positive sputum culture for PA and had been previously treated with aerosolized antibiotics without demonstration of drug intolerance. The randomized phase of this study, used for hypotheses testing, enrolled participants from both the United States (US) and EU. An open-label, single-arm extension was available for participants in the EU who completed at least one course of AZLI or TIS during the randomized portion of the study. These participants were eligible to receive 3 additional cycles of AZLI in a 28-day, intermittent, repeating treatment regimen. Results of the extension phase will be available the first quarter (Q1) of 2012. Randomized Phase Study Design (US and EU): This was an open-label, multicenter, randomized, parallel group study. The study design consisted of 2 treatment arms of 28-day, intermittent, repeating treatment regimens: aztreonam for inhalation solution (AZLI) or tobramycin inhalation solution (TIS). The total study period was 26 weeks. The study schedule included 9 visits - Screening, Baseline, Day 14, Day 28, followed by visits every 28 days through the end of the study.
Interventions
DRUGTobramycin Inhalation Solution (TIS)
Tobramycin inhalation solution (300 mg) was administered 2 times a day (BID) for 28 days for each treatment cycle via the PARI LC Plus nebulizer with compressor or via another nebulizer compatible with country-specified labeling.
Aztreonam for inhalation solution (75 mg) was administered 3 times a day (TID) for 28 days for each treatment cycle via the PARI eFlow electronic nebulizer.
Sponsors
Chiltern International Inc.
ClinPhone, Inc.
Covance
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females aged 6 years and older * Subjects with CF as diagnosed by one of the following: documented sweat chloride \>= 60 mEq/L by quantitative pilocarpine iontophoresis test, or documented sweat sodium \>= 60 mmol/L, or 2 well characterized genetic mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, or abnormal nasal potential difference with accompanying symptoms characteristic of CF * Documented PA in an expectorated sputum or throat swab culture within 3 months prior to Visit 1 or at Visit 1 * Subjects must be able to provide written informed consent/assent prior to any study related procedures; parent/guardian must be able to give written informed consent as necessary prior to any study related procedure * Subjects must have received previous treatment with aerosolized antibiotics without demonstration of drug intolerance * FEV1 \<= 75% predicted at Visit 1 * Ability to perform reproducible pulmonary function tests * Chest radiograph at Visit 1 without significant acute findings (eg, infiltrates \[lobar or diffuse interstitial\], pleural effusion, pneumothorax); or chest radiograph or magnetic resonance image (MRI) obtained within the 180 days prior to Visit 1 without acute findings and no significant intercurrent illness; chronic, stable findings (eg, chronic scarring or atelectasis) are allowed
Exclusion criteria
* Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone a day or 20 mg prednisone every other day * History of sputum or throat swab culture yielding B. cepacia in the previous 2 years * Current requirement for daily continuous oxygen supplementation or requirement for more than 2 L/minute at night * Administration of any investigational drug or device within 28 days of Visit 1 or within 6 half-lives of the investigational drug (whichever is longer) * Known local or systemic hypersensitivity to monobactam antibiotics * Known allergies/intolerance to tobramycin * Inability to tolerate inhalation of a short acting beta agonist * Changes in or initiation of chronic azithromycin treatment within 28 days prior to Visit 1 * Administration of antipseudomonal antibiotics by inhalation, intravenous or oral routes within the 14 days prior to Randomization/Visit 2 * Changes in antimicrobial, bronchodilator (BD), dornase alfa, or corticosteroid medications within 7 days prior to Visit 1 * Changes in physiotherapy technique or schedule within 7 days prior to Visit 1 * History of lung transplantation * Abnormal renal or hepatic function or serum chemistry at Visit 1, defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT) \> 5 times upper limit of normal range (ULN) or creatinine \> 2 times ULN * Positive pregnancy test at Visit 1; all women of childbearing potential will be tested * Female of childbearing potential who is lactating or is not (in the opinion of the investigator) practicing an acceptable method of birth control; female subjects who utilize hormonal contraceptives as one of their birth control methods must have used the same method for at least 3 months before study dosing * Any serious or active medical or psychiatric illness, which in the opinion of the investigator, would interfere with patient treatment, assessment, or compliance with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted at Day 28 | Baseline and end of treatment Course 1 (Day 28) | Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested using an analysis of covariance (ANCOVA) model-based method. |
| Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses | Baseline, and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20) | Spirometry was performed according to ATS guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the average adjusted means for the actual change in FEV1 percent predicted at Visits 4, 6, and 8 (Weeks 4, 12, and 20) was tested by mixed-effect model repeated measures (MMRM) analysis using the ITT population analysis set. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in FEV1 Percent Predicted at Day 28 in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization | Baseline and end of treatment Course 1 (Day 28) | Spirometry was performed according to ATS guidelines. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested using an ANCOVA model-based method, using the population of participants with prior inhaled tobramycin use of \>= 84 days in the previous 12 months. |
| Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization | Baseline and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20) | Spirometry was performed according to ATS guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the average adjusted means for the actual change in FEV1 percent predicted at Visits 4, 6, and 8 (Weeks 4, 12, and 20) was tested by MMRM analysis using the population of participants with prior inhaled tobramycin use of \>=84 days in the previous 12 months. |
| Time to Need for Intravenous (IV) Antipseudomonal Antibiotics for Respiratory Events | Day 0 to Day 168 (end of study) | IV antipseudomonal antibiotic use for a respiratory event was determined through the adjudication of events by a sponsor-independent, blinded review committee. Use was compiled from data recorded on the concomitant medications electronic case report form (eCRF) and compared to reported adverse events (AEs) to determine use for a respiratory event. The time to IV antipseudomonal antibiotic use was measured in days from baseline (Visit 2) to the date of first IV antipseudomonal antibiotic use or the date of study completion (last visit)/or early withdrawal if censored. |
| Time to First Respiratory Hospitalization | Day 0 to Day 168 (end of study) | This endpoint was determined through the adjudication of events by a sponsor-independent, blinded review committee. Committee members reviewed all hospitalizations and determined which were related to respiratory events. Details of all hospitalizations, including the dates of admission and discharge, were recorded on the serious adverse event (SAE) eCRF. Time to first respiratory hospitalization was the number of days from baseline (Visit 2) to the date of first respiratory hospitalization or the date of study completion (last visit) /or early withdrawal if censored. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Actual Change From Baseline in CF Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28 | Baseline and end of treatment Course 1 (Day 28) | The CFQ-R is a validated patient-reported outcome tool measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from baseline, assessed with the CFQ-R RSS (range of scores \[units\]: 0-100; higher scores indicate fewer symptoms). |
| Mean Actual Change From Baseline in CFQ-R RSS Score Across 3 Treatment Courses | Baseline and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20) | The CFQ-R is a validated patient-reported outcome tool measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The endpoint was the average actual change in respiratory symptoms (e.g., coughing, congestion, wheezing) from baseline, assessed with the CFQ-R RSS (range of scores \[units\]: 0-100; higher scores indicate fewer symptoms) at the end of each treatment course (Weeks 4, 12, and 20). |
| Treatment Satisfaction Questionnaire for Medication (TSQM) - Global Satisfaction Results at Week 20 | At Week 20 | This 14 item questionnaire consists of 3 subscales that gauge participant perceptions of a medication's effectiveness, side effects, and convenience. The measure also contains a global satisfaction scale to evaluate overall participant satisfaction. The global satisfaction score is the endpoint reported here. The range of scores is 0 to 100, with higher scores indicating greater satisfaction. |
| Total Number of Respiratory Hospitalizations | Day 0 to Day 168 (end of study) | Respiratory hospitalizations were determined through the adjudication of events by a sponsor-independent, blinded review committee. Committee members reviewed hospitalizations and determined which were related to respiratory events. |
| Number of Respiratory Events Requiring IV and/or Inhaled Antipseudomonal Antibiotics (Other Than Randomized Treatment) | Day 0 through Day 168 (end of study) | Inhaled and/or IV antipseudomonal antibiotic use for respiratory event was determined through event adjudication by a sponsor-independent, blinded review committee. Use of IV and/or inhaled antipseudomonal antibiotics was compiled from data recorded on the concomitant medications eCRF and compared to reported AEs to determine use for a respiratory event. The time to IV and/or inhaled antipseudomonal antibiotic use was measured in days from baseline (Visit 2) to the date of first antipseudomonal antibiotic use or the date of study completion (last visit)/or early withdrawal if censored. |
| Time to Need for Inhaled and/or IV Antipseudomonal Antibiotics for Respiratory Event (Other Than Randomized Treatment) | Day 0 to Day 168 (end of study) | Antipseudomonal antibiotic use for respiratory event was determined through event adjudication by a sponsor-independent, blinded review committee. Use of IV and/or inhaled antibiotics for a respiratory event was compiled from data recorded on the concomitant medications eCRF and compared to reported AEs to determine use for a respiratory event. The time to antibiotic use for a respiratory event was measured in days from baseline (Day 0) to the date of first antibiotic use for a respiratory event or the date of study completion (last visit)/or early withdrawal if censored. |
Countries
Austria, Belgium, Denmark, France, Germany, Ireland, Italy, Netherlands, Portugal, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Seventy-three sites in the United States (US) and European Union (EU) enrolled a total of 274 participants in the study.
