Cystic Fibrosis, Pseudomonas Aeruginosa Respiratory Tract Infection/Colonization
Conditions
Brief summary
The primary objective of this study is to evaluate the safety and efficacy of a 14-day course versus a 28-day course of aztreonam for inhalation solution (AZLI) in pediatric participants with new onset Pseudomonas aeruginosa respiratory tract infection or colonization.
Interventions
DRUGAZLI
Administered via the PARI Altera® Nebulizer System. Participants \< 2 years will receive via the SmartMask® Baby, 2 to \< 6 years via the SmartMask Kids® and \> 6 years via the nebulizer mouthpiece.
DRUGPlacebo
Administered via the PARI Altera® Nebulizer System. Participants \< 2 years will receive via the SmartMask® Baby, 2 to \< 6 years via the SmartMask Kids® and \> 6 years via the nebulizer mouthpiece.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
3 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosis of cystic fibrosis (CF) as determined by the 2008 CF Consensus Conference criteria: Sweat chloride level ≥ 60 milliequivalents per liter (mEq/L) by quantitative pilocarpine iontophoresis; or a genotype with 2 identifiable mutations consistent with CF; or an abnormal nasal transepithelial potential difference (NPD), and 1 or more clinical features consistent with CF * Documented new onset of positive respiratory tract culture for PA within 30 days of screening defined as either first lifetime documented PA-positive culture, or PA recovered after at least a 2-year history of PA-negative respiratory cultures (at least 2 cultures per year) * Forced expiratory volume in one second (FEV1) ≥ 80% predicted (for subjects ≥ 6 years of age who can reliably perform spirometry assessments) * Clinically stable with no evidence of acute significant respiratory symptoms that would require administration of intravenous (IV) antipseudomonal antibiotics, oxygen supplementation, or hospitalization Key
Exclusion criteria
* Use of IV or inhaled antipseudomonal antibiotics within 2 years of screening * Use of oral antipseudomonal antibiotics for a respiratory event within 30 days of study entry (screening visit) * History of intolerance to inhaled short acting β2 agonists * History of lung transplantation * Current requirement for daily continuous oxygen supplementation or requirement of more than 2 L/minute at night * Hospitalization for a respiratory event within 30 days prior to screening * Changes in bronchodilator, corticosteroid, dornase alfa, or hypertonic saline medications within 7 days prior to screening. * Significant changes (per investigators discretion) in physiotherapy technique or schedule within 7 days prior to screening * Abnormal renal or hepatic function results at most recent test within the previous 12 months, defined as Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 5 times upper limit of normal (ULN), or Serum creatinine \> 2 times ULN for age * Presence of a condition or abnormality that would compromise the subject's safety or the quality of the study data, in the opinion of the Investigator * Known hypersensitivity to aztreonam, its metabolites, or formulation excipients in AZLI * Respiratory cultures performed within 24 months prior to screening that are positive for ANY Burkholderia spp. or Non-tuberculous mycobacteria (NTM) Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Pseudomonas Aeruginosa (PA)-Negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs 28-Day Treatment Group | 28 days post treatment (Weeks 4 to 6 for the 14 Day treatment group and Weeks 4 to 8 for the 28 Day treatment group) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Primary Eradication to PA Recurrence Over a 108-Week Post-Treatment Follow-up Period | Last dose date of AZLI up to Week 112 | The primary eradication was achieved when all cultures through 28 days post AZLI treatment were PA negative. Recurrence after PA eradication was defined as first positive PA culture result in participant who successfully met primary endpoint and had no PA-positive culture from local lab at Week 4 through Week 6 for AZLI 14 Days group or through Week 8 for AZLI 28 Days group. |
| Percentage of Participants With PA-negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs Historical Pooled Data for PA Eradication at 28 Days Post-Treatment in Participants Treated With Tobramycin Nebulizer Solution (TNS) | 28 days post treatment (Weeks 4 to 6 for the 14 Day treatment group) | — |
