Cystic Fibrosis
Conditions
Brief summary
The primary objective of this study is to evaluate the safety and efficacy of a CAT regimen with aztreonam for inhalation solution (AZLI) and tobramycin inhalation solution (TIS) in adult and pediatric subjects with cystic fibrosis (CF) and pulmonary Pseudomonas aeruginosa (PA) infection. Participants will be enrolled in a 28 day TIS run-in phase, and will be eligible for randomization in the comparative phase if they have not received non-study oral antibiotics for a respiratory event, or IV or inhaled antibiotics for any indication between Visits 2 and 3, have not developed a condition requiring hospitalization or other change in clinical status which, in the opinion of the investigator would preclude their ability to continue in the study, and have demonstrated at least 50% TIS compliance. Participants enrolled in the comparative phase will be randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI or placebo for 28 days followed by TIS for 28 days.
Interventions
DRUGAZLI
Aztreonam for Inhalation Solution (AZLI) 75 mg 3 times daily combined with diluent administered using an eFlow nebulizer
DRUGPlacebo to match AZLI
Placebo to match AZLI 3 times daily combined with diluent administered using an eFlow nebulizer
Tobramycin inhalation solution (TIS) 300 mg 2 times daily using a PARI® LC Plus nebulizer and DeVilbiss Pulmo-Aide® air compressor
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of CF * Presence of PA in 2 lower respiratory tract cultures in the 12 months prior to screening * Forced expiratory volume (FEV)1 ≥ 25 and ≤ 75% predicted * History of 1 hospitalization or 1 course of IV antibiotics for an acute respiratory exacerbation in the 12 months prior to screening
Exclusion criteria
* Concurrent use of oral, IV or inhaled antibiotics at enrollment * Concurrent hospitalization at enrollment * History of local or systemic hypersensitivity to monobactams or aminoglycoside antibiotics or history of aminoglycoside antibiotic associated toxicity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Protocol-defined Exacerbations (PDE) From Baseline Through Week 24 | Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days) | PDEs were characterized by a change or worsening from baseline of 1 or more documented signs or symptoms (decreased exercise tolerance, increased cough, increased sputum or chest congestion, decreased appetite, or other signs or symptoms) associated with the use of non-study IV or inhaled antibiotics and be verified by a blinded independent adjudication committee. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Actual Change From Baseline in FEV1 % Predicted Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20) | Comparative Phase: Baseline and Weeks 4, 12 and 20 | FEV1 % predicted is defined as FEV1 of the patient divided by the average FEV1 in the population for any person of similar age, sex and body composition. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction. |
| Percentage of Participants Who Used Non-study IV or Inhaled Antibiotics for PDEs | Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days) | — |
| Time to First Protocol-defined Pulmonary Exacerbation | Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days) | The time to first protocol-defined pulmonary exacerbation was calculated using the Kaplan-Meier method. |
| Rate of Hospitalizations for a Respiratory Event | Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days) | The rate of hospitalizations for a respiratory event per participant year was calculated using negative binomial regression analysis. |
| Average Change From Baseline in the CFQ-R Respiratory Symptom Scale (RSS) Score Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20) | Comparative Phase: Baseline and Weeks 4, 12 and 20 | Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS). The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States. The first participant was screened on 13 December 2012. The last study visit occurred on 15 January 2015.
Pre-assignment details
Following enrollment, participants received tobramycin inhalation solution (TIS) in the TIS Run-In Phase, and if still eligible were randomized 1 to 1 to receive aztreonam for inhalation solution (AZLI) or placebo to match AZLI alternating with TIS in the Comparative Phase.