Pre-assignment details
Of the 274 participants enrolled in the study, 273 were randomized between 07 August 2008 and 12 November 2009. One subject experienced a serious adverse event (SAE) between Visits 1 and 2; this subject did not receive study drug. A total of 268 participants received study drug (136 AZLI; 132 TIS).
Participants by arm
| Arm | Count |
|---|---|
| AZLI (75 mg TID) AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent \[0.17% saline\]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg). AZLI was self-administered by inhalation three times a day (TID) for 28 days for each treatment cycle using the investigational nebulizer. | 136 |
| TIS (300 mg BID) TIS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) for 28 days for each treatment cycle using the PARI LC PLUS(TM) Nebulizer with Compressor. | 132 |
| Total | 268 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 0 | 2 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Safety or Tolerability | 3 | 5 |
| Overall Study | Withdrawal by Subject | 8 | 12 |
Baseline characteristics
| Characteristic | AZLI (75 mg TID) | TIS (300 mg BID) | Total |
|---|---|---|---|
| Age Categorical > 12 years to < 18 years | 20 participants | 26 participants | 46 participants |
| Age Categorical >= 18 years | 108 participants | 101 participants | 209 participants |
| Age Categorical >= 6 years to <= 12 years | 8 participants | 5 participants | 13 participants |
| Age Continuous | 25.8 years STANDARD_DEVIATION 9.1 | 25.1 years STANDARD_DEVIATION 9 | 25.5 years STANDARD_DEVIATION 9 |
| Body Mass Index (BMI) | 20.22 kg/m^2 STANDARD_DEVIATION 2.95 | 20.49 kg/m^2 STANDARD_DEVIATION 2.82 | 20.35 kg/m^2 STANDARD_DEVIATION 2.88 |
| Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score | 62.87 units on a scale STANDARD_DEVIATION 20.42 | 58.02 units on a scale STANDARD_DEVIATION 20.76 | 60.44 units on a scale STANDARD_DEVIATION 20.69 |
| Disease Severity <= 50% predicted | 60 participants | 57 participants | 117 participants |
| Disease Severity > 50% predicted | 76 participants | 75 participants | 151 participants |
| Forced Expiratory Volume (FEV1) Percent Predicted | 52.30 percent STANDARD_DEVIATION 15.56 | 52.24 percent STANDARD_DEVIATION 14.57 | 52.27 percent STANDARD_DEVIATION 15.06 |
| Inhaled Tobramycin Use in the Previous 12 Months < 84 days | 21 participants | 19 participants | 40 participants |
| Inhaled Tobramycin Use in the Previous 12 Months >= 84 days | 115 participants | 113 participants | 228 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 130 Participants | 131 Participants | 261 Participants |
| Region of Enrollment Europe | 92 participants | 82 participants | 174 participants |
| Region of Enrollment United States | 44 participants | 50 participants | 94 participants |
| Sex: Female, Male Female | 68 Participants | 66 Participants | 134 Participants |
| Sex: Female, Male Male | 68 Participants | 66 Participants | 134 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 128 / 136 | 127 / 132 |
| serious Total, serious adverse events | 42 / 136 | 44 / 132 |
Outcome results
Primary
Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses
Spirometry was performed according to ATS guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the average adjusted means for the actual change in FEV1 percent predicted at Visits 4, 6, and 8 (Weeks 4, 12, and 20) was tested by mixed-effect model repeated measures (MMRM) analysis using the ITT population analysis set.