| Time to PA Recurrence for a Sub-Group of Participants Matching the Population in the TNS ELITE Study Over a 108-Week Post-Treatment Follow-up Period | Last dose date of AZLI up to Week 112 | In ELITE study (NCT00391976), participants with cystic fibrosis who had early PA infection received TNS. Published criteria for efficacy analysis population in ELITE study included: * Participants must be ≥ 6 months at randomization * No history of positive anti-PA antibody (no anti-PA immunoglobulin G \[IgG\] antibody interpretation at Screening/Baseline) on record * Did not use anti-pseudomonal antibiotics through 28 days after completion of active treatment and within 2 years of Screening * Non-missing PA culture result at 28 days after last dose of AZLI * PA negative through 28 days after completion of active treatment * No important protocol deviation related to compliance with study drug administration * Documented new onset of positive respiratory tract culture for PA within 30 days of Screening defined as either first lifetime documented PA-positive culture, or PA recovered after at least a 2-year history of PA-negative respiratory cultures (at least 2 cultures per year). |
Countries
Austria, Belgium, Denmark, France, Germany, Greece, Israel, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Europe, Israel, and the United States. The first participant was screened on 28 November 2017. The last study visit occurred on 23 September 2021.
Pre-assignment details
149 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| AZLI 14 Days + Placebo 14 Days 75 mg/ml of aztreonam was administered TID for 14 days followed by PTM aztreonam TID for 14 days, both aztreonam and PTM aztreonam were delivered via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI and PTM aztreonam via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece. | 74 |
| AZLI 28 Days 75 mg/ml of aztreonam was administered TID for 28 days via the PARI Altera® Nebulizer System. Participants below 2 years received AZLI via the SmartMask® Baby, 2 to below 6 years via the SmartMask Kids® and above 6 years via the nebulizer mouthpiece. | 75 |
| Total | 149 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Non-Compliance with Study Drug | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 16 | 12 |
| Overall Study | Withdrew Assent | 1 | 0 |
| Overall Study | Withdrew Consent by Parent/Guardian | 5 | 4 |
Baseline characteristics
| Characteristic | AZLI 28 Days | Total | AZLI 14 Days + Placebo 14 Days |
|---|---|---|---|
| Age, Continuous | 6.5 years STANDARD_DEVIATION 4.91 | 6.9 years STANDARD_DEVIATION 5.13 | 7.3 years STANDARD_DEVIATION 5.34 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 9 Participants | 17 Participants | 8 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 65 Participants | 131 Participants | 66 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 73 Participants | 142 Participants | 69 Participants |
| Region of Enrollment Austria | 3 participants | 7 participants | 4 participants |
| Region of Enrollment Belgium | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Denmark | 5 participants | 9 participants | 4 participants |
| Region of Enrollment France | 5 participants | 11 participants | 6 participants |
| Region of Enrollment Germany | 3 participants | 7 participants | 4 participants |
| Region of Enrollment Greece | 1 participants | 4 participants | 3 participants |
| Region of Enrollment Israel | 4 participants | 8 participants | 4 participants |
| Region of Enrollment Italy | 4 participants | 12 participants | 8 participants |
| Region of Enrollment Netherlands | 3 participants | 3 participants | 0 participants |
| Region of Enrollment Spain | 14 participants | 20 participants | 6 participants |
| Region of Enrollment United Kingdom | 17 participants | 33 participants | 16 participants |
| Region of Enrollment United States | 16 participants | 32 participants | 16 participants |
| Sex: Female, Male Female | 33 Participants | 68 Participants | 35 Participants |
| Sex: Female, Male Male | 42 Participants | 81 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 74 | 0 / 75 |
| other Total, other adverse events | 28 / 74 | 22 / 75 |
| serious Total, serious adverse events | 5 / 74 | 4 / 75 |
Outcome results
Primary
Percentage of Participants With Pseudomonas Aeruginosa (PA)-Negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs 28-Day Treatment Group