Participants by arm
| Arm | Count |
|---|---|
| AZLI Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI (75 mg 3 times daily) for 28 days followed by TIS (300 mg 2 times daily) for 28 days. | 43 |
| Placebo Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS (300 mg 2 times daily) for 28 days. | 47 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Comparative Phase | Adverse event, serious fatal | 0 | 1 | 0 |
| Comparative Phase | Investigator's discretion | 0 | 0 | 1 |
| Comparative Phase | Noncompliance with study drug | 0 | 1 | 0 |
| Comparative Phase | Pregnancy | 0 | 0 | 1 |
| Comparative Phase | Protocol-specified criteria for withdraw | 0 | 1 | 1 |
| Comparative Phase | Withdrew consent | 0 | 3 | 7 |
| Run-in Phase | Adverse Event | 3 | 0 | 0 |
| Run-in Phase | Noncompliance with study drug | 1 | 0 | 0 |
| Run-in Phase | Protocol-specified criteria for withdraw | 9 | 0 | 0 |
| Run-in Phase | Withdrew consent | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | AZLI | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 28.8 years STANDARD_DEVIATION 12.1 | 28.0 years STANDARD_DEVIATION 10.88 | 28.4 years STANDARD_DEVIATION 11.42 |
| Age, Customized 13 - 17 years | 5 participants | 6 participants | 11 participants |
| Age, Customized ≥ 18 years | 35 participants | 40 participants | 75 participants |
| Age, Customized 6 - 12 years | 3 participants | 1 participants | 4 participants |
| CFQ-R Respiratory Score at Day 1 | 59.72 units on a scale STANDARD_DEVIATION 18.408 | 64.24 units on a scale STANDARD_DEVIATION 15.044 | 62.11 units on a scale STANDARD_DEVIATION 16.773 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 43 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| FEV1 % predicted at Day 1 | 49.95 percentage of FEV1 % predicted STANDARD_DEVIATION 17.5 | 50.25 percentage of FEV1 % predicted STANDARD_DEVIATION 15.131 | 50.11 percentage of FEV1 % predicted STANDARD_DEVIATION 16.213 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Other | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized White | 41 participants | 45 participants | 86 participants |
| Region of Enrollment United States | 43 participants | 47 participants | 90 participants |
| Sex: Female, Male Female | 24 Participants | 28 Participants | 52 Participants |
| Sex: Female, Male Male | 19 Participants | 19 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 107 | 38 / 42 | 44 / 46 |
| serious Total, serious adverse events | 4 / 107 | 21 / 42 | 24 / 46 |
Outcome results
Primary
Rate of Protocol-defined Exacerbations (PDE) From Baseline Through Week 24
PDEs were characterized by a change or worsening from baseline of 1 or more documented signs or symptoms (decreased exercise tolerance, increased cough, increased sputum or chest congestion, decreased appetite, or other signs or symptoms) associated with the use of non-study IV or inhaled antibiotics and be verified by a blinded independent adjudication committee.
Time frame: Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
Population: Intent-to-Treat (ITT) Analysis Set: all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZLI | Rate of Protocol-defined Exacerbations (PDE) From Baseline Through Week 24 | 1.309 PDEs per participant year |
| Placebo | Rate of Protocol-defined Exacerbations (PDE) From Baseline Through Week 24 | 1.762 PDEs per participant year |
Comparison: Ratio between ratesp-value: 0.2595% CI: [0.446, 1.238]Negative binomial regression
Secondary
Average Actual Change From Baseline in FEV1 % Predicted Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20)
FEV1 % predicted is defined as FEV1 of the patient divided by the average FEV1 in the population for any person of similar age, sex and body composition. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction.
Time frame: Comparative Phase: Baseline and Weeks 4, 12 and 20
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZLI | Average Actual Change From Baseline in FEV1 % Predicted Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20) | 1.37 percentage of FEV1 % predicted | Standard Error 0.674 |
| Placebo | Average Actual Change From Baseline in FEV1 % Predicted Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20) | 0.04 percentage of FEV1 % predicted | Standard Error 0.658 |
Comparison: Difference in change in FEV1 % predictedp-value: 0.1695% CI: [-0.55, 3.2]Mixed Models Analysis
Secondary
Average Change From Baseline in the CFQ-R Respiratory Symptom Scale (RSS) Score Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20)
Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS). The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction.
Time frame: Comparative Phase: Baseline and Weeks 4, 12 and 20
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZLI | Average Change From Baseline in the CFQ-R Respiratory Symptom Scale (RSS) Score Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20) | 1.00 units on a scale | Standard Deviation 1.736 |
| Placebo | Average Change From Baseline in the CFQ-R Respiratory Symptom Scale (RSS) Score Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20) | -2.06 units on a scale | Standard Deviation 1.629 |
Comparison: Difference in change in CFQ-R RSSp-value: 0.2195% CI: [-1.71, 7.82]Mixed Models Analysis
Secondary
Percentage of Participants Who Used Non-study IV or Inhaled Antibiotics for PDEs
Time frame: Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZLI | Percentage of Participants Who Used Non-study IV or Inhaled Antibiotics for PDEs | 48.8 percentage of participants |
| Placebo | Percentage of Participants Who Used Non-study IV or Inhaled Antibiotics for PDEs | 55.3 percentage of participants |
Comparison: Comparison of percentagesp-value: 0.67Fisher Exact
Secondary
Rate of Hospitalizations for a Respiratory Event
The rate of hospitalizations for a respiratory event per participant year was calculated using negative binomial regression analysis.
Time frame: Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
Population: ITT Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZLI | Rate of Hospitalizations for a Respiratory Event | 1.043 hospitalizations per participant year |
| Placebo | Rate of Hospitalizations for a Respiratory Event | 1.624 hospitalizations per participant year |
Comparison: Comparison of hospitalization ratep-value: 0.1495% CI: [0.355, 1.164]Negative binomial regression
Secondary
Time to First Protocol-defined Pulmonary Exacerbation
The time to first protocol-defined pulmonary exacerbation was calculated using the Kaplan-Meier method.
Time frame: Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZLI | Time to First Protocol-defined Pulmonary Exacerbation | 175 days |
| Placebo | Time to First Protocol-defined Pulmonary Exacerbation | 140.0 days |
Comparison: Comparison of time to exacerbationp-value: 0.7195% CI: [0.5, 1.59]Log Rank