Time frame: Baseline, and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
Population: Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI (75 mg TID) | Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses | 2.05 actual change in FEV1 percent predicted | Standard Error 0.69 |
| TIS (300 mg BID) | Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses | -0.66 actual change in FEV1 percent predicted | Standard Error 0.72 |
Comparison: Null hypothesis: there was no difference between AZLI and TIS treatment groups in the mean actual change of FEV1 percent predicted across 3 treatment courses among all participants.~With 120 subjects per treatment group, there was at least 90% power at a 5% significance level to detect differences based upon actual change from baseline in FEV1 percent predicted (3.61%, 2.98%, 2.32%) between AZLI and TIS at Weeks 4, 12, and 20 with a common standard deviation of 9%.p-value: 0.0023MMRM analysis
Primary
Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted at Day 28
Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested using an analysis of covariance (ANCOVA) model-based method.
Time frame: Baseline and end of treatment Course 1 (Day 28)
Population: Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). The last observation carried forward (LOCF) method was used to impute missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI (75 mg TID) | Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted at Day 28 | 8.35 percent change in FEV1 percent predicted | Standard Error 1.7 |
| TIS (300 mg BID) | Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted at Day 28 | 0.55 percent change in FEV1 percent predicted | Standard Error 1.77 |
Comparison: Null hypothesis: AZLI was inferior to TIS by more than 4% in the mean relative change of FEV1 percent predicted at Day 28. With 120 subjects per treatment group there was at least 85% power to declare noninferiority based on relative change from baseline at Day 28 in FEV1 percent predicted using the upper bound of a 2-tailed 95% CI for the difference in means with a noninferiority margin of 4, assuming a common standard deviation of 18% and true difference in means \[TIS-AZLI\] of -3.2%.p-value: 0.000195% CI: [-11.73, -3.86]ANCOVA
Secondary
Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization
Spirometry was performed according to ATS guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the average adjusted means for the actual change in FEV1 percent predicted at Visits 4, 6, and 8 (Weeks 4, 12, and 20) was tested by MMRM analysis using the population of participants with prior inhaled tobramycin use of \>=84 days in the previous 12 months.
Time frame: Baseline and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
Population: Analysis was based on participants with prior inhaled tobramycin use \>= 84 days in the previous 12 months using the ITT analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI (75 mg TID) | Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization | 3.26 actual change in FEV1 percent predicted | Standard Error 0.65 |
| TIS (300 mg BID) | Mean Actual Change From Baseline in FEV1 Percent Predicted Across 3 Treatment Courses in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization | -0.21 actual change in FEV1 percent predicted | Standard Error 0.66 |
Comparison: Null hypothesis: there was no difference between AZLI and TIS treatment groups in the mean actual change of FEV1 percent predicted across 3 treatment courses in the stratum of subjects having \>=84 days of inhaled tobramycin use in the previous 12 months.p-value: 0.0002MMRM analysis
Secondary
Relative Change From Baseline in FEV1 Percent Predicted at Day 28 in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization
Spirometry was performed according to ATS guidelines. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested using an ANCOVA model-based method, using the population of participants with prior inhaled tobramycin use of \>= 84 days in the previous 12 months.
Time frame: Baseline and end of treatment Course 1 (Day 28)
Population: Analysis was based on participants with previous inhaled tobramycin use of \>= 84 days within the previous 12 months using the ITT analysis set. The last observation carried forward (LOCF) method was used to impute missing data for statistical analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI (75 mg TID) | Relative Change From Baseline in FEV1 Percent Predicted at Day 28 in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization | 10.04 percent change in FEV1 percent predicted | Standard Error 1.56 |
| TIS (300 mg BID) | Relative Change From Baseline in FEV1 Percent Predicted at Day 28 in Subjects Who Received Inhaled Tobramycin for >= 84 Days in the 12 Months Prior to Randomization | 0.54 percent change in FEV1 percent predicted | Standard Error 1.57 |
Comparison: Null hypothesis: AZLI was inferior to TIS by more than 4% in terms of the participant means in relative change of FEV1 percent predicted at Day 28 among all participants having \>= 84 days of inhaled tobramycin use in the previous 12 months.p-value: <0.000195% CI: [-13.86, -5.14]ANCOVA
Secondary
Time to First Respiratory Hospitalization
This endpoint was determined through the adjudication of events by a sponsor-independent, blinded review committee. Committee members reviewed all hospitalizations and determined which were related to respiratory events. Details of all hospitalizations, including the dates of admission and discharge, were recorded on the serious adverse event (SAE) eCRF. Time to first respiratory hospitalization was the number of days from baseline (Visit 2) to the date of first respiratory hospitalization or the date of study completion (last visit) /or early withdrawal if censored.