Time frame: 28 days post treatment (Weeks 4 to 6 for the 14 Day treatment group and Weeks 4 to 8 for the 28 Day treatment group)
Population: Evaluable Analysis Set included participants who completed study drug with at least 75% compliance, did not use any anti-PA antibiotics while on study treatment with AZLI.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZLI 14 Days + Placebo 14 Days | Percentage of Participants With Pseudomonas Aeruginosa (PA)-Negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs 28-Day Treatment Group | 55.9 percentage of participants |
| AZLI 28 Days | Percentage of Participants With Pseudomonas Aeruginosa (PA)-Negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs 28-Day Treatment Group | 63.4 percentage of participants |
95% CI: [-24.6, 8.6]
Secondary
Percentage of Participants With PA-negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs Historical Pooled Data for PA Eradication at 28 Days Post-Treatment in Participants Treated With Tobramycin Nebulizer Solution (TNS)
Time frame: 28 days post treatment (Weeks 4 to 6 for the 14 Day treatment group)
Population: AZLI 14 Day treatment group: Evaluable Analysis Set. No data was collected for the AZLI 28 Day treatment group for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZLI 14 Days + Placebo 14 Days | Percentage of Participants With PA-negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs Historical Pooled Data for PA Eradication at 28 Days Post-Treatment in Participants Treated With Tobramycin Nebulizer Solution (TNS) | 55.9 percentage of participants |
Secondary
Time From Primary Eradication to PA Recurrence Over a 108-Week Post-Treatment Follow-up Period
The primary eradication was achieved when all cultures through 28 days post AZLI treatment were PA negative. Recurrence after PA eradication was defined as first positive PA culture result in participant who successfully met primary endpoint and had no PA-positive culture from local lab at Week 4 through Week 6 for AZLI 14 Days group or through Week 8 for AZLI 28 Days group.
Time frame: Last dose date of AZLI up to Week 112
Population: Participants in the Evaluable Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZLI 14 Days + Placebo 14 Days | Time From Primary Eradication to PA Recurrence Over a 108-Week Post-Treatment Follow-up Period | 19.3 months |
| AZLI 28 Days | Time From Primary Eradication to PA Recurrence Over a 108-Week Post-Treatment Follow-up Period | NA months |
Secondary
Time to PA Recurrence for a Sub-Group of Participants Matching the Population in the TNS ELITE Study Over a 108-Week Post-Treatment Follow-up Period
In ELITE study (NCT00391976), participants with cystic fibrosis who had early PA infection received TNS. Published criteria for efficacy analysis population in ELITE study included: * Participants must be ≥ 6 months at randomization * No history of positive anti-PA antibody (no anti-PA immunoglobulin G \[IgG\] antibody interpretation at Screening/Baseline) on record * Did not use anti-pseudomonal antibiotics through 28 days after completion of active treatment and within 2 years of Screening * Non-missing PA culture result at 28 days after last dose of AZLI * PA negative through 28 days after completion of active treatment * No important protocol deviation related to compliance with study drug administration * Documented new onset of positive respiratory tract culture for PA within 30 days of Screening defined as either first lifetime documented PA-positive culture, or PA recovered after at least a 2-year history of PA-negative respiratory cultures (at least 2 cultures per year).
Time frame: Last dose date of AZLI up to Week 112
Population: ELITE Study Matching Analysis Set included participants from Evaluable Analysis Set (who did not meet evaluability criteria due to \< 75% compliance, use of anti-PA antibiotics while on AZLI treatment, missing PA culture result during initial eradication phase) who also satisfied the published criteria for efficacy analysis population in ELITE study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZLI 14 Days + Placebo 14 Days | Time to PA Recurrence for a Sub-Group of Participants Matching the Population in the TNS ELITE Study Over a 108-Week Post-Treatment Follow-up Period | 19.3 months |
| AZLI 28 Days | Time to PA Recurrence for a Sub-Group of Participants Matching the Population in the TNS ELITE Study Over a 108-Week Post-Treatment Follow-up Period | 15.2 months |