Time frame: Day 0 to Day 168 (end of study)
Population: Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZLI (75 mg TID) | Time to First Respiratory Hospitalization | NA days |
| TIS (300 mg BID) | Time to First Respiratory Hospitalization | NA days |
Comparison: Null hypothesis: there was no difference between AZLI and TIS treatment groups with respect to time to first respiratory hospitalization.p-value: 0.1114Log Rank
Secondary
Time to Need for Intravenous (IV) Antipseudomonal Antibiotics for Respiratory Events
IV antipseudomonal antibiotic use for a respiratory event was determined through the adjudication of events by a sponsor-independent, blinded review committee. Use was compiled from data recorded on the concomitant medications electronic case report form (eCRF) and compared to reported adverse events (AEs) to determine use for a respiratory event. The time to IV antipseudomonal antibiotic use was measured in days from baseline (Visit 2) to the date of first IV antipseudomonal antibiotic use or the date of study completion (last visit)/or early withdrawal if censored.
Time frame: Day 0 to Day 168 (end of study)
Population: Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZLI (75 mg TID) | Time to Need for Intravenous (IV) Antipseudomonal Antibiotics for Respiratory Events | NA days |
| TIS (300 mg BID) | Time to Need for Intravenous (IV) Antipseudomonal Antibiotics for Respiratory Events | 151 days |
Comparison: Null hypothesis: there was no difference between AZLI and TIS treatment groups with respect to time to need for IV antipseudomonal antibiotics for respiratory events.p-value: 0.0025Log Rank
Other Pre-specified
Actual Change From Baseline in CF Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28
The CFQ-R is a validated patient-reported outcome tool measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The endpoint was change in respiratory symptoms (e.g., coughing, congestion, wheezing) from baseline, assessed with the CFQ-R RSS (range of scores \[units\]: 0-100; higher scores indicate fewer symptoms).
Time frame: Baseline and end of treatment Course 1 (Day 28)
Population: Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). LOCF method was used to impute missing data for statistical analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI (75 mg TID) | Actual Change From Baseline in CF Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28 | 8.20 Units on a scale | Standard Error 1.68 |
| TIS (300 mg BID) | Actual Change From Baseline in CF Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score at Day 28 | 2.59 Units on a scale | Standard Error 1.73 |
Comparison: Null hypothesis: there was no difference between AZLI and TIS treatment groups in change from baseline in CFQ-R RSS scores at Day 28.p-value: 0.0048ANCOVA
Other Pre-specified
Mean Actual Change From Baseline in CFQ-R RSS Score Across 3 Treatment Courses
The CFQ-R is a validated patient-reported outcome tool measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. The endpoint was the average actual change in respiratory symptoms (e.g., coughing, congestion, wheezing) from baseline, assessed with the CFQ-R RSS (range of scores \[units\]: 0-100; higher scores indicate fewer symptoms) at the end of each treatment course (Weeks 4, 12, and 20).
Time frame: Baseline and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
Population: Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). The LOCF method was used to impute missing data for statistical purposes.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI (75 mg TID) | Mean Actual Change From Baseline in CFQ-R RSS Score Across 3 Treatment Courses | 6.30 units on a scale | Standard Error 1.49 |
| TIS (300 mg BID) | Mean Actual Change From Baseline in CFQ-R RSS Score Across 3 Treatment Courses | 2.17 units on a scale | Standard Error 1.54 |
Comparison: Null hypothesis: there was no difference between AZLI and TIS treatment groups in the average actual change in respiratory symptoms at the end of each treatment course (Weeks 4, 12, and 20).p-value: 0.0189ANCOVA
Other Pre-specified
Number of Respiratory Events Requiring IV and/or Inhaled Antipseudomonal Antibiotics (Other Than Randomized Treatment)
Inhaled and/or IV antipseudomonal antibiotic use for respiratory event was determined through event adjudication by a sponsor-independent, blinded review committee. Use of IV and/or inhaled antipseudomonal antibiotics was compiled from data recorded on the concomitant medications eCRF and compared to reported AEs to determine use for a respiratory event. The time to IV and/or inhaled antipseudomonal antibiotic use was measured in days from baseline (Visit 2) to the date of first antipseudomonal antibiotic use or the date of study completion (last visit)/or early withdrawal if censored.
Time frame: Day 0 through Day 168 (end of study)
Population: Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZLI (75 mg TID) | Number of Respiratory Events Requiring IV and/or Inhaled Antipseudomonal Antibiotics (Other Than Randomized Treatment) | 84 events |
| TIS (300 mg BID) | Number of Respiratory Events Requiring IV and/or Inhaled Antipseudomonal Antibiotics (Other Than Randomized Treatment) | 121 events |
Comparison: Null hypothesis: there was no difference between AZLI and TIS treatment groups in the total number of respiratory events requiring IV and/or inhaled antipseudomonal antibiotics (other than randomized treatment) from Day 0 to Day 168 (end of study).p-value: 0.004negative binomial regression method
Other Pre-specified
Time to Need for Inhaled and/or IV Antipseudomonal Antibiotics for Respiratory Event (Other Than Randomized Treatment)
Antipseudomonal antibiotic use for respiratory event was determined through event adjudication by a sponsor-independent, blinded review committee. Use of IV and/or inhaled antibiotics for a respiratory event was compiled from data recorded on the concomitant medications eCRF and compared to reported AEs to determine use for a respiratory event. The time to antibiotic use for a respiratory event was measured in days from baseline (Day 0) to the date of first antibiotic use for a respiratory event or the date of study completion (last visit)/or early withdrawal if censored.
Time frame: Day 0 to Day 168 (end of study)
Population: Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZLI (75 mg TID) | Time to Need for Inhaled and/or IV Antipseudomonal Antibiotics for Respiratory Event (Other Than Randomized Treatment) | NA days |
| TIS (300 mg BID) | Time to Need for Inhaled and/or IV Antipseudomonal Antibiotics for Respiratory Event (Other Than Randomized Treatment) | 117 days |
Comparison: Null hypothesis: there was no difference between AZLI and TIS treatment groups with respect to time to need for inhaled and/or IV antipseudomonal antibiotics for respiratory events.p-value: 0.0004Log Rank
Other Pre-specified
Total Number of Respiratory Hospitalizations
Respiratory hospitalizations were determined through the adjudication of events by a sponsor-independent, blinded review committee. Committee members reviewed hospitalizations and determined which were related to respiratory events.
Time frame: Day 0 to Day 168 (end of study)
Population: Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZLI (75 mg TID) | Total Number of Respiratory Hospitalizations | 40 hospitalizations |
| TIS (300 mg BID) | Total Number of Respiratory Hospitalizations | 58 hospitalizations |
Comparison: Null hypothesis: there was no difference between AZLI and TIS treatment groups in the total number of respiratory hospitalizations from Day 0 to Day 168 (end of study).p-value: 0.044negative binomial regression method
Other Pre-specified
Treatment Satisfaction Questionnaire for Medication (TSQM) - Global Satisfaction Results at Week 20
This 14 item questionnaire consists of 3 subscales that gauge participant perceptions of a medication's effectiveness, side effects, and convenience. The measure also contains a global satisfaction scale to evaluate overall participant satisfaction. The global satisfaction score is the endpoint reported here. The range of scores is 0 to 100, with higher scores indicating greater satisfaction.
Time frame: At Week 20
Population: Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZLI (75 mg TID) | Treatment Satisfaction Questionnaire for Medication (TSQM) - Global Satisfaction Results at Week 20 | 75.85 units on a scale | Standard Error 4.58 |
| TIS (300 mg BID) | Treatment Satisfaction Questionnaire for Medication (TSQM) - Global Satisfaction Results at Week 20 | 61.73 units on a scale | Standard Error 4.9 |
Comparison: Null hypothesis: there was no difference between AZLI and TIS treatment groups in the global satisfaction results of the TSQM at Week 20 (Day 140).p-value: 0.0097ANCOVA